Primary Microgliopathy Presenting as Degenerative Dementias: A Case Series of Novel Gene Mutations from India.

Introduction: Microglia exert a crucial role in homeostasis of white matter integrity, and several studies highlight the role of microglial dysfunctions in neurodegeneration. Primary microgliopathy is a disorder where the pathogenic abnormality of the microglia causes white matter disorder and leads to a neuropsychiatric disease. Triggering receptor expressed on myeloid cells (TREM2), TYRO protein tyrosine kinase binding protein (TYROBP) and colony-stimulating factor 1 receptor (CSF1R) are genes implicated in primary microgliopathy. The clinical manifestations of primary microgliopathy are myriad ranging from neuropsychiatric syndrome, motor disability, gait dysfunction, ataxia, pure dementia, frontotemporal dementia (FTD), Alzheimer's dementia (AD), and so on. It becomes imperative to establish the diagnosis of microgliopathy masquerading as degenerative dementia, especially with promising therapies on horizon for the same. We aimed to describe a case series of subjects with dementia harbouring novel genes of primary microgliopathy, along with their clinical, neuropsychological, cognitive profile and radiological patterns. Methods: The prospective study was conducted in a university referral hospital in South India, as a part of an ongoing clinico-genetic research on dementia subjects, and was approved by the Institutional Ethics Committee. All patients underwent detailed assessment including sociodemographic profile, clinical and cognitive assessment, pedigree analysis and comprehensive neurological examination. Subjects consenting for blood sampling underwent genetic testing by whole-exome sequencing (WES). Results: A total of 100 patients with dementia underwent genetic analysis using WES and three pathogenic variants, one each of TREM2, TYROBP, and CSF1R and two variants of uncertain significance in CSF1R were identified as cause of primary microgliopathy. TREM2 and TYROBP presented as frontotemporal syndrome whereas CSF1R presented as frontotemporal syndrome and as AD. Conclusion: WES has widened the spectrum of underlying neuropathology of degenerative dementias, and diagnosing primary microglial dysfunction with emerging therapeutic options is of paramount importance. The cases of primary microgliopathy due to novel mutations in TREM2, TYROBP, and CSF1R with the phenotype of degenerative dementia are being first time reported from Indian cohort. Our study enriches the spectrum of genetic variants implicated in degenerative dementia and provides the basis for exploring complex molecular mechanisms like microglial dysfunction, as underlying cause for neurodegeneration.

Clinical significance of frusemide stress test in predicting the severity of acute kidney injury / Significância clínica do teste de estresse com furosemida na predição da gravidade da lesão renal aguda

Abstract Introduction: The outcomes of Acute Kidney Injury (AKI) remain dismal even today, owing in part due to the lack of an ideal biomarker for detecting renal damage early enough. We conducted this pilot study to determine the clinical significance of Frusemide Stress Test (FST) to predict the severity of AKI. Methods: A total of 80 patients with AKI-KDIGO (Kidney Disease: Improving Global Outcomes) stage 1 or stage 2 underwent FST by administering a bolus dose of frusemide (1mg/kg for frusemide naïve and 1.5mg/kg for prior frusemide exposure in the past week), and urine output was then measured for the next two hours with volume replacement as desirable. The progression to AKI-KDIGO stage 3 within 14 days of FST was studied as the primary outcome. The composite end point of achieving AKI-KDIGO stage 3 or death within 14 days of FST was studied as the secondary outcome. Results: Out of 80 patients, 28(35%) patients met the primary outcome, and 34(42.5%) patients met the secondary composite outcome. Except for baseline Chronic Kidney Disease (CKD) status (p=0.018), other demographic characteristics were comparable between progressors and non-progressors group. Using receiver operating characteristics (ROC) curve analysis, a cumulative 2-hour post-FST urine output of ≤300 mL predicted progression to stage 3 AKI with 82.14% sensitivity, 82.69% specificity, and AUC of 0.89±0.03 (p<0.0001). Conclusion: The FST showed promising results as a novel tubular biomarker to identify progression to severe AKI with good predictive ability.

Resumo Introdução: Os desfechos da Lesão Renal Aguda (LRA) permanecem desanimadores ainda hoje, em parte pela falta de um biomarcador ideal para detectar danos renais com a devida antecedência. Realizamos este estudo piloto para determinar a importância clínica do Teste de Estresse com Furosemida (TEF) em prever a gravidade da LRA. Métodos: Um total de 80 pacientes com LRA-KDIGO estágio 1 ou 2 foram submetidos ao TEF pela administração de uma dose em bolus de furosemida (1mg/kg para pacientes virgens de furosemida e 1,5mg/kg para exposição prévia à furosemida na semana anterior). O débito urinário foi então medido durante as duas horas seguintes com reposição de volume conforme desejável. A progressão para LRA-KDIGO estágio 3 dentro de 14 dias de TEF foi estudada como principal desfecho. O desfecho composto de atingir a LRA-KDIGO estágio 3 ou óbito em 14 dias após TEF foi estudado como desfecho secundário. Resultados: Dos 80 pacientes, 28 (35%) atingiram desfecho primário, e 34 (42,5%) pacientes atingiram o desfecho composto secundário. Exceto pelo estado basal da Doença Renal Crônica (DRC) (p=0,018), outras características demográficas foram comparáveis entre o grupo progressores e não progressores. Usando a análise da Curva Característica de Operação do Receptor (ROC), um débito urinário cumulativo de 2 horas pós-TEF de ≤300 mL previu a progressão para estágio 3 da LRA com 82,14% de sensibilidade, 82,69% de especificidade, e AUC de 0,89±0,03 (p<0,0001). Conclusão: O TEF mostrou resultados promissores como novo biomarcador tubular para identificar progressão para LRA grave com boa capacidade preditiva.

Clinical significance of frusemide stress test in predicting the severity of acute kidney injury.

INTRODUCTION: The outcomes of Acute Kidney Injury (AKI) remain dismal even today, owing in part due to the lack of an ideal biomarker for detecting renal damage early enough. We conducted this pilot study to determine the clinical significance of Frusemide Stress Test (FST) to predict the severity of AKI. METHODS: A total of 80 patients with AKI-KDIGO (Kidney Disease: Improving Global Outcomes) stage 1 or stage 2 underwent FST by administering a bolus dose of frusemide (1mg/kg for frusemide naïve and 1.5mg/kg for prior frusemide exposure in the past week), and urine output was then measured for the next two hours with volume replacement as desirable. The progression to AKI-KDIGO stage 3 within 14 days of FST was studied as the primary outcome. The composite end point of achieving AKI-KDIGO stage 3 or death within 14 days of FST was studied as the secondary outcome. RESULTS: Out of 80 patients, 28(35%) patients met the primary outcome, and 34(42.5%) patients met the secondary composite outcome. Except for baseline Chronic Kidney Disease (CKD) status (p=0.018), other demographic characteristics were comparable between progressors and non-progressors group. Using receiver operating characteristics (ROC) curve analysis, a cumulative 2-hour post-FST urine output of ≤300 mL predicted progression to stage 3 AKI with 82.14% sensitivity, 82.69% specificity, and AUC of 0.89±0.03 (p<0.0001). CONCLUSION: The FST showed promising results as a novel tubular biomarker to identify progression to severe AKI with good predictive ability.