Biotics (Pre-, Pro-, Post-) and Uremic Toxicity: Implications, Mechanisms, and Possible Therapies.

In recent years, more scientific data have pointed out the close connection between intestinal microbial community, nutritional habits, lifestyle, and the appearance of various affections located at certain anatomical systems. Gut dysbiosis enhances the formation and accumulation of specific metabolites with toxic potential that induce the appearance of kidney-associated illnesses. Intestinal microbes are involved in the degradation of food, drugs, or other ingested products that lead to the formation of various metabolites that end up in renal tissue. Over the last few years, the possibilities of modulating the gut microbiota for the biosynthesis of targeted compounds with bioactive properties for reducing the risk of chronic illness development were investigated. In this regard, the present narrative review provides an overview of the scientific literature across the last decade considering the relationship between bioactive compounds, pre-, pro-, and post-biotics, uremic toxicity, and kidney-associated affections, and the possibility of alleviating the accumulation and the negative effects of uremic toxins into the renal system.

Histological Changes in the Background Renal Parenchyma in Neoplastic Nephrectomies and Nephroureterectomy: A 10-Year Single-Center Experience.

Background: Nephrectomies and nephroureterectomies specimen with neoplastic diagnosis provide a great opportunity to examine the background kidney parenchyma. This will help in exploring any microscopic abnormality that may affect the functional capacity of the residual renal tissue and assess the possible need for nephrologist intervention in maximizing the function of the residual renal parenchyma. Aim: Evaluation of this part of the kidney is overlooked in different centers around the world. Method: A total of 124 specimens of nephrectomies and nephroureterectomies performed at King Abdulaziz University Hospital between January 2010 and December 2019 were reviewed. The microscopic findings in the nonneoplatic parenchyma were documented. Furthermore, the extent to which these findings were initially identified, investigated, and reported was measured. Results: Hypertensive and diabetic nephropathy were among the most common findings in the diseased kidney. The nonneoplastic kidney was well sampled in 95% of the cases and mentioned in the report in 25% of the cases. Conclusion: Although, the evaluation of this part of the kidney is essential, and of great help for the patient prognosis, and quality of kidney function, it is overlooked in different centers around the world, and the causes behind this requires further exploration.

Association Between Childhood Obesity and Later Life Kidney Disorders: A Systematic Review.

Childhood obesity is considered one of the important risk factors for many long-term morbidities. However, the long-term consequences of childhood obesity on kidney function are largely unknown. In this systematic review, all prospective or retrospective cohort studies and nested case-control articles which investigated association of childhood obesity with later life kidney function were searched via some international databases including PubMed, Scopus, Web of Science and Google Scholar. After screening 6,843 published articles, 8 prospective cohorts studies were included in the qualitative synthesis. All the included studies were published in the last 10 years. The overall follow-up duration of studies ranged from 8 to 64 years. Out of 8 included studies, 6 reported a statistically significant positive association between higher BMI levels in early life and greater renal disease risk in later life. Evidence from various populations implicates a positive link between obesity in early life and kidney disease in later life.

Advanced Drug Delivery Systems for Renal Disorders.

Kidney disease management and treatment are currently causing a substantial global burden. The kidneys are the most important organs in the human urinary system, selectively filtering blood and metabolic waste into urine via the renal glomerulus. Based on charge and/or molecule size, the glomerular filtration apparatus acts as a barrier to therapeutic substances. Therefore, drug distribution to the kidneys is challenging, resulting in therapy failure in a variety of renal illnesses. Hence, different approaches to improve drug delivery across the glomerulus filtration barrier are being investigated. Nanotechnology in medicine has the potential to have a significant impact on human health, from illness prevention to diagnosis and treatment. Nanomaterials with various physicochemical properties, including size, charge, surface and shape, with unique biological attributes, such as low cytotoxicity, high cellular internalization and controllable biodistribution and pharmacokinetics, have demonstrated promising potential in renal therapy. Different types of nanosystems have been employed to deliver drugs to the kidneys. This review highlights the features of the nanomaterials, including the nanoparticles and corresponding hydrogels, in overcoming various barriers of drug delivery to the kidneys. The most common delivery sites and strategies of kidney-targeted drug delivery systems are also discussed.

Eosinophils: A Friend or Foe in Human Health and Diseases.

Background: Since their discovery, around 150 years, eosinophils research has been a field of changing perspective, and new directions are emerging since then. Summary: Initially, eosinophils were perceived as terminally differentiated cytotoxic effector cells. Clearly, eosinophils are capable of playing functions other than immune responses, which is not surprising given their intricate interactions with pathogens as well as other circulating leukocytes. Attempts to comprehend the eosinophil biology and functions have yielded remarkable insights into their roles in human health and sickness. The use of FDA-approved eosinophils-targeting biologics has provided exciting opportunities to directly explore the contributions of eosinophils in disease etiology in humans. Key Messages: In this review, we will focus on the eosinophils' lifecycle and discuss the current state of knowledge from mouse models and retrospective human studies demonstrating eosinophils' roles in the pathogenesis of human diseases such as asthma, cancer, and kidney disorders. Despite three recently approved anti-eosinophil agents, a number of key questions and challenges remain far from settled, thereby generating opportunity to further explore this enigmatic cell. A comprehensive understanding of eosinophils biology and function will surely aid in developing improved therapeutic strategies against eosinophils-associated disorders.

Association between depressive symptoms and bone density in elderly patients with non-dialysis dependent chronic kidney disease.

BACKGROUND: Depression is a disease that is commonly accompanied by elderly chronic kidney disease (CKD) patients, but when the two diseases are accompanied, etiology or combination are not well known. We aimed to evaluate the etiology of CKD and comorbid depression by investigating bone disorders that are observed in persons affected by both CKD and depression. METHODS: We conducted a cross-sectional study with a total of 646 patients with CKD. We compared the sociodemographic factors, kidney function, markers for CKD-Mineral and Bone Disorder (CKD-MBD) and bone mineral density according to the depressive symptoms. We conducted a univariate and multivariate logistic regression analysis to calculate odd ratios (95 % confidence interval) between depressive symptoms and low bone mineral density. RESULTS: Individuals with CKD and depressive symptoms were associated with lower level of education attained, living alone, exercising less, low 24-hour urine phosphorus, and low bone density. Depressive symptoms were significantly associated with low bone density in lowest parts (1.55 [1.06-2.29]) and in total hip (1.72 [1.17-2.53]) even after adjusting for diabetes mellitus, hypertension, kidney function, proteinuria, age, sex, smoking, and body mass index. LIMITATIONS: A cross-sectional design was used in this study and the bone biopsy for diagnosis of CKD-MBD was not done because of invasiveness and practical difficulties. CONCLUSION: Low bone density was associated with depressive symptoms in elderly patients with non-dialysis chronic kidney disease.

State of the Science for Kidney Disorders in Phelan-McDermid Syndrome: UPK3A, FBLN1, WNT7B, and CELSR1 as Candidate Genes.

Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder caused by chromosomal rearrangements affecting the 22q13.3 region or by SHANK3 pathogenic variants. The scientific literature suggests that up to 40% of individuals with PMS have kidney disorders, yet little research has been conducted on the renal system to assess candidate genes attributed to these disorders. Therefore, we first conducted a systematic review of the literature to identify kidney disorders in PMS and then pooled the data to create a cohort of individuals to identify candidate genes for renal disorders in PMS. We found 7 types of renal disorders reported: renal cysts, renal hypoplasia or agenesis, hydronephrosis, vesicoureteral reflux, kidney dysplasia, horseshoe kidneys, and pyelectasis. Association analysis from the pooled data from 152 individuals with PMS across 22 articles identified three genomic regions spanning chromosomal bands 22q13.31, 22q13.32, and 22q13.33, significantly associated with kidney disorders. We propose UPK3A, FBLN1, WNT7B, and CELSR1, located from 4.5 Mb to 5.5 Mb from the telomere, as candidate genes. Our findings support the hypothesis that genes included in this region may play a role in the pathogenesis of kidney disorders in PMS.

Organs-on-chip technology: a tool to tackle genetic kidney diseases.

Chronic kidney disease (CKD) is a major healthcare burden that takes a toll on the quality of life of many patients. Emerging evidence indicates that a substantial proportion of these patients carry a genetic defect that contributes to their disease. Any effort to reduce the percentage of patients with a diagnosis of nephropathy heading towards kidney replacement therapies should therefore be encouraged. Besides early genetic screenings and registries, in vitro systems that mimic the complexity and pathophysiological aspects of the disease could advance the screening for targeted and personalized therapies. In this regard, the use of patient-derived cell lines, as well as the generation of disease-specific cell lines via gene editing and stem cell technologies, have significantly improved our understanding of the molecular mechanisms underlying inherited kidney diseases. Furthermore, organs-on-chip technology holds great potential as it can emulate tissue and organ functions that are not found in other, more simple, in vitro models. The personalized nature of the chips, together with physiologically relevant read-outs, provide new opportunities for patient-specific assessment, as well as personalized strategies for treatment. In this review, we summarize the major kidney-on-chip (KOC) configurations and present the most recent studies on the in vitro representation of genetic kidney diseases using KOC-driven strategies.

Therapeutic potential of mangiferin against kidney disorders and its mechanism of action: A review.

There is a swing in research developments concerning the utilization of natural products as effective pharmacotherapeutic agents due to their comparatively lower toxicities than synthetic compounds. Among natural products, mangiferin is a natural C-glucosyl xanthonoid polyphenol with remarkable pharmacological activities. Emerging evidence indicates the therapeutic benefits of mangiferin against various kidney disorders, including renal injury, diabetic nephropathy, renal fibrosis, hyperuricemic nephropathy, and lupus nephritis, in experimental animal models. The mangiferin induced antioxidant response resulting in vital functions, such as protection against renal inflammation, inhibits renal cell apoptosis, activates autophagy, causes immunomodulation, regulates renal urate transporters and modulates cell signalling pathways. The purpose of this review provide a brief overview of the in vitro/in vivo reno-protective effect of mangiferin and the underlying mechanism(s) in protecting against kidney disorders. Understanding the pharmacological actions of mangiferin is prominence due to its excellent therapeutic potential in managing kidney disorders. Thus, in addition to this review, in-silico molecular docking is performed against nuclear factor kappa B (NF-κB) and soluble epoxide hydrolase (sEH) to study the mechanism of action of mangiferin. It is believed that mangiferin is a safe reno-protective molecule. The observed positive effects are attributed to the inhibition of inflammation caused by NF-κB and sEH upregulation and oxidative stress activation. Studies on the efficacy and safety of mangiferin in clinical trials are further warranted to confirm its medicinal potential as therapeutic agent for kidney disorders in humans.

Treat-to-Target in Lupus Nephritis. What is the Role of the Repeat Kidney Biopsy?

Kidney involvement, termed lupus nephritis (LN), develops in 35-60% of patients with systemic lupus erythematosus, often early during the disease course. When not treated promptly and efficiently, LN may lead to rapid and severe loss of kidney function, being the reason why it is considered one of the most severe lupus manifestations. Despite improved pharmacotherapy, 5-20% of LN patients develop end-stage kidney disease within ten years from the LN diagnosis. While the principal ground of LN therapy is prevention of renal function worsening, resembling a race against nephron loss, consensual agreement upon outcome measures and clinically meaningful short- and long-term targets of LN therapy have yet to be determined. Literature points to the importance of inclusion of tissue-based approaches in the determination of those targets, and evidence accumulates regarding the importance of per-protocol repeat kidney biopsies in the evaluation of the initial phase of therapy and prediction of long-term renal prognosis. The latter leads to the hypothesis that the information gleaned from repeat biopsies may contribute to optimised therapeutic decision making, and, therefore, increased probability to attain complete renal response in the short term, and a more favourable renal prognosis within a longer prospect. The multinational project ReBioLup was recently designed to serve as a key contributor to form evidence about the role of per-protocol repeat biopsies in a randomised fashion and aspires to unify the global LN community towards improved kidney and patient survival.

Biochemical Parameters as Predictors of Underlying Liver Disease in Patients with Chronic Kidney Disorders.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is an increasingly common cause of chronic liver disease and is becoming a major public health problem. NAFLD has been recognized as a hepatic manifestation of metabolic syndrome, associated with systemic diseases such as cardiovascular disease (CVD) and chronic kidney disease (CKD). OBJECTIVE: The aim of this study was to examine the role of serum LFT parameters and renal function parameters as predictors of unmanifested liver disease. METHODS: In this study, the presence of possible liver disease detected by biochemical parameters and confirmed by Transient Liver Elastography (TE) in a group of patients with different stages of chronic kidney disease (CKD) was investigated. Patients with various stages of CKD were divided into five subgroups regarding aetiology: nephroangiosclerosis, diabetic nephropathy, glomerulonephritis and pyelonephritis, autoimmune kidney disease, and polycystic and another morphological kidney disease. Liver stiffness was used to quantify liver fibrosis while Controlled attenuation parameter (CAP) was used to quantify liver steatosis. Functional liver tests and biochemical parameters of kidney function were measured in all patients. RESULTS: Statistical analysis used in this study was a decision tree as a predictive model to map observed variables resulting in the conclusion about outcomes. The application of existing laboratory parameters, in combination with other parameters in presence of the defined etiological factors of kidneys diseases, indicate development of hepatic diseases. Higher values of phosphorus and low values of ferritin in patients with autoimmune kidney disease, and polycystic and another morphological kidney disease, expresses steatosis of the hepatic parenchyma. CONCLUSION: In contrary, low values of phosphorus and higher values of ferritin in patients with nephroangiosclerosis, diabetic nephropathy, glomerulonephritis and pyelonephritis, are in a favour steatosis of the hepatic parenchyma. Serum values of phosphorus and ferritin are valuable predictors of the liver disease in patients with end-stage kidney diseases of different aetiology.

[Application of proteomics and metabolomics to study inherited kidney disorders: from big data to precision medicine].

The recent application of proteomics and metabolomics to clinical medicine has demonstrated their potential role in complementing genomics for a better understanding of diseases' patho-physiology. These technologies offer the clear opportunity to identify risk factors, disease-specific or stage-specific biomarkers and to predict therapeutic response. This article is an overview of the recent insights obtained by metabolomic and proteomic studies in inherited kidney disorders. Proteomics studies have allowed the definition of a detailed picture of protein composition, post-translational modifications and interactions in kidney-derived samples, improving our understanding of renal physiology, especially of tubular transport and primary cilium-related functions. Studies on patients' urine samples and experimental models of inherited kidney diseases have provided clues suggesting novel potential pathological mechanisms and biomarkers of disease, for example in polycystic kidney disease. Metabolomic-based studies have been recently applied to assess biological system disturbances caused by specific genetic mutations resulting in inherited kidney disorders. These studies have been mainly carried out on mouse and rat models of cystic and metabolic disorders (such as Fabry disease), and on patients' urine samples. They have provided a significant contribution in understanding disease pathophysiology, promoting the discovery of aberrant biochemical pathways and contributing to the development of targeted therapies.

Renal Expression of Light Chain Binding Proteins.

Overproduction of human light chains (LCs) and immunoglobulins can result in various forms of renal disease such as cast nephropathy, monoclonal immunoglobulin deposition disease, LC proximal tubulopathy, AL amyloidosis, and crystal storing histiocytosis. This is caused by cellular uptake of LCs and overwhelmed intracellular transport and degradation in patients with high urine LC concentrations. LC kappa and lambda purification was evaluated by sodium dodecyl sulfate gel electrophoresis. LC and myeloma protein binding to immobilized renal proteins was measured by enzyme-linked immunosorbent assay (ELISA). The human protein microarray (HuProt™) was screened with purified kappa and lambda LC. Identified LC partners were subsequently analyzed in silico for renal expression sites using protein databases, Human Protein Atlas, UniProt, and Bgee. Binding of urinary LCs and immunoglobulins to immobilized whole renal proteins from 22 patients with myeloma or plasma cell dyscrasia was shown by ELISA. Forty lambda and 23 kappa interaction partners were identified from HuProt™ array screens, of which 21 were shared interactors. Among the total of 42 interactors, 12 represented cell surface proteins. Lambda binding signals were approximately 40% higher than kappa signals. LC interaction with renal cells and disease-causing pathologies are more complex than previously thought. It involves an extended spectrum of proteins expressed throughout the nephron, and their identification has been enabled by recently developed methods of protein analysis such as protein microarray screening. Further biochemical studies on interacting proteins are warranted to elucidate their clinical relevance.

The economic burden of kidney disorders in Korea.

AIMS: To estimate the economic burden of kidney disorders in Korea. MATERIALS AND METHODS: The economic burden of kidney disorders was estimated using a prevalence-based approach. Related kidney diseases in patients with kidney disorders (RPWKD) were defined using codes from the tenth International Classification of Disease (E70-E90, F30-F48, F60-F69, F90-F99, K65-K67, N00-N08, N17-N19, and N30-N39). All diseases in patients with kidney disorders (APWKD) were defined as kidney disorders that involved all disease codes. Economic costs were divided into direct costs (medical costs and non-medical costs) and indirect costs (productivity loss because of morbidity and premature mortality). RESULTS: The prevalence of kidney disorders increased from 0.08% (2008) to 0.11% (2011). The total economic burden of RPWKD also substantially increased from $898.9 million (2008) to $1.43 billion (2011). This ∼59.4% increase in the economic burden was equal to 0.12% of the Korean gross domestic product. The economic burden of APWKD also increased during the study period: $1.06 billion (2008), $1.23 billion (2009), $1.44 billion (2010), and $1.46 billion (2011). CONCLUSIONS: The present study provides the first data regarding the economic burden of kidney disorders in Korea. The findings support the need for early intervention services and prevention programs to prevent, identify, and manage kidney disorders.

Correlation of cadmium and aluminum in blood samples of kidney disorder patients with drinking water and tobacco smoking: related health risk.

The combined exposure to aluminum (Al) and cadmium (Cd) causes more pronounced adverse health effects on humans. The kidneys are the main organs affected by internal exposure to Cd and Al via food and non-food items. The objective of present study was to measure the Al and Cd concentrations in cigarettes tobacco (branded and non-branded) and drinking water (domestic treated, ground and lake water) samples in southern part of Pakistan, to assess the risk due to ingestion of water and inhalation of cigarettes smoke containing high concentrations of both elements. The study population (kidney disorder and healthy) divided into two group based on consuming lake and ground water, while smoking non-branded cigarette as exposed, while drinking domestic treated water and smoking branded cigarette as non-exposed. Electrothermal atomic absorption spectrometry was used to determined Cd and Al concentrations in tobacco, drinking water and blood samples. The resulted data indicated that the levels of Al and Cd in lake and underground water were higher than the permissible limit in drinking water recommended by the World Health Organization. The biochemical parameters of exposed and referent patients, especially urinary N-acetyl-h-glucosaminidase, were used as a biomarkers of kidney disorder. Exposed kidney disorder patients have higher levels of Cd and Al than the exposed referents subjects, while difference was significant when compared to resulted data of non-exposed patients and referents (p = 0.01-0.001). The pearson correlation showed positive correlation between both toxic element concentrations in water, cigarettes versus blood samples of exposed subjects (r = 0.20-0.67 and 0.71-0.82), while lower values were observed for non-exposed subjects (r = 0.123-0.423 and 0.331-0.425), respectively.

Is a long term work in automotive industry a risk factor for renal dysfunction?

BACKGROUND: Disorders of renal system can cause renal failure; therefore screening is necessary especially in workers who are exposed to harmful materials. Hypertension, diabetes mellitus, and hazardous exposures are non-occupational and occupational risk factors for renal diseases. AIM: The objective of this study was to determine the effects of working in automotive industry on renal function in Iran. SUBJECTS AND METHODS: In a historical cohort study, workers of automotive industry who worked in production and had low exposure to metal fumes were selected and divided to three groups with 5-10, 11-20, and 21-30 years work duration. risk factors for renal diseases were collected and analyzed with SPSS using one-way ANOVA, correlation coefficient and with P < 0.05 and relative risk with a confidence interval (CI). RESULTS: The means of work duration in Groups (A), (B) and (C) were 9.8 (0.6), 13.8 (2.0), 22.3 (1.6) years respectively with ANOVA (F) =187.864 and P < 0.01. Glomerular filtration rate (GFR) was 59.75 (0.70), 59.16 (1.52) and 59.10 (2.23) in Groups (A), (B), and (C) respectfully The relative risk of creatinine clearance, uric acid and mean blood pressure were the highest in Group (B); 1.970 - CI, 0.541-7.169, 1.571 95% CI: 0.198-12.470, and 1.519 95% CI: 0.425-5.426, but the differences were not significant. CONCLUSION: GFRs were decreased with work duration, but the differences were not significant. Working in automotive Industry with low exposure to toxic metals and solvents has no significant effect on GFR, creatinine clearance, uric acid, and mean blood pressure.