Síndrome nefrótico secundario a preeclampsia: presentación, manejo y evolución clínica observados en 5 años de experiencia / Nephrotic syndrome due to preeclampsia: Presentation, management and clinical evolution observed in 5 years experience

Introducción: El síndrome nefrótico (SN) es una entidad rara durante el embarazo. En esta etapa, la preeclampsia (PE) severa es la principal causa. Nuestro objetivo fue describir la presentación clínica, las características analíticas, el manejo médico y la evolución de mujeres con SN por PE. Materiales y métodos: Estudio descriptivo, retrospectivo, realizado entre el 1 de enero de 2017 y el 1 de enero de 2022 (5años). Incluyó mujeres con embarazo ≥20semanas de edad gestacional (EG), internadas por trastorno hipertensivo del embarazo (THE), sin evidencia de daño renal previo a la gestación. Resultados: Entre 652 THE se identificaron 452 PE y 21 SN. La edad materna fue de 25±5,7 años, y la EG al diagnóstico, de 33,1±5,1 semanas. Todas presentaron edema facial y periféricos: 5 derrame pleural, 3 derrame pericárdico y 2 anasarca. La P24 fue de 6,17±2,34g (3,10-10,8), la albúmina sérica de 2,5±0,27g/dl (2,10-2,90) y el colesterol sérico de 281,4±21,7mg/dl (251-316). Hubo 13 que desarrollaron complicaciones maternas: daño renal agudo, edema pulmonar, miocardiopatía dilatada, eclampsia y síndrome HELLP. Todas permanecieron hipertensas en el posparto, requiriendo combinación de dos a tres fármacos antihipertensivos. En el posparto todas recibieron estatinas e inhibidores de la enzima convertidora de angiotensina (IECA) para el manejo de la proteinuria; ninguna desarrolló hiperkalemia o elevaciones de creatinina. La estancia hospitalaria fue de 10,4±3,7 días. Todas revirtieron los parámetros proteinúricos de rango nefrótico antes del alta. No se registraron muertes. Conclusión: La presentación incluyó desde edemas periféricos hasta compromiso seroso. La severidad de la proteinuria fue variable. El uso de IECA no precipitó hiperkalemia ni fallo renal. Las complicaciones maternas fueron frecuentes, pero no se observaron óbitos. (AU)

Introduction: Nephrotic syndrome (NS) is rare during pregnancy. The main cause is severe pre-eclampsia (PR). Our aim was to describe the clinical presentation, analytical features, medical management, and progress of women with NS due to PE. Materials and methods: A descriptive, retrospective study, conducted from 01/01/2017 to 01/01/2022 (5years). Women with a gestational age (GA) ≥20weeks were included in the study, hospitalised due to hypertensive disorders in pregnancy (HDP), with no evidence of kidney damage prior to gestation. Results: Of the 652 HDP, 452 PE and 21 NS were identified. Maternal age was 25±5.7 years, GA at diagnosis was 33.1±5.1 weeks. All the women had facial and peripheral oedema: 5 pleural effusion, 3 pericardial effusion, and 2 anasarca. Their p24 was 6.17±2.34grams (3.10-10.8), serum albumin 2.5±0.27g/dL (2.10-2.90), and serum cholesterol 281.4±21.7mg/dL (251-316). Thirteen developed maternal complications: acute kidney damage, pulmonary oedema, dilated cardiomyopathy, eclampsia, and HELLP syndrome. They all remained hypertensive postpartum, and required a combination of two to three antihypertensive drugs. They all received statins postpartum, and angiotensin converting enzyme (ACE) inhibitors to manage proteinuria. None developed hyperkalaemia or creatinine elevation. Hospital stay was 10.4±3.7days. All nephrotic range proteinuria parameters reversed prior to discharge. No deaths were recorded. Conclusion: Presentation ranged from peripheral oedema to serous involvement. Severity of proteinuria varied. Use of ACE inhibitors did not precipitate hyperkalaemia or kidney failure. Maternal complications were frequent, but no deaths were recorded. (AU)

[Nephrotic syndrome due to preeclampsia: Presentation, management and clinical evolution observed in 5 years experience]. / Síndrome nefrótico secundario a preeclampsia: presentación, manejo y evolución clínica observados en 5 años de experiencia.

INTRODUCTION: Nephrotic syndrome (NS) is rare during pregnancy. The main cause is severe pre-eclampsia (PR). Our aim was to describe the clinical presentation, analytical features, medical management, and progress of women with NS due to PE. MATERIALS AND METHODS: A descriptive, retrospective study, conducted from 01/01/2017 to 01/01/2022 (5years). Women with a gestational age (GA) ≥20weeks were included in the study, hospitalised due to hypertensive disorders in pregnancy (HDP), with no evidence of kidney damage prior to gestation. RESULTS: Of the 652 HDP, 452 PE and 21 NS were identified. Maternal age was 25±5.7 years, GA at diagnosis was 33.1±5.1 weeks. All the women had facial and peripheral oedema: 5 pleural effusion, 3 pericardial effusion, and 2 anasarca. Their p24 was 6.17±2.34grams (3.10-10.8), serum albumin 2.5±0.27g/dL (2.10-2.90), and serum cholesterol 281.4±21.7mg/dL (251-316). Thirteen developed maternal complications: acute kidney damage, pulmonary oedema, dilated cardiomyopathy, eclampsia, and HELLP syndrome. They all remained hypertensive postpartum, and required a combination of two to three antihypertensive drugs. They all received statins postpartum, and angiotensin converting enzyme (ACE) inhibitors to manage proteinuria. None developed hyperkalaemia or creatinine elevation. Hospital stay was 10.4±3.7days. All nephrotic range proteinuria parameters reversed prior to discharge. No deaths were recorded. CONCLUSION: Presentation ranged from peripheral oedema to serous involvement. Severity of proteinuria varied. Use of ACE inhibitors did not precipitate hyperkalaemia or kidney failure. Maternal complications were frequent, but no deaths were recorded.

Combining conventional tree-ring measurements with wood anatomy and strontium isotope analyses enables dendroprovenancing at the local scale.

Dendroprovenancing provides critical information regarding the origin of wood, allowing further insights into economic exploitation strategies and source regions of timber products. Traditionally, dendroprovenancing relies on pattern-matching of tree rings, but its spatial resolution is limited by the geographical coverage of species-specific chronologies available for crossdating and, in the case of short-distance trades, by scarce environmental variability. Here, we present an approach to provenance timber with high spatial resolution from forested areas that have been exploited intensively throughout history, with the aim to understand the sustainability of the various woodland management practices used to supply timber products. To this end, we combined tree-ring width (TRW), wood anatomical and geochemical analyses in addition to multivariate statistical validation procedures to trace the origin of living oak trees (Quercus robur) sampled in four stands located within a 30-km radius around the city of Limoges (Haute-Vienne, France). We demonstrate that TRW and wood anatomical variables (and in particular cell density) robustly discriminate the eastern from the western site, while failing to trace the origin of trees from the northern and southern sites. Here, strontium isotopic ratios (87Sr/86Sr) and Ca concentrations identify clusters of trees which could not be identified with TRW or wood anatomy. Ultimately, our study demonstrates that the coupling of wood anatomy with geochemical signatures allows to correctly pinpoint the origin of trees. Given the small geographic scale of our study and the limited differences in elevation and climate between study sites, our results are particularly promising for future dendroprovenancing studies. We thus conclude that the combination of multiple approaches will not only increase the accuracy of dendroprovenancing studies at local scales, but could also be implemented at much larger scales to identify trends in historic timber supply throughout Europe.

Differential effects on gene transcription and hematopoietic differentiation correlate with GATA2 mutant disease phenotypes.

Heterozygous GATA2 mutations underlie an array of complex hematopoietic and lymphatic diseases. Analysis of the literature reporting three recurrent GATA2 germline (g) mutations (gT354M, gR396Q and gR398W) revealed different phenotype tendencies. Although all three mutants differentially predispose to myeloid malignancies, there was no difference in leukemia-free survival for GATA2 patients. Despite intense interest, the molecular pathogenesis of GATA2 mutation is poorly understood. We functionally characterized a GATA2 mutant allelic series representing major disease phenotypes caused by germline and somatic (s) mutations in zinc finger 2 (ZF2). All GATA2 mutants, except for sL359V, displayed reduced DNA-binding affinity and transactivation compared with wild type (WT), which could be attributed to mutations of arginines critical for DNA binding or amino acids required for ZF2 domain structural integrity. Two GATA2 mutants (gT354M and gC373R) bound the key hematopoietic differentiation factor PU.1 more strongly than WT potentially perturbing differentiation via sequestration of PU.1. Unlike WT, all mutants failed to suppress colony formation and some mutants skewed cell fate to granulocytes, consistent with the monocytopenia phenotype seen in GATA2-related immunodeficiency disorders. These findings implicate perturbations of GATA2 function shaping the course of development of myeloid malignancy subtypes and strengthen complete or nearly complete haploinsufficiency for predisposition to lymphedema.

A four-gene LincRNA expression signature predicts risk in multiple cohorts of acute myeloid leukemia patients.

Prognostic gene expression signatures have been proposed as clinical tools to clarify therapeutic options in acute myeloid leukemia (AML). However, these signatures rely on measuring large numbers of genes and often perform poorly when applied to independent cohorts or those with older patients. Long intergenic non-coding RNAs (lincRNAs) are emerging as important regulators of cell identity and oncogenesis, but knowledge of their utility as prognostic markers in AML is limited. Here we analyze transcriptomic data from multiple cohorts of clinically annotated AML patients and report that (i) microarrays designed for coding gene expression can be repurposed to yield robust lincRNA expression data, (ii) some lincRNA genes are located in close proximity to hematopoietic coding genes and show strong expression correlations in AML, (iii) lincRNA gene expression patterns distinguish cytogenetic and molecular subtypes of AML, (iv) lincRNA signatures composed of three or four genes are independent predictors of clinical outcome and further dichotomize survival in European Leukemia Net (ELN) risk groups and (v) an analytical tool based on logistic regression analysis of quantitative PCR measurement of four lincRNA genes (LINC4) can be used to determine risk in AML.

A novel, somatic, transforming mutation in the extracellular domain of Epidermal Growth Factor Receptor identified in myeloproliferative neoplasm.

We describe a novel ERBB1/EGFR somatic mutation (p. C329R; c.985 T > C) identified in a patient with JAK2V617F Polycythaemia Vera (PV). This substitution affects a conserved cysteine residue in EGFR domain 2 and leads to the formation of a ligand-independent covalent receptor dimer, associated with increased transforming potential. Aberrant signalling from the EGFRC329R receptor is cell type-dependent and in the TF1.8 erythroid cell line expression of this mutant suppresses EPO-induced differentiation. Clonal analysis shows that the dominant JAK2V617F-positive clone in this PV patient harbors EGFRC329R, thus this mutation may contribute to clonal expansion. Somatic mutations affecting other ERBB and related receptor tyrosine kinases are observed in myeloproliferative neoplasms (MPN), and we show elevated EGFR levels in MPN samples, consistent with previous reports. Thus activation of this group of receptors, via multiple mechanisms, may contribute to clonal growth and survival of the JAK2V617F disease clone in MPN.

Hypoxia inducible factor (HIF)-2α accelerates disease progression in mouse models of leukemia and lymphoma but is not a poor prognosis factor in human AML.

Hypoxia-inducible factor (HIF)-1α accumulation promotes hematopoietic stem cells' quiescence and is necessary to maintain their self-renewal. However, the role of HIF-2α in hematopoietic cells is less clear. We investigated the role of HIF-2α in leukemia and lymphoma cells. HIF-2α expression was high in subsets of human and mouse leukemia and lymphoma cells, whereas it was low in normal bone marrow leukocytes. To investigate the role of HIF-2α, we transduced human HIF-2α cDNA in mouse syngeneic models of myeloid preleukemia and a transgenic model of B lymphoma. Ectopic expression of HIF-2α accelerated leukemia cell proliferation in vitro. Mice transplanted with cells transduced with HIF-2α died significantly faster of leukemia or B lymphoma than control mice transplanted with empty vector-transduced cells. Conversely, HIF-2α knockdown in human myeloid leukemia HL60 cells decreased proliferation in vitro and significantly prolonged animal survival following transplantation. In human acute myeloid leukemia (AML), HIF-2α mRNA was significantly elevated in several subsets such as the t(15;17), inv(16), complex karyotype and favorable cytogenetic groups. However, patients with high HIF-2α expression had a trend to higher disease-free survival in univariate analysis. The different effects of HIF-2α overexpression in mouse models of leukemia and human AML illustrates the complexity of this mutliclonal disease.

Dual epigenetic targeting with panobinostat and azacitidine in acute myeloid leukemia and high-risk myelodysplastic syndrome.

Therapeutic options are limited for elderly patients with acute myeloid leukemia (AML). A phase Ib/II study was undertaken to evaluate the maximum-tolerated dose (MTD) and preliminary efficacy of the pan-histone deacetylase inhibitor panobinostat (LBH589) in combination with azacitidine in patients with AML or high-risk myelodysplastic syndrome (MDS) naïve to intensive chemotherapy. Thirty-nine patients (AML=29, MDS=10) received azacitidine 75 mg/m(2) subcutaneously (days 1-5) and oral panobinostat (starting on day 5, thrice weekly for seven doses) in 28-day cycles until toxicity or disease progression. Dose-limiting toxicities during the phase Ib stage were observed in 0/4 patients receiving 10 mg panobinostat, in 1/7 patients (fatigue) receiving 20 mg, in 1/6 patients (fatigue) receiving 30 mg and in 4/5 patients (fatigue, syncope, hyponatremia and somnolence) receiving 40 mg. In phase II, an additional 17 patients received panobinostat at a MTD of 30 mg. The overall response rate (ORR=CR+CRi+PR) in patients with AML was 31% (9/29) and that in patients with MDS was 50% (5/10). After a median follow-up of 13 months, the median overall survival was 8 and 16 months in patients with AML and MDS, respectively. Increased histone H3 and H4 acetylation was a useful early biomarker of clinical response. Combining panobinostat with azacitidine was tolerable and clinically active in high-risk MDS/AML patients, warranting further exploration.

Contrasting effects of diclofenac and ibuprofen on active imatinib uptake into leukaemic cells.

BACKGROUND: The human organic cation transporter-1 (OCT-1) is the primary active protein for imatinib uptake into target BCR-ABL-positive cells. Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently used by chronic myeloid leukaemia (CML) patients on imatinib to manage musculoskeletal complaints. METHODS: Here we investigated the impact of NSAIDs on functional activity of the OCT-1 (OCT-1 activity; OA) in CML cells. RESULTS: Although ten of twelve NSAIDs tested had no significant impact on OA (P>0.05), we observed increased OA (27% increase in K562; 22% increase in KU812 cells, P<0.05) and reduced IC50(imatinib) when treated with diclofenac. Co-incubation with imatinib and diclofenac resulted in a significantly lower viable cell number compared with imatinib alone. In contrast, ibuprofen led to a significant decrease in OA, an increase in IC50(imatinib) and thus reduced the cytotoxicity of imatinib. In primary CML samples, diclofenac significantly increased OA, particularly in patients with low OA (<4 ng per 200 000 cells), and significantly decreased IC50(imatinib). Ibuprofen induced significant decreases in OA in CML samples and healthy donors. CONCLUSION: On the basis of the expected impact of these two drugs on OA, ibuprofen should be avoided in combination with imatinib. Further studies are warranted regarding the potential benefit of diclofenac to improve OA in a clinical setting.

Blocking cytokine signaling along with intense Bcr-Abl kinase inhibition induces apoptosis in primary CML progenitors.

In chronic myeloid leukemia (CML) cell lines, brief exposure to pharmacologically relevant dasatinib concentrations results in apoptosis. In this study, we assess the impact of intensity and duration of Bcr-Abl kinase inhibition on primary CD34(+) progenitors of chronic phase CML patients. As CML cells exposed to dasatinib in vivo are in a cytokine-rich environment, we also assessed the effect of cytokines (six growth factors cocktail or granulocyte-macrophage colony-stimulating factor (CSF) or granulocyte-CSF) in combination with dasatinib. In the presence of cytokines, short-term intense Bcr-Abl kinase inhibition (>or=90% p-Crkl inhibition) with 100 nM dasatinib did not reduce CD34(+) colony-forming cells (CFCs). In contrast, without cytokines, short-term exposure to dasatinib reduced CML-CD34(+) CFCs by 70-80%. When cytokines were added immediately after short-term exposure to dasatinib, CML-CD34(+) cells remained viable, suggesting that oncogene dependence of these cells can be overcome by concomitant or subsequent exposure to cytokines. Additional inhibition of Janus tyrosine kinase (Jak) activity re-established the sensitivity of CML progenitors to intense Bcr-Abl kinase inhibition despite the presence of cytokines. These findings support the contention that therapeutic strategies combining intense Bcr-Abl kinase inhibition and blockade of cytokine signaling pathways can be effective for eradication of CML progenitors.

Repression of Gadd45alpha by activated FLT3 and GM-CSF receptor mutants contributes to growth, survival and blocked differentiation.

The tumor suppressor Gadd45alpha was earlier shown to be a repressed target of sustained receptor-mediated ERK1/2 signaling. We have identified Gadd45alpha as a downregulated gene in response to constitutive signaling from two FLT3 mutants (FLT3-ITD and FLT3-TKD) commonly found in AML, and a leukemogenic GM-CSF receptor trans-membrane mutant (GMR-V449E). GADD45A mRNA downregulation is also associated with FLT3-ITD(+) AML. Sustained ERK1/2 signaling contributes significantly to receptor-mediated downregulation of Gadd45alpha mRNA in FDB1 cells expressing activated receptor mutants, and in the FLT3-ITD(+) cell line MV4;11. Knockdown of Gadd45alpha with shRNA led to increased growth and survival of FDB1 cells and enforced expression of Gadd45alpha in FDB1 cells expressing FLT3-ITD or GMR-V449E resulted in reduced growth and viability. Gadd45alpha overexpression in FLT3-ITD(+) AML cell lines also resulted in reduced growth associated with increased apoptosis and G(1)/S cell cycle arrest. Overexpression of Gadd45alpha in FDB1 cells expressing GMR-V449E was sufficient to induce changes associated with myeloid differentiation suggesting Gadd45alpha downregulation contributes to the maintenance of receptor-induced myeloid differentiation block. Thus, we show that ERK1/2-mediated downregulation of Gadd45alpha by sustained receptor signaling contributes to growth, survival and arrested differentiation in AML.

Major abdominal surgery and postoperative pain control: are protocols enough?

Suitable postoperative pain control (POPC) requires both the application of appropriate pain therapy and the continuous supervision of its therapeutic effects. In our hospital, POPC was, until recently, limited to the first 48 postoperative hours. The purpose of this retrospective study was to assess, the evolution of POPC at the end of the first postoperative 48 hours among major abdominal surgery patients using the Acute Pain Service (APS) database. Further we sought to establish the indications to extend POPC to the entire postoperative period. Regardless of the type of protocol applied after surgery, 79.6% of cases showed pain control was still needed after the 48(th) hour. In about half of the cases, POPC was perpetuated with only the drug category or by dosage modifications, while in roughly one third of the cases we adopted both drug and administration route changes. These changes were made by the APS after a thorough evaluation of the patients' conditions and needs in terms of analgesia. Interestingly, in approximately 5% of cases the surgeon decided to interrupt pain therapy. When applying evidence-based guideline protocols, organizational issues are important as well as a better definition of the APS role in POPC, at least from the timing point of view.