Uncommon Noninvasive Biomarkers for the Evaluation and Monitoring of the Etiopathogenesis of Alzheimer's Disease.

BACKGROUND: Alzheimer´s disease (AD) is the most widespread dementia in the world, followed by vascular dementia. Since AD is a heterogeneous disease that shows several varied phenotypes, it is not easy to make an accurate diagnosis, so it arises when the symptoms are clear and the disease is already at an advanced stage. Therefore, it is important to find out biomarkers for early AD diagnosis that facilitate treatment or slow down the disease. Classic biomarkers are obtained from cerebrospinal fluid and plasma, along with brain imaging by positron emission tomography. Attempts have been made to discover uncommon biomarkers from other body fluids, which are addressed in this update. OBJECTIVE: This update aims to describe recent biomarkers from minimally invasive body fluids for the patients, such as saliva, urine, eye fluid or tears. METHODS: Biomarkers were determined in patients versus controls by single tandem mass spectrometry and immunoassays. Metabolites were identified by nuclear magnetic resonance and microRNAs with genome-wide high-throughput real-time polymerase chain reaction-based platforms. RESULTS: Biomarkers from urine, saliva, and eye fluid were described, including peptides/proteins, metabolites, and some microRNAs. The association with AD neuroinflammation and neurodegeneration was analyzed, highlighting the contribution of matrix metalloproteinases, the immune system and microglia, as well as the vascular system. CONCLUSION: Unusual biomarkers have been developed, which distinguish each stage and progression of the disease, and are suitable for the early AD diagnosis. An outstanding relationship of biomarkers with neuroinflammation and neurodegeneration was assessed, clearing up concerns about the etiopathogenesis of AD.

Alternative complement pathway activation in thrombotic microangiopathy associated with lupus nephritis.

INTRODUCTION/OBJECTIVE: Thrombotic microangiopathy (TMA) in systemic lupus erythematosus is a rare manifestation associated with activation of the complement system. This study aimed to compare plasma and urine complement activation products between patients with active lupus nephritis (aLN) and those with acute TMA plus concomitant active LN (aTMA+aLN). METHODS: Plasma and urine samples were obtained from 20 patients with aTMA+aLN, 20 patients with aLN matched by the histological activity index, 5 patients with chronic TMA, 20 patients with inactive LN, and 10 kidney donors. Complement fragments C3a, C4a, C4d, Ba, C5a, C5bC9, and factor H were determined by ELISA; and kidney C4d deposition was detected by immunohistochemistry. Patients were followed for > 12 months and complement activation products re-measured after treatment in 10 aTMA+aLN patients. RESULTS: Both aTMA+aLN and aLN groups had increased circulating C3a, Ba, and C5bC9; and decreased circulating C3, C4, C4a, C4d, and factor H. Urinary C3a, C5a, Ba, and C5bC9 were higher in patients with aTMA+aLN than in aLN. After treatment, levels of circulating C3, C4, and factor H increased; while levels of urinary C3a, C5a, Ba, and C5bC9 decreased in patients with aTMA+aLN. These changes were observed at each aTMA episode in two patients studied during repeated TMA episodes. There was no difference in C4d deposition in glomerular capillaries, tubular basement membrane, peritubular capillaries, and arterioles between patients with aLN and those aTMA+aLN. CONCLUSIONS: Circulating and urine complement activation products suggest that thrombotic microangiopathy associated with LN is mediated through activation of the alternative complement pathway. Key Points • Immune-complex kidney disease in systemic lupus erythematosus (SLE) is associated with activation of the classical, lectin, and alternative complement pathways • Indirect evidence from measurement of circulating and urinary complement pathway activation products suggests that renal acute thrombotic microangiopathy in SLE is mediated by activation of the alternative complement pathway • C4d kidney immunohistochemistry may be positive in both immune complex nephritis and thrombotic microangiopathy. Therefore, it is not a specific marker of renal thrombotic microangiopathy in SLE.

HSP72 is an early biomarker to detect cisplatin and acetaminophen nephrotoxicity.

OBJECTIVE: To evaluate whether the urinary HSP72 levels (uHSP72) are a useful biomarker for early diagnosis of acute kidney injury (AKI) induced by two widely used drugs: cisplatin and acetaminophen. MATERIALS AND METHODS: To analyze the time-course of nephrotoxic injury and uHSP72 levels, male Wistar rats were administered a single high dose of cisplatin (7 mg/kg) or acetaminophen (750 mg/kg) and were assessed at 6, 12, 24, 48, 72, 96 and 120 h. RESULTS: AKI induced by cisplatin was characterized by tubular injury that started at 6 h and was enhanced after 48 h. Plasma creatinine was increased only after 72 h. In contrast, uHSP72 levels were augmented after 6 h and were enhanced after 48 h of cisplatin administration, which was consistent with the tubular injury. In acetaminophen-induced AKI, the tubular lesions were less severe and predominantly characterized by tubular cell detachment. Interestingly, uHSP72 levels were increased after 6 h of acetaminophen injection and remained elevated at the following time points, reflecting the tubular injury, even in the absence of major functional changes. CONCLUSIONS: In two models of renal injury induced by nephrotoxic drugs, we showed that uHSP72 could be used as an early biomarker to detect subtle to severe tubular injury.

Urine biomarkers of kidney injury among adolescents in Nicaragua, a region affected by an epidemic of chronic kidney disease of unknown aetiology.

BACKGROUND: An epidemic of chronic kidney disease (CKD) of non-traditional aetiology has been recently recognized by health authorities as a public health priority in Central America. Previous studies have identified strenuous manual work, agricultural activities and residence at low altitude as potential risk factors; however, the aetiology remains unknown. Because individuals are frequently diagnosed with CKD in early adulthood, we measured biomarkers of kidney injury among adolescents in different regions of Nicaragua to assess whether kidney damage might be initiated during childhood. METHODS: Participants include 200 adolescents aged 12-18 years with no prior work history from four different schools in Nicaragua. The location of the school served as a proxy for environmental exposures and geographic locations were selected to represent a range of factors that have been associated with CKD in adults (e.g. altitude, primary industry and CKD mortality rates). Questionnaires, urine dipsticks and kidney injury biomarkers [interleukin-18, N-acetyl-d-glucosaminidase (NAG), neutrophil gelatinase-associated lipocalin (NGAL) and albumin-creatinine ratio] were assessed. Biomarker concentrations were compared by school using linear regression models. RESULTS: Protein (3.5%) and glucose (1%) in urine measured by dipstick were rare and did not differ by school. Urine biomarkers of tubular kidney damage, particularly NGAL and NAG, showed higher concentrations in those schools and regions within Nicaragua that were defined a priori as having increased CKD risk. Painful urination was a frequent self-reported symptom. CONCLUSIONS: Although interpretation of these urine biomarkers is limited because of the lack of population reference values, results suggest the possibility of early kidney damage prior to occupational exposures in these adolescents.