Why Do Patients With Well-Controlled Vascular Risk Factors Develop Progressive Chronic Kidney Disease?

Aggressive blood pressure reduction and renin–angiotensin system blockade in chronic kidney disease: time for re-evaluation?

On Being Better Kidney Doctors: Understanding Trajectories, Probabilities, Predictability, and People

α-Klotho and Kidney Function Decline: An Important Step Forward in Understanding the Link Between Mineral Metabolism and Kidney Disease Progression

Randomized controlled trials have demonstrated the efficacy of mineralocorticoid receptor (MR) antagonism in delaying chronic kidney disease (CKD) progression in diabetes; however, they have not investigated the role of aldosterone or whether these beneficial effects could be achieved in individuals without diabetes. The association between serum aldosterone concentrations and kidney disease progression was investigated among 3680 participants in the Chronic Renal Insufficiency Cohort. The primary outcome was CKD progression [defined as the composite of 50% decline in estimated glomerular filtration rate (eGFR) or end-stage kidney disease, whichever occurred first]. The associations between serum aldosterone and kidney disease outcomes were assessed using Cox proportional hazard models. At baseline, higher aldosterone concentrations were associated with a lower eGFR, lower serum potassium, greater urinary potassium, and protein excretion. Over a median follow-up of 9.6 years, 1412 participants developed CKD progression. In adjusted models, each doubling of serum aldosterone was associated with a 11% increased risk of CKD progression [hazard ratio (HR) 1.11, 95% confidence interval (CI) 1.04-1.18]. Individuals with the highest quartile of serum aldosterone had a 45% increased risk of CKD progression (HR 1.45, 95% CI 1.22-1.73) compared with the lowest quartile. The risk for CKD progression was similar regardless of whether patients had concomitant diabetes (P-interaction = 0.10). Higher serum aldosterone levels among individuals with CKD are independently associated with an increased risk for kidney disease progression, irrespective of concomitant diabetes. These findings provide mechanistic support for MR antagonists in delaying CKD progression and suggest that they may also have a role in those without diabetes.

Background Chronic Kidney Disease (CKD) is a progressive condition leading to End-Stage Kidney Disease (ESKD). With limited treatment options, identifying biomarkers related to CKD onset and progression is essential. The complement system, an immune network, has shown potential involvement in CKD pathogenesiss. This study investigates the causal role of diverse plasma complement proteins in CKD and its clinical types to discover new biomarkers and therapeutic targets. Method Using two-sample Mendelian randomization (MR), we examined the causal relationships between 28 plasma complement proteins and CKD outcomes. Plasma complement levels were sourced from a genome-wide association studies involving 35,559 Icelandic individuals, CKD outcome sourced from the FinnGen R11 and kidney function indicators sourced from CKDgen. Protein-protein interactions and GO enrichment analyses were used to identify related biological pathways. Results MR analysis identified causal relationships between 19 specific plasma complement proteins and CKD, 6 of which remained significant after false discovery rate correction. In addition, CR1 and CFD were not only found to be risk factors for CKD, but were also determined to be positively correlated with membranous nephropathy and diabetic nephropathy, respectively. CD55, C6, CR2, CFHR2, CFD were also correlated with renal function indicators, highlighting the role of complement proteins in CKD. Conclusion This study supports plasma complement proteins as potential biomarkers and therapeutic targets for CKD. The identified causal associations highlight the relevance of complement activation in CKD progression, suggesting future potential for clinical applications in early diagnosis, risk stratification, and therapeutic intervention.

April 2021 <i>Stroke</i> Highlights

This study aims to investigate the determinants of the progression of Chronic Kidney Disease (CKD) and the role of antioxidant supplementation in managing oxidative stress and kidney function. The research used a cross-sectional study with 120 participants, considering variables such as age, gender, smoking, family history, diet, alcohol consumption, education, and occupation. Key findings from the analysis were that age was a significant contributing factor to CKD progression, with older individuals having greater likelihood of developing advanced disease stages. Males, particularly those with hypertension, had increased prevalence of kidney damage. Smoking was also found to accelerate CKD progression, with intake of a diet rich in fruits and vegetables being associated with high antioxidant use. The intervention group, supplemented with antioxidants, evidenced remarkable reductions in indicators of oxidative stress as well as improvement of kidney function compared to existing levels, as shown by statistical comparison through Paired t-tests and Wilcoxon Signed-Rank Tests (p &lt; 0.05). The control group, on the other hand, experienced no similar significant alterations. In addition, a multivariable regression model proved the impact of age, baseline kidney function, and comorbid illness on CKD outcomes with poorer outcomes in older patients and reduced baseline eGFR. The findings suggest that lifestyle modifications such as smoking abstinence and diet change, and antioxidant supplementation may have a significant role in CKD progression and oxidative stress and are potential targets for clinical intervention. This study highlights key determinants influencing Chronic Kidney Disease (CKD) progression, emphasizing modifiable risk factors like smoking, diet, alcohol use, and physical activity. Findings support antioxidant supplementation and lifestyle modifications as crucial strategies for slowing CKD progression and improving renal health outcomes.

The Impact of APOL1 on Chronic Kidney Disease and Hypertension.

To investigate the value of serum adropin in predicting chronic kidney disease (CKD) progression in subjects with type 2 diabetes (T2D). Serum adropin levels were measured in normal control and T2D patients with various stage of CKD. CKD progression was defined as ≥ 30% decline from the baseline estimated glomerular filtration rate. Logistic regression analysis was applied to assess the association between adropin levels and CKD progression. The study included 58 subjects with T2D (18 early CKD and 40 advanced CKD) and 9 subjects without diabetes (control). Subjects with T2D had significantly higher adropin levels than controls (6393.10 ± 1611.84 vs. 3470.30 ± 1284.41 pg/ml; P < 0.001). Meanwhile, T2D patients with advanced CKD had higher adropin levels than those with early CKD (6848.89 ± 1287.04 vs. 5380.25 ± 1826.44 pg/ml; P = 0.003). Among T2D patients, subjects experienced CKD progression had higher adropin levels than those without (7520.15 ± 843.21 vs. 6151.16 ± 1661.61 pg/mL, P =0.003). Thus, adropin predicts CKD progression in T2D patients with 86% sensitivity and 70% specificity at 6872.24 pg/ml cutoff value. The association with CKD progression was still significant after adjusting for age, gender and body mass index (adjusted odds ratio = 27.188, 95% confidence interval 1.415-522.527, P =0.029). The above findings suggest that serum adropin could be applied as a potential biomarker for predicting CKD progression in subjects with T2D. Further research is needed to validate these results and explore the underlying mechanisms.

Funding Acknowledgements Type of funding sources: None. Obstructive sleep apnea (OSA) is diagnosed late, especially in older people. The presence of chronic hypoxia and glomerular hypertension decrease renal function in patients with OSAS, which causes the progression of chronic kidney disease (CKD) [3]. The aim of the study was to investigate epidemiological aspects of OSA in older patients with stable cardiovascular disease and chronic kidney disease. Materials and methods 80 older patients with stable cardiovascular disease (43 males, mean age was 67.6 ± 6.1 years) were studied. CKD was diagnosed and classified according to the KDIGO guidelines (2012). OSA was observed according to Clinical Guidelines for Obstructive Sleep Apnea and Insomnia (U.S., 2020). Berlin Questionnaire and Epworth Sleepiness Scale, cardiorespiratory monitoring for screening and diagnosis of OSA were used. Follow-up period was 12 months. Results Chronic kidney disease was observed in 48 (60%) patients. There were no patients with stages 1 and 2 of CKD, stage 3a was detected in 35 (43.8%), 3b - in 10 (12.5%), stage 4 - in 3 (3.8%) patients. Significant daytime sleepiness was observed in every fourth elderly and senile patient with CKD (12; 25%). A high risk of OSA was observed in the majority of patients with CKD - 34 (70.8%). OSA was first diagnosed in 31 (64.5%) patients with CKD. Moreover, the frequency did not depend on gender (p = 0.39) and age (p = 0.48). There were no differences between elderly (60-74 years old) and senile patients (75-89 years old) in the prevalence of OSAS (p&amp;gt; 0.05).More than half had an average degree of OSA (19; 61.3%). Mild and severe degrees were observed with the same frequency in 6 (19.4%) older patients with CKD. Severity of OSA in men and women did not differ (p&amp;gt; 0.05). The average level of oxygen saturation was higher in men: 93.4 (92.4; 94.15) and 92.3 (91.7; 93.1)%, respectively, p = 0.02. There were no differences in the frequency of OSA detection depending on the stage of CKD (p&amp;gt; 0.05). Only 2 (6.5%) patients with OSA and CKD was consulted a somnologist after 12 months of observation Conclusion A high prevalence of OSA was observed in most older patients with stable cardiovascular disease and CKD (34; 70.8%), significant daytime sleepiness was observed in every fourth patient. OSA was first diagnosed in 31 (64.5%) patients with CKD, despite the high risk and clinical symptoms. The severity of OSAS did not depend on gender, age, and the presence of CKD in older patients with stable cardiovascular disease . Subsequently only 2 (6.5%) patients in a sleep consulted, which reflects a low level of overall patient health awareness and availability of quality somnological aid.

Chronic kidney disease as a global public health problem: Approaches and initiatives – a position statement from Kidney Disease Improving Global Outcomes

Chronic Kidney Disease (CKD) patients are at increased risk for atherosclerosis, cardiovascular disease (CVD), and progression to end-stage kidney disease (ESKD). This heavy CVD risk cannot be solely attributed to traditional Framingham risk factors. Oxidative stress, defined as the disruption of the balance between prooxidants and antioxidants in favor of the former, has emerged as a novel risk factor for CVD and CKD progression. Specifically, lipid peroxidation has been identified as a trigger for endothelial dysfunction, the first step towards atherogenesis, and protein oxidation has been associated with CKD progression. The oxidation of proteins and lipids starts early in CKD, increases gradually with disease progression, and is further exacerbated in ESKD due to dialysis-related factors. In order to counteract the deleterious effects of free radicals and thereby ameliorate, or delay, CV disease and progression of CKD, exogenous administration of antioxidants has been proposed. Here, we attempt to summarize existing data from experimental and clinical studies that test antioxidants for their possible beneficial effects against CVD and CKD progression, such as vitamins E and C, statins, omega-3 fatty acids, trace elements, polyphenols, and N-acetylcysteine.

Background and Aims The Chronic Kidney Disease Prognosis Consortium (CKD-PC) recently developed risk models to predict the 3-year risk of a ≥40% decrease in estimated glomerular filtration rate (eGFR) or to predict kidney failure in the general population. Unlike the kidney failure risk equation, the CKD-PC model is valid for all levels of eGFR (above and below 60 mL/min/1.73 m2) and includes chronic kidney disease (CKD) progression risk factors besides age, sex, eGFR and albuminuria; namely: systolic blood pressure, antihypertensive medication use, history of heart failure, coronary heart disease, atrial fibrillation, smoking status, body mass index, glycated hemoglobin, insulin use, and oral diabetes medication use [1]. We evaluated whether the CKD-PC model, developed using electronic health record data, is valid for use in a contemporary clinical population using the FIDELITY pooled dataset from international randomized clinical trials of finerenone [2]. Additionally, to inform clinical practice, we evaluated the efficacy of finerenone using categories of 3-year CKD progression risk as predicted by the model. Method FIDELITY was an individual, patient-level, prespecified, pooled efficacy and safety analysis of the phase III FIDELIO-DKD and FIGARO-DKD trials of patients with CKD and type 2 diabetes (T2D), randomized 1:1 to finerenone or placebo. The 3-year CKD progression risk of these patients was predicted and the validity of the CKD-PC model was evaluated using area under the curve (AUC) score (with higher scores indicating better risk prediction), Brier score (lower scores indicating better prediction), and by calibration plots of observed versus predicted risk by deciles of 3-year CKD progression risk. To evaluate the efficacy of finerenone, 3-year risk was categorized in quartiles and the effect of finerenone versus placebo on a kidney composite outcome, defined as kidney failure, a sustained ≥40% decrease in eGFR from baseline over ≥4 weeks, or renal death, was assessed. Results The FIDELITY population comprised 13,026 individuals with a mean eGFR of 58 mL/min/1.73 m2 and urine albumin-to-creatinine ratio of 515 mg/g. The median follow-up was 3 years and there were 1849 total kidney outcome events. Of 12,968 patients analyzed, the median 3-year risk of kidney failure was 15% (Q1–Q3: 9–24%). Overall, the model demonstrated good discrimination to predict a ≥40% kidney composite outcome for patients with CKD and T2D in FIDELITY: AUC score 0.726 (95% confidence interval [CI] 0.712–0.739) and Brier score 0.100 (95% CI 0.097–0.103). The predicted 3-year risk was generally slightly higher than the observed risk (Fig. 1). Finerenone was effective in preventing CKD progression across the risk quartiles (p-interaction = 0.094) with a trend towards greater efficacy in the higher risk quartiles (3-year risk of CKD progression ≥10%) (Fig. 2). All risk groups showed benefit with finerenone compared to placebo regarding eGFR decline in the chronic phase. Conclusion The CKD-PC risk model for CKD progression performed well in a large global clinical trial population of patients with CKD and T2D. Finerenone was effective across the range of baseline risk of CKD progression.

Today, it is universally acknowledged that, in hypertension, the kidney is both culprit and victim.1 Kidney malfunction causes hypertension, and hypertension, in turn, aggravates chronic kidney disease (CKD) and accelerates its progression. High blood pressure (frank hypertension and blood pressure values in the high normal range) are clearly correlated to progressive kidney injury, both in experimental2 and in clinical3 observations. All of the current guidelines4,5 recommend lowering of systolic blood pressure to 130 or 125 mm Hg in CKD, and even lower values are recommended if the target level of proteinuria of <1 g per 24 hours has not been achieved.4 There is good evidence of “renoprotection” by lowering blood pressure in patients with renal disease, at least in the presence of proteinuria.3 In CKD patients without proteinuria, eg, autosomal polycystic kidney disease, further renoprotection cannot be achieved by lowering blood pressure below the target blood pressure recommended in patients without CKD6; nevertheless, these patients have a markedly elevated cardiovascular risk, and more stringent lowering of blood pressure is desirable, because, eg, reduction of left ventricular hypertrophy as an index of cardiovascular risk had been documented in such patients.6 The worldwide problem of neglect of hypertension and of insufficient implementation of antihypertensive treatment in CKD patients prompted the International Society of Nephrology and the International Federation of Kidney Foundations to devote this year’s World Kidney Day (http://www.worldkidneyday.org) on March 12th to the issue …

Background/Aims: Abnormal serum potassium is associated with higher mortality in dialysis patients, but its impact on outcomes in predialysis chronic kidney disease (CKD) is less clear. Furthermore, blacks with normal kidney function have lower urinary potassium excretion, but it is unclear if such differences have a bearing on race-associated outcomes in CKD. Methods: We studied predialysis mortality and slopes of estimated glomerular filtration rate, eGFR) associated with serum potassium in 1,227 males with CKD. Mortality was examined in time-dependent Cox models, and slopes of eGFR in linear mixed effects models with adjustments for case mix and laboratory values. Results: Both hypo- and hyperkalemia were associated with mortality overall and in 933 white patients, but in 294 blacks hypokalemia was a stronger death predictor. Hypokalemia was associated with loss of kidney function independent of race: a 1 mEq/l lower potassium was associated with an adjusted difference in slopes of eGFR of -0.13 ml/min/1.73 m²/year (95% CI: -0.20 to -0.07), p < 0.001. Conclusion: Hypo- and hyperkalemia are associated with higher mortality in CKD patients. Blacks appear to better tolerate higher potassium than whites. Hypokalemia is associated with faster CKD progression independent of race. Hyperkalemia management may warrant race-specific consideration, and hypokalemia correction may slow CKD progression. This is a work of the US Government and is not subject to copyright protection in the USA. Foreign copyrights may apply. Published by S. Karger AG, Basel