Animal models to study cognitive impairment of chronic kidney disease.

Mild cognitive impairment (MCI) is common in people with chronic kidney disease (CKD), and its prevalence increases with progressive loss of kidney function. MCI is characterized by a decline in cognitive performance greater than expected for an individual age and education level but with minimal impairment of instrumental activities of daily living. Deterioration can affect one or several cognitive domains (attention, memory, executive functions, language, and perceptual motor or social cognition). Given the increasing prevalence of kidney disease, more and more people with CKD will also develop MCI causing an enormous disease burden for these individuals, their relatives, and society. However, the underlying pathomechanisms are poorly understood, and current therapies mostly aim at supporting patients in their daily lives. This illustrates the urgent need to elucidate the pathogenesis and potential therapeutic targets and test novel therapies in appropriate preclinical models. Here, we will outline the necessary criteria for experimental modeling of cognitive disorders in CKD. We discuss the use of mice, rats, and zebrafish as model systems and present valuable techniques through which kidney function and cognitive impairment can be assessed in this setting. Our objective is to enable researchers to overcome hurdles and accelerate preclinical research aimed at improving the therapy of people with CKD and MCI.

The impact of chronic kidney disease on cognitive function.

PURPOSE OF REVIEW: The risk of cognitive impairment is higher in people with CKD than in the general population. The complex relationship between CKD and cognitive dysfunction has not been extensively characterized. Here, we review epidemiological associations, specific patterns of CKD-related cognitive impairment, the underlying mechanisms, and recently published data on relevant biomarkers. RECENT FINDINGS: Despite some discrepancies, recent published studies have confirmed that CKD is associated with cognitive function (e.g. incident cognitive events). Although patients with CKD often exhibit impairments in executive functions and attention, it is noteworthy that other cognitive functions (e.g. memory) can be preserved. The key mechanisms described recently include vascular damage, genetic factors, the accumulation of uremic toxins, disruption of the blood-brain barrier, glymphatic system dysfunction, and changes in the gut-brain axis. Kidney function is increasingly seen as a game changer in the interpretation of biomarkers of cognitive impairment and, especially, hallmarks of Alzheimer disease. SUMMARY: The data reviewed here highlight the need for interdisciplinary collaboration between nephrologists and neurologists in the care of patients with CKD at risk of cognitive impairment. In order to further improving diagnosis and therapy, future research must elucidate the mechanisms underlying the CKD-cognitive impairment association and confirm the value of biomarkers.

Sex and the Risk of Atheromatous and Nonatheromatous Cardiovascular Disease in CKD: Findings From the CKD-REIN Cohort Study.

RATIONALE & OBJECTIVE: Sex differences in cardiovascular disease (CVD) are well established, but whether chronic kidney disease (CKD) modifies these risk differences and whether they differ between atheromatous CVD (ACVD) and nonatheromatous CVD (NACVD) is unknown. Assessing this interaction was the principal goal of this study. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Adults enrolled in the CKD-REIN (CKD-Renal Epidemiology and Information Network) cohort, a nationally representative sample of 40 nephrology clinics in France, from 2013 to 2020. EXPOSURE: Sex. OUTCOMES: Fatal and nonfatal composite ACVD events (ischemic coronary, cerebral, and peripheral artery disease) and composite NACVD events (heart failure, hemorrhagic stroke, and arrhythmias). ANALYTICAL APPROACH: Multivariable cause-specific Cox proportional hazards models. RESULTS: 1,044 women and 1,976 men with moderate to severe CKD (median age, 67 vs 69y; mean estimated glomerular filtration rate [eGFR], 32±12 vs 33±12mL/min/1.73m2) were studied. During a median follow-up of 5.0 (IQR, 4.8-5.2) years, the ACVD rate (per 100 patient-years) was significantly lower in women than in men, at 2.1 (95% CI, 1.6-2.5) versus 3.6 (3.2-4.0; P<0.01), whereas the NACVD rate was not, at 5.7 (5.0-6.5) versus 6.4 (5.8-7.0; P=0.55). NACVD had a steeper relationship with eGFR than did ACVD. There was an interaction (P<0.01) between sex and baseline eGFR and the ACVD hazard: the adjusted HR for women versus men was 0.42 (0.25-0.71) at 45mL/min/1.73m2 and gradually attenuated at lower levels of eGFR, reaching 1.00 (0.62-1.63) at 16mL/min/1.73m2. In contrast, the NACVD hazard did not differ between sexes across the eGFR range studied. LIMITATIONS: Cardiovascular biomarkers and sex hormones were not assessed. CONCLUSIONS: This study shows how the lower risk of ACVD among women versus men attenuates fully with kidney disease progression. The equal risk of NACVD between sexes across CKD stages and its steeper association with eGFR suggest an important contribution of CKD to the development of this CVD type. PLAIN-LANGUAGE SUMMARY: Sex differences in the risks of atheromatous and nonatheromatous cardiovascular disease (CVD) are well established in the general population. If or how chronic kidney disease (CKD) might modify these risks is unknown. In this large cohort of 3,010 patients with CKD, women had a lower risk than men of atheromatous CVDs such as coronary artery disease or stroke when they were at an early stage of CKD. This advantage, partly due to women's better cardiovascular risk profile, tended to attenuate as CKD progressed to kidney failure. In contrast, the risk of nonatheromatous CVDs such as heart failure for women with CKD appeared similar to that of men with CKD at all kidney function levels.

Translational research on cognitive impairment in chronic kidney disease.

Cognitive decline is common in patients with acute or chronic kidney disease. Several areas of brain function can be affected, including short and long-term memory, attention and inhibitory control, sleep, mood, eating control and motor function. Cognitive decline in kidney disease shares risk factors with cognitive dysfunction in people without kidney disease, such as diabetes, high blood pressure, sedentary lifestyle and unhealthy diet. However, additional kidney-specific risk factors may contribute, such as uremic toxins, electrolyte imbalances, chronic inflammation, acid-base disorders or endocrine dysregulation. Traditional and kidney-specific risk factors may interact to cause damage to the blood-brain barrier, induce vascular damage in the brain, and cause neurotoxicity or neuroinflammation. Here, we discuss recent insights into the pathomechanisms of cognitive decline from animal models and novel avenues for prevention and therapy. We focus on a several areas that influence cognition: blood-brain barrier disruption, the role of skeletal muscle, physical activity and the endocrine factor irisin, and the emerging therapeutic role of sodium-glucose transporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists. Taken together, these studies demonstrate the importance of animal models in providing a mechanistic understanding of this complex condition and their potential to explain the mechanisms of novel therapies.

Haemoglobin trajectories in chronic kidney disease and risk of major adverse cardiovascular events.

BACKGROUND: The trajectories of haemoglobin in patients with chronic kidney disease (CKD) have been poorly described. In such patients, we aimed to identify typical haemoglobin trajectory profiles and estimate their risks of major adverse cardiovascular events (MACE). METHODS: We used 5-year longitudinal data from the CKD-REIN cohort patients with moderate to severe CKD enrolled from 40 nationally representative nephrology clinics in France. A joint latent class model was used to estimate, in different classes of haemoglobin trajectory, the competing risks of (i) MACE + defined as the first event among cardiovascular death, non-fatal myocardial infarction, stroke or hospitalization for acute heart failure, (ii) initiation of kidney replacement therapy (KRT) and (iii) non-cardiovascular death. RESULTS: During the follow-up, we gathered 33 874 haemoglobin measurements from 3011 subjects (median, 10 per patient). We identified five distinct haemoglobin trajectory profiles. The predominant profile (n = 1885, 62.6%) showed an overall stable trajectory and low risks of events. The four other profiles had nonlinear declining trajectories: early strong decline (n = 257, 8.5%), late strong decline (n = 75, 2.5%), early moderate decline (n = 356, 11.8%) and late moderate decline (n = 438, 14.6%). The four profiles had different risks of MACE, while the risks of KRT and non-cardiovascular death consistently increased from the haemoglobin decline. CONCLUSION: In this study, we observed that two-thirds of patients had a stable haemoglobin trajectory and low risks of adverse events. The other third had a nonlinear trajectory declining at different rates, with increased risks of events. Better attention should be paid to dynamic changes of haemoglobin in CKD.

The number of nephroprotection targets attained is associated with cardiorenal outcomes and mortality in patients with diabetic kidney disease. The CKD-REIN cohort study.

AIM: The risk of cardiorenal events remains high among patients with diabetes and chronic kidney disease (CKD), despite the prescription of recommended treatments. We aimed to determine whether the attainment of a combination of nephroprotection targets at baseline (glycated haemoglobin <7.0%, urinary albumin-creatinine ratio <300 mg/g, blood pressure <130/80 mmHg, renin-angiotensin system inhibition) was associated with better cardiorenal outcomes and lower mortality. MATERIALS AND METHODS: From the prospective French CKD-REIN cohort, we studied 1260 patients with diabetes and CKD stages 3-4 (estimated glomerular filtration rate: 15-60 ml/min/1.73 m2); 69% were men, and at inclusion, mean ± SD age: 70 ± 10 years; estimated glomerular filtration rate: 33 ± 11 ml/min/1.73 m2. The median follow-up was 4.9 years. RESULTS: In adjusted Cox regression models, the attainment of two nephroprotection targets was consistently associated with a lower risk of cardiorenal events [hazard ratio 0.70 (95% confidence interval 0.57-0.85)], incident kidney failure with replacement therapy [0.58 (0.43-0.77)], four major adverse cardiovascular events (cardiovascular death, myocardial infarction, stroke, hospitalization for heart failure) [0.75 (0.57-0.99)] and all-cause mortality [0.59 (0.42-0.82)] when compared with the attainment of zero or one target. For patients with a urinary albumin-creatinine ratio ≥300 mg/g, those who attained at least two targets had lower hazard ratios for cardiorenal events [0.61 (0.39-0.96)], four major adverse cardiovascular events [0.53 (0.28-0.98)] and all-cause mortality [0.35 (0.17-0.70)] compared with those who failed to attain any targets. CONCLUSIONS: These findings suggest that the attainment of a combination of nephroprotection targets is associated with better cardiorenal outcomes and a lower mortality rate in people with diabetic kidney disease.

Extracorporeal Techniques in Kidney Failure.

During the last decades, various strategies have been optimized to enhance clearance of a variable spectrum of retained molecules to ensure hemodynamic tolerance to fluid removal and improve long-term survival in patients affected by kidney failure. Treatment effects are the result of the interaction of individual patient characteristics with device characteristics and treatment prescription. Historically, the nephrology community aimed to provide adequate treatment, along with the best possible quality of life and outcomes. In this article, we analyzed blood purification techniques that have been developed with their different characteristics.

Kidney Function Decline and Serious Adverse Drug Reactions in Patients With CKD.

RATIONALE & OBJECTIVE: Adverse drug reactions (ADRs) are common in patients with chronic kidney disease (CKD). The impact of kidney function decline on serious ADR risk has been poorly investigated. We comprehensively describe ADRs and assess the relationship between estimated glomerular filtration rate (eGFR) and serious ADR risk. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 3,033 participants in French Chronic Kidney Disease-Renal Epidemiology and Information Network (CKD-REIN) cohort study, a nationwide sample of nephrology outpatients with moderate to advanced CKD. PREDICTORS: Demographic and biological data (including eGFR), medication prescriptions. OUTCOME: ADRs (preventable or not) were prospectively identified from hospital discharge reports, medical records, and patient interviews. Expert pharmacologists used validated tools to adjudicate ADRs. ANALYTICAL APPROACH: Restricted cubic splines in fully adjusted cause-specific Cox proportional hazard models were used to evaluate the relationship between eGFR and the risk of serious ADRs (overall and by subtype). RESULTS: During a median follow-up period of 4.7 years, 360 patients experienced 488 serious ADRs. Kidney and urinary disorders (n=170) and hemorrhage (n=170) accounted for 70% of serious ADRs. The most common medications classes were antithrombotics and renin-angiotensin system inhibitors. The majority of those serious ADRs were associated with hospitalization (n=467), with 32 directly or indirectly associated with death and 22 associated with a life-threatening event. More than 27% of the 488 serious ADRs were preventable or potentially preventable. The eGFR is a major risk factor for serious ADRs. The risk of acute kidney injury was 2.2% higher and risk of bleeding ADRs was 8% higher for each 1mL/min/1.73m2 lower baseline eGFR. LIMITATIONS: The results cannot be extrapolated to patients who are not being treated by a nephrologist. CONCLUSIONS: ADRs constitute a major cause of hospitalization in CKD patients for whom lower eGFR level is a major risk factor. PLAIN-LANGUAGE SUMMARY: Patients with chronic kidney disease (CKD) have complex clinical presentations, take multiple medications, and often receive inappropriate prescriptions. Using data from a large, prospective CKD cohort, we found a high incidence of serious adverse drug reactions (ADRs). The 2 most common serious ADRs were drug-induced acute kidney injury and bleeding. A large proportion of serious ADRs required hospital admission, and 11% led to death or were life threatening. Lower kidney function was a major risk factor for serious ADRs. Many of these serious ADRs were determined to be partly preventable through greater adherence to prescription guidelines. This report enhances our understanding of the potential toxicity of drugs taken by patients with moderate to advanced CKD. It emphasizes the importance of monitoring kidney function when prescribing drugs, particularly for high-risk medications such as antithrombotic agents.

Prevalence of prediabetes and undiagnosed diabetes in a large urban middle-aged population: the CARVAR 92 cohort.

BACKGROUND: The aim of this study was to assess the prevalence of prediabetes and unknown diabetes and its long-term change in a large middle-aged urban population. METHODS: We conducted a screening campaign between 2007 and 2018 for cardiovascular risk factors in the western suburbs of Paris including subjects aged 40-70 (CARVAR 92). Among subjects who reported no previous diabetes, prediabetes and undiagnosed diabetes were defined as follows: fasting plasma glucose (FPG) ≥ 6.1 mmol/l (110 mg/dl) and < 7 mmol/l (126 mg/dl) for prediabetes according to WHO criteria (FPG between 5.6 and 6.9 mmol/l according to ADA criteria) and FPG ≥ 7.0 mmol/l for undiagnosed diabetes. RESULTS: Of the 32,721 subjects in the CARVAR 92 cohort, 32,675 were included in this analysis. The median age of the patients was 56 years [30, 94], 45.4% were male, 5.9% had known diabetes, 36.4% were overweight and 18.7% obese. Among patients without previously known diabetes (n = 30,759), 8.1% had prediabetes according to WHO criteria (27.2% according to ADA criteria) and 2.3% had diabetes. Subjects with prediabetes and unknown diabetes were more likely to be male, older, and overweight or obese than non-diabetic subjects. From 2007 to 2018, the prevalence of prediabetes, unknown diabetes, and known diabetes decreased, except for prediabetes which remained stable for people aged 55-64. CONCLUSION: The prevalence of prediabetes and unknown diabetes remains high but decreased during a 12-year period. About one-quarter of diabetes cases remain undiagnosed. Our results highlight that there is still a room for screening and cardiovascular prevention campaigns. TRIAL REGISTRATION: IRB00012437.

Cognitive performance is associated with glomerular filtration rate in patients with chronic kidney disease: results from the CKD-REIN cohort.

BACKGROUND: Chronic kidney disease (CKD) is associated with cognitive impairment in general population. We assessed the association between kidney and cognitive functions in patients with CKD and the influence of cardiovascular (CV) risk factors, and depression on this association. METHODS: The CKD-Renal Epidemiology and Information Network cohort included 3033 patients with CKD stages 3-4, followed for 5 years. Cognitive function was assessed with the Mini-Mental State Examination (MMSE) and estimated glomerular filtration rate (eGFR) with the CKD-Epidemiology Collaboration equation-creatinin formula. Evolution of the MMSE score over time and its association with baseline eGFR were investigated with linear mixed models. We assessed the risk of incident cognitive outcome (hospitalisation or death with relevant International Classification of Disease-10 codes), with a Cox proportional hazard model. RESULTS: The mean age was 66.8, the mean eGFR was 33 mL/min/1.73 m2 and 387 patients (13.0%) had an MMSE score below 24 at baseline. A 10 mL/min/1.73 m2 decrement of baseline eGFR was associated with a mean MMSE decrease of 0.12 (95% CI 0.04 to 0.19) after adjustment for demographic characteristics, depression, CV risk factors and disease; but baseline eGFR was not associated with MMSE temporal evolution. HR for cognitive outcome during follow-up (median 2.01 years) associated with a 10 mL/min/1.73 m2 decrement of baseline eGFR was 1.35 (1.07, 1.70) (p=0.01) after adjustment. CONCLUSIONS: In patients with CKD, lower eGFR was associated with worse cognitive performance and incident cognitive events, independently of demographics, CV risk factors and depression. TRIAL REGISTRATION NUMBER: NCT03381950.

Comparison of homocitrulline and carbamylated albumin as biomarkers of carbamylation reactions in hemodialyzed patients.

To describe the association between levels of homocitrulline (HCit) and the degree of albumin carbamylation in a cohort of hemodialyzed patients. Plasma total and protein-bound HCit concentrations in samples from hemodialyzed patients included in NICOREN trial were determined by LC-MS/MS at baseline and after 24 weeks of treatment with either sevelamer or nicotinamide. HCit concentrations at all timepoints and in both groups were positively and significantly correlated with the degree of albumin carbamylation. Plasma concentrations of total HCit, protein-bound HCit and carbamylated albumin did not decrease after 24 weeks of treatment with either sevelamer or nicotinamide. The present results demonstrate that plasma total and protein-bound HCit concentrations were closely associated with albumin carbamylation in hemodialyzed patients. Therefore, total and protein-bound HCit concentrations might be valuable biomarkers of the overall intensity of protein carbamylation in this context. Given the less complex and time-consuming analytical methods required, these markers should be favored in future clinical studies of carbamylation reaction.

Factors influencing kidney transplantation rates: a study from the ERA Registry.

BACKGROUND: Large international differences exist in kidney transplantation (KT) rates. We aimed to investigate which factors may explain the total, deceased donor and living donor KT rates over the last decade. METHODS: KT experts from 39 European countries completed the Kidney Transplantation Rate Survey on measures and barriers and their potential effect on the KT rate in their country. In the analyses, countries were divided into low, middle and high KT rate countries based on the KT rate at the start of study period in 2010. RESULTS: Experts from low KT rate countries reported more frequently that they had taken measures regarding staff, equipment and facilities to increase the total KT rate compared with middle and high KT rate countries. For donor type-specific KT, the largest international differences in measures taken were reported for deceased donor KT, with middle and high KT rate countries taking more measures, such as the use of expanded criteria donor kidneys, the presence of transplantation coordinators and (inter)national exchange of donor kidneys. Once a measure was taken, experts' opinion on its success was similar across the low, middle and high KT rate countries. Experts from low KT rate countries more often reported potential barriers, such as patients' lack of knowledge and distrust in the healthcare system. CONCLUSIONS: Particularly in low KT rate countries, the KT rate might be stimulated by optimizing staff, equipment and facilities. In addition, all countries may benefit from measures specific to deceased and living donors.

A New Approach for Cognitive Impairment Pattern in Chronic Kidney Disease.

BACKGROUND AND HYPOTHESIS: Chronic kidney disease (CKD) is associated with an elevated risk of neurocognitive disorders (NCDs). It remains unclear whether CKD-related NCDs have specific cognitive pattern or are earlier-onset phenotypes of the main NCDs (vascular NCDs and Alzheimer's disease). METHODS: We used the Mini Mental State Examination score (MMSE) to assess cognitive pattern in 3003 CKD patients (stage 3 to 4) followed up over 5 years in the Chronic Kidney Disease-Renal Epidemiology and Information Network (CKD-REIN) cohort. After normalizing MMSE scores to a 0-to-100 scale, the associations between the baseline estimated glomerular filtration rate (eGFR, using the CKD-EPI-creatinine formula) and changes in each MMSE domain score were assessed in linear mixed models. RESULTS: Patients (age: 67±13 years old; males: 65%, mean eGFR: 33±12 ml/min/1.73 m²) had a good baseline cognitive functions: the mean MMSE score was 26.9/30 ±2.9. After adjustment for age, sex, educational level, depression (past or present), cardiovascular risk factors, cerebrovascular disease, a lower baseline eGFR (per 10 ml/min/1.73 m²) was associated with a 0.53-point decrement (p<0.001; 95%CI [-0.98,-0.08]) for orientation, a 1.04-point decrement (p=0.03; 95%CI [-1.96,-0.13]) for attention and calculation, a 0.78-point decrement (p=0.003; 95%CI [-1.30,-0.27]) for language, and a 0.94-point decrement (p=0.02; 95%CI [-1.75,-0.13]) for praxis. Baseline eGFR was not, however, associated with significant changes over time in MMSE domain scores. CONCLUSION: A lower eGFR in CKD patients was associated with early impairments in certain cognitive domains: praxis, language and attention domains before an obvious cognitive decline. Early detection of NCD in CKD patients must be perform before clinically cognitive decline using preferably tests assessing executive, attentional functions and language than memory test. This could lead to a better management of cognitive impairment and their consequences on CKD management.

Preparing European Nephrology for the next pandemic: lessons from the ERACODA collaboration.

Owing to the vulnerability of patients with chronic kidney disease to infectious diseases, the coronavirus disease 2019 (COVID-19) pandemic has been particularly devastating for the nephrology community. Unfortunately, the possibility of future COVID-19 waves or outbreaks of other infectious diseases with pandemic potential cannot be ruled out. The nephrology community made tremendous efforts to contain the consequences of the COVID-19 pandemic. Despite this, the COVID-19 pandemic has highlighted several shortcomings in our response to the pandemic and has taught us important lessons that can be utilized to improve our preparedness for any future health crises of a similar nature. In this article we draw lessons from the European Renal Association COVID-19 Database (ERACODA) project, a pan-European collaboration initiated in March 2020 to understand the prognosis of COVID-19 in patients on kidney function replacement therapy. We discuss the challenges faced in generating timely and robust evidence for informed management of patients with kidney disease and give recommendations for our preparedness for the next pandemic in Europe. Limited collaboration, the absence of common data architecture and the sub-optimal quality of available data posed challenges in our response to COVID-19. Aligning different research initiatives, strengthening electronic health records, and involving experts in study design and data analysis will be important in our response to the next pandemic. The European Renal Association may take a leading role in aligning research initiatives via its engagement with other scientific societies, national registries, administrators and researchers.

Cognitive disorders in patients with chronic kidney disease: Approaches to prevention and treatment.

BACKGROUND: Cognitive impairment is common in patients with chronic kidney disease (CKD), and early intervention may prevent the progression of this condition. METHODS: Here, we review interventions for the complications of CKD (anemia, secondary hyperparathyroidism, metabolic acidosis, harmful effects of dialysis, the accumulation of uremic toxins) and for prevention of vascular events, interventions that may potentially be protective against cognitive impairment. Furthermore, we discuss nonpharmacological and pharmacological methods to prevent cognitive impairment and/or minimize the latter's impact on CKD patients' daily lives. RESULTS: A particular attention on kidney function assessment is suggested during work-up for cognitive impairment. Different approaches are promising to reduce cognitive burden in patients with CKD but the availabe dedicated data are scarce. CONCLUSIONS: There is a need for studies assessing the effect of interventions on the cognitive function of patients with CKD.

International practice patterns of dyslipidemia management in patients with chronic kidney disease under nephrology care: is it time to review guideline recommendations?

BACKGROUND: In contrast to guidelines related to lipid therapy in other areas, 2012 Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend conducting a lipid profile upon diagnosis of chronic kidney disease (CKD) and treating all patients older than 50 years without defining a target for lipid levels. We evaluated multinational practice patterns for lipid management in patients with advanced CKD under nephrology care. METHODS: We analyzed lipid-lowering therapy (LLT), LDL- cholesterol (LDL-C) levels, and nephrologist-specified LDL-C goal upper limits in adult patients with eGFR < 60 ml/min from nephrology clinics in Brazil, France, Germany, and the United States (2014-2019). Models were adjusted for CKD stage, country, cardiovascular risk indicators, sex, and age. RESULTS: LLT treatment differed significantly by country, from 51% in Germany to 61% in the US and France (p = 0.002) for statin monotherapy. For ezetimibe with or without statins, the prevalence was 0.3% in Brazil to 9% in France (< 0.001). Compared with patients not taking lipid-lowering therapy, LDL-C was lower among treated patients (p < 0.0001) and differed significantly by country (p < 0.0001). At the patient level, the LDL-C levels and statin prescription did not vary significantly by CKD stage (p = 0.09 LDL-C and p = 0.24 statin use). Between 7-23% of untreated patients in each country had LDL-C ≥ 160 mg/dL. Only 7-17% of nephrologists believed that LDL-C should be < 70 mg/dL. CONCLUSION: There is substantial variation in practice patterns regarding LLT across countries but not across CKD stages. Treated patients appear to benefit from LDL-C lowering, yet a significant proportion of hyperlipidemia patients under nephrologist care are not receiving treatment.

Proposal for a New Classification of Solutes of Interest in Uremia and Hemodialysis.

Uremic toxins contribute to clinical manifestations of kidney dysfunction. These toxins include organic and inorganic elements or compounds. While the kidney typically clears uremic toxins, gut dysbiosis, and tissue inflammation could lead to increased production of substances that can further the clinical manifestations of uremia. The uremic toxins are quantitatively measurable in biological fluids and have an established relationship with azotemia signs and symptoms. Their elimination is associated with mitigated uremic manifestations, while their administration to the uremic levels leads to uremic signs in animal or human models or in vitro studies. Besides, the uremic toxins have an established and plausible pathophysiologic relationship with uremic manifestations. The previous classification of uremic toxins was mainly focused on the physicochemical characteristics of these substances to divide them into three categories, (1) free water-soluble low-molecular-weight (<500 Da) solutes, (2) protein-bound, water-soluble, low molecular weight (<500 Da), (3) middle molecular weight (>500 Da and <12,000 Da), and (4) high molecular weight (>12,000 Da). Unfortunately, the classification named above was not centered around patient outcomes and quality of life among those with severe kidney failure. Therefore, a panel of experts convened virtually to provide additional insights into the current state and propose a new uremic toxin classification. This article describes the group's consensus recommendations regarding the new classification of uremic toxins into more clinically oriented categories.

The Role of Uremic Retention Solutes in the MIA Syndrome in Hemodialysis Subjects.

INTRODUCTION: In chronic kidney disease (CKD), the high morbidity and mortality risk for cardiovascular disease (CVD) are not easily explained only on the basis of traditional factors. Among nontraditional ones involved in CKD, malnutrition, inflammation, and atherosclerosis/calcification have been described as the "MIA syndrome." METHODS: In this pilot study, we evaluated the association between the variation in serum levels of 27 uremic retention solutes plus 6 indexes related to the MIA syndrome processes in a population of dialysis patients. RESULTS: As expected, we found a direct correlation between serum albumin and both phosphate and total cholesterol (r = 0.54 and 0.37, respectively; p < 0.05). Moreover, total cholesterol and phosphate directly correlate (r = 0.40, p < 0.05). The relationship between malnutrition and inflammation is highlighted by the correlation of serum cholesterol levels with serum alpha-1 acid glycoprotein and IL-6 levels (r = -0.56, r = -0.39, respectively; p < 0.05). Moreover, the relation between inflammation and atherosclerosis/calcification is supported by the correlation of IL-6 with VEGF levels and vascular smooth muscle cell high-Pi in vitro calcification (r = 0.81, r = 0.66, respectively; p < 0.01). CONCLUSION: We found significant correlations between several uremic retention solutes and malnutrition, inflammation, and atherosclerosis/calcification. Our findings support the hypothesis of a central role of the uremic milieu in the MIA syndrome and ultimately in the pathogenesis of CKD-specific CVD risk factors.

Kidney Histopathology Can Predict Kidney Function in ANCA-Associated Vasculitides with Acute Kidney Injury Treated with Plasma Exchanges.

BACKGROUND: Data from the PEXIVAS trial challenged the role of plasma exchange (PLEX) in ANCA-associated vasculitides (AAV). We aimed to describe kidney biopsy from patients with AAV treated with PLEX, evaluate whether histopathologic findings could predict kidney function, and identify which patients would most benefit from PLEX. METHODS: We performed a multicenter, retrospective study on 188 patients with AAV and AKI treated with PLEX and 237 not treated with PLEX. The primary outcome was mortality or KRT at 12 months (M12). RESULTS: No significant benefit of PLEX for the primary outcome was found. To identify patients benefitting from PLEX, we developed a model predicting the average treatment effect of PLEX for an individual depending on covariables. Using the prediction model, 223 patients had a better predicted outcome with PLEX than without PLEX, and 177 of them had >5% increased predicted probability with PLEX compared with without PLEX of being alive and free from KRT at M12, which defined the PLEX-recommended group. Risk difference for death or KRT at M12 was significantly lower with PLEX in the PLEX-recommended group (-15.9%; 95% CI, -29.4 to -2.5) compared with the PLEX not recommended group (-4.8%; 95% CI, 14.9 to 5.3). Microscopic polyangiitis, MPO-ANCA, higher serum creatinine, crescentic and sclerotic classes, and higher Brix score were more frequent in the PLEX-recommended group. An easy to use score identified patients who would benefit from PLEX. The average treatment effect of PLEX for those with recommended treatment corresponded to an absolute risk reduction for death or KRT at M12 of 24.6%. CONCLUSIONS: PLEX was not associated with a better primary outcome in the whole study population, but we identified a subset of patients who could benefit from PLEX. However, these findings must be validated before utilized in clinical decision making.

Sortilin, carbamylation, and cardiovascular calcification in chronic kidney disease.

Sortilin appears to play important roles in the pathogenesis of vascular and metabolic diseases, such as cardiovascular calcification. Post-translational modifications of sortilin (i.e., phosphorylation or carbamylation) are among the key mechanisms of its actions. Recent data extended the role of carbamylated sortilin to the pathogenesis of cardiovascular calcifications in chronic kidney disease. Whether therapeutic tools potentially available to inhibit the carbamylation process in chronic kidney disease patients would allow preventing cardiovascular calcifications remains to be demonstrated.