Effects of uremic toxins on hippocampal synaptic transmission: implication for neurodegeneration in chronic kidney disease

AbstractPatients affected by chronic kidney disease (CKD) have an increased risk of developing cognitive impairment. The cause of mental health disorders in CKD and in chronic hemodialysis patients is multifactorial, due to the interaction of classical cardiovascular disease risk factors, kidney- and dialysis-related risk factors with depression, and multiple drugs overuse. A large number of compounds, defined as uremic toxins that normally are excreted by healthy kidneys, accumulate in the circulations, in the tissues, and in the organs of CKD patients. Among the candidate uremic toxins are several guanidino compounds, such as Guanidine. Uremic toxins may also accumulate in the brain and may have detrimental effects on cerebral resident cells (neurons, astrocytes, microglia) and microcirculation. The present study aims to analyze the effect of Guanidine on hippocampal excitatory postsynaptic field potentials (fEPSPs) and in CA1 pyramidal neurons recorded intracellularly. Moreover, we compared these effects with the alterations induced in vitro by CKD patients derived serum samples. Our results show an increased, dose-dependent, synaptic activity in the CA1 area in response to both synthetic Guanidine and patient’s serum, through a mechanism involving glutamatergic transmission. In particular, the concomitant increase of both NMDA and AMPA component of the excitatory postsynaptic currents (EPSCs) suggests a presynaptic mechanism. Interestingly, in presence of the lower dose of guanidine, we measure a significant reduction of EPSCs, in fact the compound does not inhibit GABA receptors allowing their inhibitory effect of glutamate release. These findings suggest that cognitive symptoms induced by the increase of uremic compounds in the serum of CKD patients are caused, at least in part, by an increased glutamatergic transmission in the hippocampus.

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Abstract MP74: Long Term Risk-Factor Profiles for Chronic Kidney Disease in the Framingham Heart Study

Circulation ◽

10.1161/circ.127.suppl_12.amp74 ◽

2013 ◽

Vol 127 (suppl_12) ◽

Author(s):

Gearoid M McMahon ◽

Sarah R Preis ◽

Shih-Jen Hwang ◽

Caroline S Fox

Keyword(s):

Risk Factors ◽

Chronic Kidney Disease ◽

Risk Factor ◽

Kidney Disease ◽

Framingham Heart Study ◽

Disease Risk ◽

Cardiovascular Disease Risk ◽

Standard Deviation Increase ◽

Heart Study ◽

Increased Risk

Background: Chronic Kidney Disease (CKD) is an important public health issue and is associated with an increased risk of cardiovascular disease. Risk factors for CKD are well established, but most are typically assessed at or near the time of CKD diagnosis. Our hypothesis was that risk factors for CKD are present earlier in the course of the disease. We compared the prevalence of risk factors between CKD cases and controls at time points up to 30 years prior to CKD diagnosis. Methods: Participants were drawn from the Framingham Heart Study Offspring cohort. CKD was defined as an estimated glomerular filtration rate of ≤60ml/min/1.73m2. Incident CKD cases occurring at examination cycles 6, 7, and 8 were age- and sex-matched 1:2 to controls. Risk factors including systolic blood pressure (SBP), hypertension, lipids, diabetes, smoking status, body mass index (BMI) and dipstick proteinuria were measured at the time of CKD diagnosis and 10, 20 and 30 years prior. Logistic regression models, adjusted for age, sex, and time period, were constructed to compare risk factor profiles at each time point between cases and controls Results: During follow-up, 441 new cases of CKD were identified and these were matched to 882 controls (mean age 69.2 years, 52.4% women). Up to 30 years prior to CKD diagnosis, those who ultimately developed CKD were more likely to have hypertension (OR 1.74, CI 1.21-2.49), be obese (OR 1.74, CI 1.15-2.63) and have higher triglycerides (OR 1.43, CI 1.12-1.84, p=0.005 per 1 standard deviation increase). Each 10mmHg increase in SBP was associated with an OR of 1.22 for future CKD (95% CI 1.10-1.35) Additionally, cases were more likely to have diabetes (OR 2.90, CI 1.59-5.29) and be on antihypertensive therapy (OR 1.65, CI 1.14-2.40, p=0.009) up to 20 years prior to diagnosis. Increasing HDLc was associated with a lower risk of CKD (OR 0.84, CI 0.81-0.97 per 10mg/dl). Conclusions: As many as 30 years prior to diagnosis, risk factors for CKD are identifiable. In particular, modifiable risk factors such as obesity, hypertension and dyslipidemia are present early in the course of the disease. These findings demonstrate the importance of early identification of risk factors in patients at risk of CKD through a life-course approach.

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Cardiotoxicity of Uremic Toxins: A Driver of Cardiorenal Syndrome

Toxins ◽

10.3390/toxins10090352 ◽

2018 ◽

Vol 10 (9) ◽

pp. 352 ◽

Cited By ~ 24

Author(s):

Suree Lekawanvijit

Keyword(s):

Risk Factors ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Heart Rhythm ◽

Cardiorenal Syndrome ◽

Uremic Toxins ◽

Excretory Function ◽

Heart Rhythm Disorders ◽

Increased Risk ◽

Uremic Cardiomyopathy

Cardiovascular disease (CVD) is highly prevalent in the setting of chronic kidney disease (CKD). Such coexistence of CVD and CKD—the so-called “cardiorenal or renocardiac syndrome”—contributes to exponentially increased risk of cardiovascular (CV) mortality. Uremic cardiomyopathy is a characteristic cardiac pathology commonly found in CKD. CKD patients are also predisposed to heart rhythm disorders especially atrial fibrillation. Traditional CV risk factors as well as known CKD-associated CV risk factors such as anemia are insufficient to explain CV complications in the CKD population. Accumulation of uremic retention solutes is a hallmark of impaired renal excretory function. Many of them have been considered inert solutes until their biological toxicity is unraveled and they become accepted as “uremic toxins”. Direct cardiotoxicity of uremic toxins has been increasingly demonstrated in recent years. This review offers a mechanistic insight into the pathological cardiac remodeling and dysfunction contributed by uremic toxins with a main focus on fibroblastic growth factor-23, an emerging toxin playing a central role in the chronic kidney disease–mineral bone disorder, and the two most investigated non-dialyzable protein-bound uremic toxins, indoxyl sulfate and p-cresyl sulfate. Potential therapeutic strategies that could address these toxins and their relevant mediated pathways since pre-dialysis stages are also discussed.

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Stroke in chronic renal failure

Orvosi Hetilap ◽

10.1556/oh.2008.28292 ◽

2008 ◽

Vol 149 (15) ◽

pp. 691-696

Author(s):

Dániel Bereczki

Keyword(s):

Risk Factors ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Renal Disease ◽

Chronic Renal Disease ◽

Kidney Diseases ◽

Cerebrovascular Diseases ◽

Lipid Lowering ◽

Increased Risk ◽

Intracerebral Hemorrhages

Chronic kidney diseases and cardiovascular diseases have several common risk factors like hypertension and diabetes. In chronic renal disease stroke risk is several times higher than in the average population. The combination of classical risk factors and those characteristic of chronic kidney disease might explain this increased risk. Among acute cerebrovascular diseases intracerebral hemorrhages are more frequent than in those with normal kidney function. The outcome of stroke is worse in chronic kidney disease. The treatment of stroke (thrombolysis, antiplatelet and anticoagulant treatment, statins, etc.) is an area of clinical research in this patient group. There are no reliable data on the application of thrombolysis in acute stroke in patients with chronic renal disease. Aspirin might be administered. Carefulness, individual considerations and lower doses might be appropriate when using other treatments. The condition of the kidney as well as other associated diseases should be considered during administration of antihypertensive and lipid lowering medications.

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THU0300 RISK FACTORS FOR COMPLICATIONS AND REFRACTORY COURSE IN PATIENTS WITH ANCA-ASSOCIATED SYSTEMIC VASCULITIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.6460 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 378.2-378

Author(s):

A. Chudinov ◽

I. Belyaeva ◽

M. Pervakova ◽

V. Mazurov ◽

O. Inamova ◽

...

Keyword(s):

Risk Factors ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Induction Therapy ◽

Granulomatosis With Polyangiitis ◽

Disease Risk ◽

Systemic Vasculitis ◽

Cardiovascular Complications ◽

Infectious Complications ◽

Eosinophilic Granulomatosis With Polyangiitis

Background:ANCA-associated systemic vasculitis (AAV) is characterized by a high incidence of complications and high mortality. The most significant complications during the first 3 years of the disease are infectious and cardiovascular. Development of chronic kidney disease also impairs the prognosis of AAV. Refractory to induction therapy can significantly increase the severity of organ lesions in patients with AAV.Objectives:The aim of this study was to determine risk factors for complications and refractory course in patients with AAV.Methods:Patients with granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA) were observed during the first 3 years of the disease and included in this study between 2010 and 2018. Most common infectious complications requiring inpatient treatment were pneumonia, mycosis, sepsis, purulent arthritis, purulent otitis media. Cardiovascular complications included pulmonary thromboembolism, myocardial infarction, ischemic stroke, venous thrombosis.Results:In total 209 (165 [79%] female and mean age 51.8 ± 13.2 years) AAV patients (94 GPA; 46 MPA; and 69 EGPA) were included in the analysis. Risk factors for infectious complications were BVAS level at the beginning of induction therapy > 25 (OR – 2.92, 95% CI (1.53;5.45) p<0.001), usage of prednisone in doses more than 60 mg / day at the induction of remission (OR – 2.76, 95% CI (1.45;5.29) p=0.003), usage of prednisone in doses ≥ 10 mg / day after 6 months of induction therapy (OR – 2.60, 95% CI (1.38;4.93) p=0.003), ANCA-PR3 positivity (OR – 2.25, 95% CI (1.13;4.46) p=0.017) and presence of diabetes mellitus in the AAV onset (OR – 1.77, 95% CI (1.14;3.45) p=0.038). Patients with AAV had following risk factors for cardiovascular complications: male (OR – 2.28, 95% CI (1.33;3.88) p=0.002), BVAS level > 25 (OR – 2.1, 95% CI (1.11;3.16) p=0.008) and presence of coronary artery disease in the AAV onset (OR – 2.2, 95% CI (1.18;4.10) p=0.015). ANCA positivity (OR – 5.62, 95% CI (2.1;14.9) p<0.001), presence of rapidly progressive glomerulonephritis in the first 3 months from onset AAV (OR – 5.02, 95% CI (3.42;7.35) p<0.001) and over 60 years of age (OR – 2.17, 95% CI (1.38;3.44) p=0.001) were risk factors of development of chronic kidney disease. Risk factors for refractory to induction therapy in patients with AAV were ANCA-PR3 positivity (OR – 3.13, 95% CI (1.63;6.02) p<0.001), BVAS level > 25 (OR – 2.63, 95% CI (1.74;4.34) p<0.001), initiation of therapy after 4 months from the onset of clinical manifestations (OR – 2.17, 95% CI (1.26;3.91) p=0.005). We additionally defined that identification of pathological phenotypes of alpha-1-antitrypsin was risk factors for refractory course in patients with GPA manifestations (OR – 2.66, 95% CI (1.12;6.33) p=0.048).Conclusion:Our study has shown that high disease activity, ANCA positivity and comorbid pathology increase risk of serious complications. Early administration of immunosuppressive therapy, adequate steroid dosing and use of risk factors for complications and refractory course in clinical practice can significantly improve the prognosis of AAV.Disclosure of Interests:None declared

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Current aspects of the development and progression of fluoride-related chronic kidney disease

Voprosy praktičeskoj pediatrii ◽

10.20953/1817-7646-2021-3-84-91 ◽

2021 ◽

Vol 16 (3) ◽

pp. 84-91

Author(s):

N.S. Morozova ◽

◽

Ad.A. Mamedov ◽

D.Yu. Lakomova ◽

L.D. Maltseva ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Molecular Markers ◽

Kidney Disease ◽

Disease Risk ◽

Chemical Elements ◽

Fluoride Concentration ◽

Underlying Disease ◽

Cochrane Library ◽

Increased Risk ◽

Asymptomatic Phase

Difficulties associated with the identification of a major risk factor for chronic kidney disease (CKD) (mainly in children without obvious anatomical causes), long-lasting asymptomatic phase, and irreversible kidney damage caused by chemical elements resulted in a particular interest to the problem of diagnosis and timely treatment of CKD. This review aims to summarize available information on the role of increased fluoride concentration in the development of CKD of uncertain etiology. We included more than 200 publications found in Scopus, Web of Science, Cochrane Library, and PubMed. We analyzed factors associated with an increased risk of fluoride-related CKD and identified possible mechanisms underlying disease progression. In addition to that, we proposed potential molecular markers to detect early stages of CKD. We described new promising therapeutic targets with the consideration of key elements of disease pathogenesis, poor prognosis, and age limits for existing nephroprotective drugs. Key words: fluoride, chronic kidney disease, risk factors, pathogenesis, molecular markers

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The obese patient (metabolic syndrome)

10.1093/med/9780199592548.003.0168 ◽

2015 ◽

Author(s):

Maarit Korkeila ◽

Bengt Lindholm ◽

Peter Stenvinkel

Keyword(s):

Risk Factors ◽

Metabolic Syndrome ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Overweight And Obesity ◽

Blood Cholesterol ◽

Long Term Effects ◽

Reverse Epidemiology ◽

Increased Risk

Overweight and obesity cause pathophysiological changes in renal function and increase the risk for chronic kidney disease in otherwise healthy subjects. This should not be a surprise as the risk factors for metabolic syndrome largely overlap with those for chronic kidney disease. Intentional weight loss has beneficial effects on risk factors, but long term effects are less clear. Bariatric surgery does seem to achieve rapid benefits on blood pressure and proteinuria as well as on other aspects of metabolic syndrome, but its long term implications for kidney function are less clear cut as there may be an increased risk of nephrolithiasis, and possibly AKI and other complications.Obesity in haemodialysis patients is one of those paradoxical examples of reverse epidemiology where a factor associated with negative outcomes in the general population is associated with better outcomes in dialysis patients. The same is true for high blood cholesterol values. Interpretation is complicated by complex competing outcomes and confounders.

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Associations of Urine Biomarkers with Kidney Function Decline in HIV-Infected and Uninfected Men

American Journal of Nephrology ◽

10.1159/000502898 ◽

2019 ◽

Vol 50 (5) ◽

pp. 401-410 ◽

Cited By ~ 4

Author(s):

Simon B. Ascher ◽

Rebecca Scherzer ◽

Michelle M. Estrella ◽

Michael G. Shlipak ◽

Derek K. Ng ◽

...

Keyword(s):

Risk Factors ◽

Kidney Disease ◽

Kidney Function ◽

Disease Risk ◽

Kidney Injury ◽

Procollagen Type ◽

Urine Albumin ◽

Urine Biomarkers ◽

Increased Risk ◽

Egfr Decline

Background: HIV-infected (HIV+) persons are at increased risk of chronic kidney disease, but serum creatinine does not detect early losses in kidney function. We hypothesized that urine biomarkers of kidney damage would be associated with subsequent changes in kidney function in a contemporary cohort of HIV+ and HIV-uninfected (HIV–) men. Methods: In the Multicenter AIDS Cohort Study, we measured baseline urine concentrations of 5 biomarkers from 2009 to 2011 in 860 HIV+ and 337 HIV– men: albumin, alpha-1-microglobulin (α1m), interleukin-18 (IL-18), kidney injury molecule-1 (KIM-1), and procollagen type III N-terminal propeptide (PIIINP). We evaluated associations of urine biomarker concentrations with annual changes in estimated glomerular filtration rate (eGFR) using multivariable linear mixed models adjusted for demographics, traditional kidney disease risk factors, HIV-related risk factors, and baseline eGFR. Results: Over a median follow-up of 4.8 years, the average annual eGFR decline was 1.42 mL/min/1.73 m2/year in HIV+ men and 1.22 mL/min/1.73 m2/year in HIV– men. Among HIV+ men, the highest vs. lowest tertiles of albumin (–1.78 mL/min/1.73 m2/year, 95% CI –3.47 to –0.09) and α1m (–2.43 mL/min/1.73 m2/year, 95% CI –4.14 to –0.73) were each associated with faster annual eGFR declines after multivariable adjustment. Among HIV– men, the highest vs. lowest tertile of α1m (–2.49 mL/min/1.73 m2/year, 95% CI –4.48 to –0.50) was independently associated with faster annual eGFR decline. Urine IL-18, KIM-1, and PIIINP showed no independent associations with eGFR decline, regardless of HIV serostatus. Conclusions: Among HIV+ men, higher urine albumin and α1m are associated with subsequent declines in kidney function, independent of eGFR.

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The first consecutive 5000 patients with Coronavirus Disease 2019 from Qatar; a nation-wide cohort study

BMC Infectious Diseases ◽

10.1186/s12879-020-05511-8 ◽

2020 ◽

Vol 20 (1) ◽

Cited By ~ 1

Author(s):

Ali S. Omrani ◽

Muna A. Almaslamani ◽

Joanne Daghfal ◽

Rand A. Alattar ◽

Mohamed Elgara ◽

...

Keyword(s):

Risk Factors ◽

Chronic Kidney Disease ◽

Cohort Study ◽

Kidney Disease ◽

Older Age ◽

Icu Admission ◽

Increased Risk ◽

All Cause Mortality ◽

Male Sex

Abstract Background There are limited data on Coronavirus Disease 2019 (COVID-19) outcomes at a national level, and none after 60 days of follow up. The aim of this study was to describe national, 60-day all-cause mortality associated with COVID-19, and to identify risk factors associated with admission to an intensive care unit (ICU). Methods This was a retrospective cohort study including the first consecutive 5000 patients with COVID-19 in Qatar who completed 60 days of follow up by June 17, 2020. The primary outcome was all-cause mortality at 60 days after COVID-19 diagnosis. In addition, we explored risk factors for admission to ICU. Results Included patients were diagnosed with COVID-19 between February 28 and April 17, 2020. The majority (4436, 88.7%) were males and the median age was 35 years [interquartile range (IQR) 28–43]. By 60 days after COVID-19 diagnosis, 14 patients (0.28%) had died, 10 (0.2%) were still in hospital, and two (0.04%) were still in ICU. Fatal COVID-19 cases had a median age of 59.5 years (IQR 55.8–68), and were mostly males (13, 92.9%). All included pregnant women (26, 0.5%), children (131, 2.6%), and healthcare workers (135, 2.7%) were alive and not hospitalized at the end of follow up. A total of 1424 patients (28.5%) required hospitalization, out of which 108 (7.6%) were admitted to ICU. Most frequent co-morbidities in hospitalized adults were diabetes (23.2%), and hypertension (20.7%). Multivariable logistic regression showed that older age [adjusted odds ratio (aOR) 1.041, 95% confidence interval (CI) 1.022–1.061 per year increase; P < 0.001], male sex (aOR 4.375, 95% CI 1.964–9.744; P < 0.001), diabetes (aOR 1.698, 95% CI 1.050–2.746; P 0.031), chronic kidney disease (aOR 3.590, 95% CI 1.596–8.079, P 0.002), and higher BMI (aOR 1.067, 95% CI 1.027–1.108 per unit increase; P 0.001), were all independently associated with increased risk of ICU admission. Conclusions In a relatively younger national cohort with a low co-morbidity burden, COVID-19 was associated with low all-cause mortality. Independent risk factors for ICU admission included older age, male sex, higher BMI, and co-existing diabetes or chronic kidney disease.

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Retrospective evaluation of risk factors and treatment outcome predictors in cats presenting to the emergency room for constipation

Journal of Feline Medicine and Surgery ◽

10.1177/1098612x19832663 ◽

2019 ◽

Vol 22 (2) ◽

pp. 153-160 ◽

Cited By ~ 2

Author(s):

Sarah E Benjamin ◽

Kenneth J Drobatz

Keyword(s):

Risk Factors ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Physical Examination ◽

Emergency Room ◽

Treatment Protocol ◽

Urgent Care ◽

Hospital Data ◽

Increased Risk ◽

Clinicopathologic Findings

Objectives Constipation is a common complaint in cats presenting to the emergency room and can become a frustrating recurrent condition. Despite widespread anecdotal reports of risk factors for constipation, at the time of writing there have been no studies supporting these associations or assessing treatment outcomes. The aim of this study was to identify risk factors in the signalment, history, physical examination and clinicopathologic findings of cats presenting to the emergency room for constipation. In addition, we aimed to assess factors contributing to the success or failure of enemas administered to these cats. Methods A medical record search identified 189 cats with a diagnosis of constipation/obstipation that were treated and discharged by the emergency service at an academic veterinary hospital. Data regarding signalment, medical history, physical examination and clinicopathologic findings, as well as treatments performed, were recorded. Ninety-nine cats presenting to the emergency room for other reasons were identified as controls. Statistical analysis was performed to assess risk factors for constipation, as well as success/failure of enema treatments. Results Older, overweight cats and cats with chronic kidney disease or previous episodes of constipation were found to be at increased risk of constipation ( P <0.0001, P = 0.0004, P = 0.0046 and P <0.0001, respectively). Ionized calcium levels were significantly higher in constipated cats, though varied significantly within the cohort ( P = 0.0133). Cats noted to be painful on abdominal palpation were less likely to defecate following an enema. Adjunctive treatments (fluids, laxatives) increased the likelihood of a successful enema but were not statistically significant. Conclusions and relevance Older, overweight cats with a history of constipation or chronic kidney disease are more likely to present for constipation. Further studies are needed to determine the most appropriate treatment protocol in an urgent care setting.

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