Tag: Renal Failure

Genetic analysis reveals hidden causes of chronic kidney disease in adults

[ad_1]

Chronic kidney disease (CKD) is extremely prevalent among adults, affecting over 800 million individuals worldwide. Many of these patients eventually require therapy to supplement or replace kidney functions, such as dialysis or kidney transplant. While most CKD cases originate from lifestyle-related factors or diseases such as diabetes and hypertension, the underlying causes of CKD remain unknown for about one in every ten people with end-stage renal failure. Could CKD in these patients stem from latent, undiagnosed genetic conditions?

In a recent study published online on 14 February 2024 in Kidney International Reports, researchers from Tokyo Medical and Dental University (TMDU) in Japan set out to answer this question through a comprehensive genetic analysis of CKD patients.

First, the researchers acquired data from 1,164 patients who underwent dialysis in four different clinics in the Kanagawa Prefecture during November 2019. From this multicenter cohort, the researchers filtered out adults who were over 50 years old, since people at that age have a lower incidence of inherited kidney diseases. They then filtered out patients who had an apparent cause for their CKD, leaving 90 adults with CKD of unknown origin who had consented to genetic testing.

We conducted a comprehensive analysis of 298 genes responsible for various inherited renal diseases using next-generation sequencing. These included polycystic kidney disease, nephronophthisis-related ciliopathies, autosomal dominant tubulointerstitial kidney disease, focal segmental glomerulosclerosis, Alport syndrome, and atypical hemolytic uremic syndrome.“

Dr. Takuya Fujimaru, Lead Author

The results revealed that 10 of the 90 patients (11% of the final cohort) had pathogenic variants in CKD-causing genes. Importantly, for these patients, the clinical diagnosis at the time of dialysis was incorrect. What was particularly noteworthy was that some of the hereditary renal diseases contemplated in this study, such as Fabry’s disease and Alport syndrome, could be diagnosed and treated early on to slow down or halt the progression of CKD.

On top of these findings, the researchers determined that 17 patients (18.9%) had genetic variants of unknown significance (VUS) with a high probability of pathological involvement. While the relationship between these variants and kidney diseases is not clear, they should not be ignored or taken lightly. “Although the interpretation of these VUS is currently unknown, some of them may indeed be responsible for CKD,” remarks senior author Dr. Takayasu Mori. “Thus, true hereditary kidney diseases may underlie many more cases than anticipated.“

This study marks one of the world’s largest comprehensive genetic analysis of patients with end-stage renal failure using clinical data. As such, the conclusions derived from the results can have important implications in how CKD is diagnosed and managed in adults. “When the primary disease underlying a case of CKD is unknown, genetic analysis could lead to accurate diagnosis and appropriate treatment before the disease progresses, which could hopefully result in a decrease in the number of patients requiring dialysis,” highlights senior author Dr. Eisei Sohara. “Thus, proactive genetic analysis is recommended for adult patients without a definitive cause of CKD.”

Notably, this research group has been conducting genetic analyses of hereditary kidney diseases since 2014, reaching over 1,500 families. They have recently filed a patent for a new genetic analysis system for Japanese individuals, which would assist in correctly diagnosing cases of CKD. With any luck, further efforts will pave the way to a brighter future for people with inherited kidney diseases.

Source:

Tokyo Medical and Dental University

Journal reference:

Fujimaru, T., et al. (2024). Genetic Diagnosis of Adult Hemodialysis Patients With Unknown Etiology. Kidney International Reports. doi.org/10.1016/j.ekir.2024.01.027.

[ad_2]

Source link

April 3, 2024
Gut bacteria and tryptophan diet can play a protective role against pathogenic E. coli

[ad_1]

Gut bacteria and a diet rich in the amino acid tryptophan can play a protective role against pathogenic E. coli, which can cause severe stomach upset, cramps, fever, intestinal bleeding and renal failure, according to a study published March 13 in Nature.

The research reveals how dietary tryptophan – an amino acid found mostly in animal products, nuts, seeds, whole grains and legumes – can be broken down by gut bacteria into small molecules called metabolites. It turns out a few of these metabolites can bind to a receptor on gut epithelial (surface) cells, triggering a pathway that ultimately reduces the production of proteins that E. coli use to attach to the gut lining where they cause infection. When E. coli fail to attach and colonize the gut, the pathogen benignly moves through and passes out of the body.

The research describes a previously unknown role in the gut for a receptor, DRD2. DRD2 has otherwise been known as a dopamine (neurotransmitter) receptor in the central and peripheral nervous systems.

It’s actually two completely different areas that this receptor could play a role in, which was not appreciated prior to our findings. We essentially think that DRD2 is moonlighting in the gut as a microbial metabolite sensor, and then its downstream effect is to help protect against infection.”

Pamela Chang, associate professor of immunology in the College of Veterinary Medicine and of chemical biology in the College of Arts and Sciences

Samantha Scott, a postdoctoral researcher in Chang’s lab, is first author of the study, “Dopamine Receptor D2 Confers Colonization Resistance via Microbial Metabolites.”

Now that Chang, Scott and colleagues have identified a specific pathway to help prevent E. coli infection, they may now begin studying the DRD2 receptor and components of its downstream pathway for therapeutic targets.

In the study, the researchers used mice infected with Citrobacter rodentium, a bacterium that closely resembles E. coli, since certain pathogenic E. coli don’t infect mice. Through experiments, the researchers identified that there was less pathogen and inflammation (a sign of an active immune system and infection) after mice were fed a tryptophan-supplemented diet. Then, to show that gut bacteria were having an effect, they gave the mice antibiotics to deplete microbes in the gut, and found that the mice were infected by C. rodentium in spite of eating a tryptophan diet, confirming that protection from tryptophan was dependent on the gut bacteria.

Then, using mass spectrometry, they ran a screen to find the chemical identities of tryptophan metabolites in a gut sample, and identified three such metabolites that were significantly increased when given a tryptophan diet. Again, based on pathogen levels and inflammation, when these three metabolites alone were fed to the mice, they had the same protective effect as giving the mice a full tryptophan diet.

Switching gears, the researchers used bioinformatics to find which proteins (and receptors) might bind to the tryptophan metabolites, and from a long list they identified three related receptors within the same family of dopamine receptors. Using a human intestinal cell line in the lab, they were able to isolate receptor DRD2 as the one that had the protective effect against infection in the presence of tryptophan metabolites.

Having identified the metabolites and the receptor, they analyzed the downstream pathway of DRD2 in human gut epithelial cells. Ultimately, they found that when the DRD2 pathway was activated, the host’s ability to produce an actin regulatory protein was compromised. C. rodentium (and E. coli) require actin to attach themselves to gut epithelial cells, where they colonize and inject virulence factors and toxins into the cells that cause symptoms. But without actin polymerization they can’t attach and the pathogen passes through and clears.

The experiments revealed a new role of dopamine receptor DRD2 in the gut that controls actin proteins and affects a previously unknown pathway for preventing a pathogenic bacteria’s ability to colonize the gut.

Jingjing Fu, a former postdoctoral researcher in Chang’s lab, is a co-author.

The study was supported by the Arnold and Mabel Beckman Foundation, a President’s Council of Cornell Women Affinito-Stewart Grant, the National Institutes of Health and a Cornell Institute of Host-Microbe Interactions and Disease Postdoctoral Fellowship.

Source:

Journal reference:

Scott, S. A., et al. (2024). Dopamine receptor D2 confers colonization resistance via microbial metabolites. Nature. doi.org/10.1038/s41586-024-07179-5

[ad_2]

Source link

March 14, 2024
Does your diet increase the risk of recurring urinary tract infections?

[ad_1]

In a recent study published in JAMA Network Open, a group of researchers assessed the influence of behavioral risk factors such as diet, body weight, and lifestyle on the prevalence of urinary infections.

Study: Incidence of Urinary Infections and Behavioral Risk Factors. Image Credit: valiantsin suprunovich/Shutterstock.com

Background

Urinary infections, increasingly prevalent with over 404.6 million cases globally in 2019, significantly impact life quality and can lead to premature death if not managed well.

Risk factors commonly caused by bacteria like Escherichia coli include age, sexual behavior, female anatomy, immune suppression, and contraceptive methods. Antibiotic misuse exacerbates pathogen resistance, complicating treatment.

Untreated urinary tract infections (UTIs) can cause severe complications like pyelonephritis, renal failure, and risks during pregnancy. Recurrences are common and are influenced by various lifestyle and health factors.

Diet and lifestyle play crucial roles in prevention, with proper nutrition, hydration, and healthy habits essential in reducing recurrence risks and improving immune resistance.

Further research is necessary to understand better and effectively address the complex interplay of factors influencing the incidence and recurrence of urinary infections.

About the study

The present study, adopting a cross-sectional observational design, utilized a 39-item questionnaire to explore the frequency of urinary infections in relation to behavioral risk factors. Literature, expert opinions, and the target population’s characteristics informed the questionnaire’s development.

Distributed online between July and August 2023 through social media, WhatsApp, and institutional emails, the survey targeted employees and students across three Romanian university centers.

An emphasis was placed on anonymity and data protection to ensure participant confidentiality and accurate responses. Only individuals over 18 residing in Romania were included in the study, which received ethical approval from the University of Medicine and Pharmacy in Craiova.

The questionnaire’s validation involved a pilot study with 170 participants, overseen by experts in urology, nutrition, and survey design. Adjustments were made for clarity and precision, achieving a Cronbach’s α of 0.86 for consistency.

The study used Cochran’s formula to determine a sample size of 601, ensuring representative data with a 95% confidence level.

Following data collection, 1033 valid responses were analyzed. The questionnaire’s reliability was reaffirmed by a Cronbach α coefficient of 0.86. Descriptive statistics provided a baseline overview of the participants, while the chi-square test and correspondence analysis evaluated the impact of various factors on urinary infection frequency.

Multinomial logistic regression was employed to assess the influence of dietary habits on infection rates. The statistical analysis, ensuring significance at p-values less than 0.05, was conducted using XLSTAT and SPSS software, ensuring a thorough and reliable exploration of the study’s objectives.

Study results

In the study, researchers gathered 1,103 valid responses predominantly from women, who made up 80.1% of the participants.

Analysis of the anthropometric data revealed that 46.6% of respondents were of normal weight, predominantly women, whereas a significant proportion of male respondents were overweight or obese.

The study found that urinary infections were more common among women, a fact reflected in the gender distribution of the participants. Most respondents, 76.2%, were under 45 years old, and most hailed from urban areas, likely due to higher online activity in these regions.

Over 80% of the participants had postsecondary education or higher. In terms of employment, the largest group comprised those who commuted to work or worked in a hybrid mode, while a small fraction worked remotely.

The study found that individuals aged 26-35 were most prone to urinary infections, while those 18-25 reported the least.

It revealed a link between infection frequency and factors like sexual contact and showed that healthier diets, especially among women over 45, correlated with lower infection rates.

Further analysis using multiple linear regression showed that age, education level, weight, and urinary infection frequency significantly influenced dietary choices.

Younger individuals, rural residents, and those with lower education levels were more likely to adhere to an unhealthy diet. Additionally, underweight individuals and those with frequent urinary infections also tended towards less healthy dietary habits.

Sex and age were also significant factors in the frequency of UTIs. Women, especially in the 26–35 age group, reported more frequent infections.

In terms of treatment, many respondents first sought over-the-counter remedies, with some turning to medical consultation only after self-medication failed. Antibiotics and antifungals were common treatments, with antibiograms used frequently by those with recurrent infections.

The study also noted that common symptoms of urinary infections included frequent urination, burning sensations, and pain. Natural treatments like cranberry-based products and herbal teas were popular among respondents.

Sedentary lifestyles were linked to more frequent infections, highlighting the role of physical activity in preventing urinary infections.

[ad_2]

Source link

February 6, 2024