Kidney and urine cell transcriptomics in IgA nephropathy and lupus nephritis: a narrative review.

This narrative review sheds light on the use of transcriptomics in the analysis of kidney biopsies and urinary cell samples from patients with immunoglobulin A nephropathy or lupus nephritis. The conventional methods of examining kidney biopsy through light microscopy, immunofluorescence and electron microscopy provide valuable clinical information for diagnosis and prognosis but have some limitations that transcriptomics can address. Some recent studies have reported that kidney transcriptomics has uncovered new molecular biomarkers implicated in the inflammatory process induced by the deposition of circulating immune complexes in the investigated kidney diseases. In addition, transcriptomics applied to urinary cells mirrors the inflammatory process that occurs in the kidney. This means that we can study urinary cell transcriptomics in clinical practice to diagnose the stage of the inflammatory process. Furthermore, the transcriptomics of urinary cells can be used to make therapy decisions during patient follow-up to avoid the stress of a second kidney biopsy. The studies analyzed in this review have a significant limitation. Biomarkers have been identified in small cohorts of patients but none of them has been validated in independent external cohorts. Further prospective studies in large cohorts of patients are necessary for accurate and complete validation. Only after that can these biomarkers be widely used in clinical practice.

Randomized clinical study to evaluate the effect of personalized therapy on patients with immunoglobulin A nephropathy.

Background: Randomized controlled trials (RCTs) have been conducted, stratifying idiopathic immunoglobulin A nephropathy (IgAN) patients based on the laboratory findings [serum creatinine, estimated glomerular filtration rate (eGFR) and daily proteinuria]. In contrast, data from kidney biopsy have been used only for clinical diagnosis. Therefore, IgAN patients with active or chronic renal lesions have been receiving the same therapy in experimental and control arms of randomized clinical trials (RCTs). Methods: Our clinical study of IgAN (CLIgAN) is a multicentre, prospective, controlled and open-label RCT based on patients' stratification at the time of their kidney biopsy. We will consider, first, the type of renal lesions, followed by serum creatinine values, eGFR and proteinuria. Primary and secondary endpoints will be monitored. Then, we will determine whether personalized therapy can slow the decline of renal function and delay end-stage kidney disease. Results: We will enrol 132 IgAN patients with active renal lesions (66 patients per arm) in the first RCT (ACIgAN). They will receive corticosteroids combined with renin-angiotensin system blockers (RASBs) or only RASBs. A total of 294 IgAN patients with chronic or moderate renal lesions at high or very high risk of chronic kidney disease (147 patients per arm) will be enrolled in the second RCT (CHRONIgAN), in which they will receive dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, combined with RASBs, or RASBs alone. Conclusion: Using this approach, we hypothesize that patients could receive personalized therapy based on renal lesions to ensure that the right drug gets to the right patient at the right time.

Erratum: Randomized clinical study to evaluate the effect of personalized therapy on patients with immunoglobulin A nephropathy.

[This corrects the article DOI: 10.1093/ckj/sfab263.].

Artificial intelligence in glomerular diseases.

In this narrative review, we focus on the application of artificial intelligence in the clinical history of patients with glomerular disease, digital pathology in kidney biopsy, renal ultrasonography imaging, and prediction of chronic kidney disease (CKD). With the development of natural language processing, the clinical history of a patient can be used to identify a computable phenotype. In kidney pathology, digital imaging has adopted innovative deep learning algorithms (DLAs) that can improve the predictive capability of the examined lesions. However, at this time, these applications can only be used in research because there is no recognized validation to replace the conventional diagnostic applications. Kidney ultrasonography, used in the clinical examination of patients, provides information about the progression of kidney damage. Machine learning algorithms (MLAs) with promising results for the early detection of CKD have been proposed, but, still, they are not solid enough to be incorporated into the clinical practice. A few tools for glomerulonephritis, based on MLAs, are available in clinical practice. They can be downloaded on computers and cellular phones but can only be applied to uniracial cohorts of patients. To improve their performance, it is necessary to organize large consortia with multiracial cohorts. Finally, in many studies MLA development has been carried out using retrospective cohorts. The performance of the models might differ in retrospective cohorts compared to real-world data. Therefore, the models should be validated in prospective external large cohorts.

Significant decrease of saturation index in erythrocytes membrane from subjects with non-alcoholic fatty liver disease (NAFLD).

BACKGROUND: The lipidomic profiling of erythrocyte membranes is expected to provide a peculiar scenario at molecular level of metabolic and nutritional pathways which may influence the lipid balance and the adaptation and homeostasis of the organism. Considering that lipid accumulation in the cell is important in promoting tissue inflammation, the purpose of this study is to analyze the fatty acid profile in red blood cell membranes of patients with Non-Alcoholic Fatty Liver Disease (NAFLD), in order to identify and validate membrane profiles possibly associated with the degree of hepatic damage. METHODS: This work presents data obtained at baseline from 101 subjects that participated to a nutritional trial (registration number: NCT02347696) enrolling consecutive subjects with NAFLD. Diagnosis of liver steatosis was performed by using vibration-controlled elastography implemented on FibroScan. Fatty acids, extracted from phospholipids of erythrocyte membranes, were quantified by gas chromatography method. RESULTS: The subjects with severe NAFLD showed a significant decrease of the ratio of stearic acid to oleic acid (saturation index, SI) compared to controls, 1.281 ± 0.31 vs 1.5 ± 0.29, respectively. Low levels of SI in red blood cell membranes, inversely associated with degree of liver damage, suggest that an impairment of circulating cell membrane structure can reflect modifications that take place in the liver. Subjects with severe NAFLDalso showed higher levels of elongase 5 enzymatic activity, evaluated as vaccenic acid to palmitoleic acid ratio. CONCLUSIONS: Starting from these evidences, our findings show the importance of lipidomic approach in the diagnosis and the staging of NAFLD.

Additive Role of a Potentially Reversible Cognitive Frailty Model and Inflammatory State on the Risk of Disability: The Italian Longitudinal Study on Aging.

OBJECTIVE: Cognitive frailty is a condition recently defined by operationalized criteria describing the simultaneous presence of physical frailty and mild cognitive impairment (MCI). Two subtypes for this clinical construct have been proposed: "potentially reversible" cognitive frailty (physical frailty plus MCI) and "reversible" cognitive frailty (physical frailty plus pre-MCI subjective cognitive decline). Here the prevalence of a potentially reversible cognitive frailty model was estimated. It was also evaluated if introducing a diagnosis of MCI in older subjects with physical frailty could have an additive role on the risk of dementia, disability, and all-cause mortality in comparison with frailty state or MCI condition alone, with analyses separately performed for inflammatory state. METHODS: In 2,373 individuals from the population-based Italian Longitudinal Study on Aging with a 3.5-year-follow-up, we operationally categorized older individuals without dementia into four groups: non-frail/non-MCI, non-frail/MCI, frail/non-MCI, and frail/MCI. RESULTS: The prevalence of potentially reversible cognitive frailty was 1%, increasing with age and more represented in women than in men, and all groups were associated with significant increased incident rate ratios of dementia, disability, and mortality. A significant difference in rates of disability has been found between the MCI and non-MCI groups (contrasts of adjusted predictions: 0.461; 95% confidence interval: 0.187-0.735) in frail individuals with high inflammatory states (fibrinogen >339 mg/dL). CONCLUSION: In older individuals without dementia and with elevated inflammation, a potentially reversible cognitive frailty model could have a significant additional predictive effect on the risk of disability than the single conditions of frailty or MCI.

Relationships of Dietary Patterns, Foods, and Micro- and Macronutrients with Alzheimer's Disease and Late-Life Cognitive Disorders: A Systematic Review.

In the last decade, the association between diet and cognitive function or dementia has been largely investigated. In the present article, we systematically reviewed observational studies published in the last three years (2014-2016) on the relationship among dietary factors and late-life cognitive disorders at different levels of investigation (i.e., dietary patterns, foods and food-groups, and dietary micro- and macronutrients), and possible underlying mechanisms of the proposed associations. From the reviewed evidence, the National Institute on Aging-Alzheimer's Association guidelines for Alzheimer's disease (AD) and cognitive decline due to AD pathology introduced some evidence suggesting a direct relation between diet and changes in the brain structure and activity. There was also accumulating evidence that combinations of foods and nutrients into certain patterns may act synergistically to provide stronger health effects than those conferred by their individual dietary components. In particular, higher adherence to a Mediterranean-type diet was associated with decreased cognitive decline. Moreover, also other emerging healthy dietary patterns such as the Dietary Approach to Stop Hypertension (DASH) and the Mediterranean-DASH diet Intervention for Neurodegenerative Delay (MIND) diets were associated with slower rates of cognitive decline and significant reduction of AD rate. Furthermore, some foods or food groups traditionally considered harmful such as eggs and red meat have been partially rehabilitated, while there is still a negative correlation of cognitive functions with saturated fatty acids and a protective effect against cognitive decline of elevated fish consumption, high intake of monounsaturated fatty acids and polyunsaturated fatty acids (PUFA), particularly n-3 PUFA.

Site-dependent biological activity of valinomycin analogs bearing derivatizable hydroxyl sites.

Valinomycin (VLM, 1) is a K(+) ionophore cyclodepsipeptide capable of depolarizing mitochondria and inducing apoptosis to several mammalian cell types, including a number of tumor cell lines. With the aim of creating VLM-based ligand-targeted anticancer drugs that may selectively convey VLM to pathological cells, we have previously introduced derivatizable hydroxyl handles into the VLM structure, allowing to access a three-entity library of monohydroxyl VLMs (HyVLMs) bearing the OH group at the isopropyl side chain of a D-Hyi, D-Val, or L-Val residue (analogs 2-4, respectively). Herein, the levels of bioactivity retained by the conjugable HyVLMs have been assessed on the basis of their ability to alter the functionality of isolated rat-liver mitochondria. Experiments run with HyVLMs in the range 1-10 nM and in 20 or 125 mM KCl medium show that the hydroxyl group reduces the potency of HyVLMs relative to VLM to an extent that depends upon the molecular site involved in the hydroxylation. On the other hand, estimation of the stability constants of complexes (in methanol at 25 °C) of each analog with Na(+), K(+), and Cs(+) reveals that HyVLMs nicely retain the VLM binding features, except for a moderate increase in the stability of Na(+) complexes. These findings, along with pertinent structural considerations, suggest that the incorporation of OH into the VLM structure might actually have altered its K(+) transporting ability across mitochondrial membranes. Besides facing new aspects of VLM structure-activity relationship, these studies set the basis for the rational design of ligand-HyVLMs conjugates through derivatization of hanging OH group.