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Glomerular filtration rate (GFR) decline is causally associated with kidney failure and is a candidate surrogate endpoint for clinical trials of chronic kidney disease (CKD) progression. Analyses across a diverse spectrum of interventions and populations is required for acceptance of GFR decline as an endpoint. In an analysis of individual participant data, for each of 66 studies (total of 186,312 participants), we estimated treatment effects on the total GFR slope, computed from baseline to 3 years, and chronic slope, starting at 3 months after randomization, and on the clinical endpoint (doubling of serum creatinine, GFR < 15 ml min -1 per 1.73 m 2 or kidney failure with replacement therapy). We used a Bayesian mixed-effects meta-regression model to relate treatment effects on GFR slope with those on the clinical endpoint across all studies and by disease groups (diabetes, glomerular diseases, CKD or cardiovascular diseases). Treatment effects on the clinical endpoint were strongly associated with treatment effects on total slope (median coefficient of determination (R 2 ) = 0.97 (95% Bayesian credible interval (BCI) 0.82-1.00)) and moderately associated with those on chronic slope (R 2  = 0.55 (95% BCI 0.25-0.77)). There was no evidence of heterogeneity across disease. Our results support the use of total slope as a primary endpoint for clinical trials of CKD progression., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Acute changes in GFR can occur after initiation of interventions targeting progression of CKD. These acute changes complicate the interpretation of long-term treatment effects., Methods: To assess the magnitude and consistency of acute effects in randomized clinical trials and explore factors that might affect them, we performed a meta-analysis of 53 randomized clinical trials for CKD progression, enrolling 56,413 participants with at least one estimated GFR measurement by 6 months after randomization. We defined acute treatment effects as the mean difference in GFR slope from baseline to 3 months between randomized groups. We performed univariable and multivariable metaregression to assess the effect of intervention type, disease state, baseline GFR, and albuminuria on the magnitude of acute effects., Results: The mean acute effect across all studies was -0.21 ml/min per 1.73 m 2 (95% confidence interval, -0.63 to 0.22) over 3 months, with substantial heterogeneity across interventions (95% coverage interval across studies, -2.50 to +2.08 ml/min per 1.73 m 2 ). We observed negative average acute effects in renin angiotensin system blockade, BP lowering, and sodium-glucose cotransporter 2 inhibitor trials, and positive acute effects in trials of immunosuppressive agents. Larger negative acute effects were observed in trials with a higher mean baseline GFR., Conclusion: The magnitude and consistency of acute GFR effects vary across different interventions, and are larger at higher baseline GFR. Understanding the nature and magnitude of acute effects can help inform the optimal design of randomized clinical trials evaluating disease progression in CKD., (Copyright © 2022 by the American Society of Nephrology.)

Background: Accurate risk prediction is needed in order to provide personalized healthcare for chronic kidney disease (CKD) patients. An overload of prognosis studies is being published, ranging from individual biomarker studies to full prediction studies. We aim to systematically appraise published prognosis studies investigating multiple biomarkers and their role in risk predictions. Our primary objective was to investigate if the prognostic models that are reported in the literature were of sufficient quality and to externally validate them., Methods: We undertook a systematic review and appraised the quality of studies reporting multivariable prognosis models for end-stage renal disease (ESRD), cardiovascular (CV) events and mortality in CKD patients. We subsequently externally validated these models in a randomized trial that included patients from a broad CKD population., Results: We identified 91 papers describing 36 multivariable models for prognosis of ESRD, 50 for CV events, 46 for mortality and 17 for a composite outcome. Most studies were deemed of moderate quality. Moreover, they often adopted different definitions for the primary outcome and rarely reported full model equations (21% of the included studies). External validation was performed in the Multifactorial Approach and Superior Treatment Efficacy in Renal Patients with the Aid of Nurse Practitioners trial (n = 788, with 160 events for ESRD, 79 for CV and 102 for mortality). The 24 models that reported full model equations showed a great variability in their performance, although calibration remained fairly adequate for most models, except when predicting mortality (calibration slope >1.5)., Conclusions: This review shows that there is an abundance of multivariable prognosis models for the CKD population. Most studies were considered of moderate quality, and they were reported and analysed in such a manner that their results cannot directly be used in follow-up research or in clinical practice., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: The increased demand for nephrology care for patients with chronic kidney disease (CKD) necessitates a critical review of the need for secondary care facilities and the possibilities for referral back to primary care. This study aimed to evaluate the characteristics and numbers of patients who could potentially be referred back to primary care, using predefined criteria developed by nephrologists and general practitioners., Method: We organised a consensus meeting with eight nephrologists and two general practitioners to define the back referral (BR) criteria, and performed a retrospective cohort study reviewing records from patients under nephrologist care in three hospitals., Results: We reached a consensus about the BR criteria. Overall, 78 of the 300 patients (26%) in the outpatient clinics met the BR criteria. The characteristics of the patients who met the BR criteria were: 56.4% male, a median age of 70, an average of 3.0 outpatients visits per year, and a mean estimated glomerular filtration rate of 46 ml/min/1,73m 2 . Hypertension was present in 67.9% of this group, while 27.3% had diabetes and 16.9% had cancer. The patients who could be referred back represented all CKD stages except stage G5. The most common stage (16%) was G3bA2 (eGFR 30 ≤ 44 and ACR 3 ≤ 30)., Conclusion: A substantial proportion of patients were eligible for referral back to primary care. These patients often have a comorbidity, such as hypertension or diabetes. Future research should focus on generalisability of the BR criteria, the feasibility of actual implementation of the back referral, follow-up assessments of renal function and patient satisfaction.

Background: Higher plasma magnesium concentrations are associated with reduced cardiovascular disease risk in chronic kidney disease (CKD) patients. The importance of plasma magnesium concentration for vascular calcification in earlier stages of CKD remains underexplored. This study investigated whether plasma magnesium is a determinant for the presence and severity of vascular calcification in moderate CKD., Methods: Retrospective analysis was performed using abdominal aortic calcification (AAC) scores in 280 patients with stage 3 and 4 CKD enrolled in the MASTERPLAN trial. Lateral abdominal X-ray was used to evaluate AAC. Plasma magnesium concentration were measured over time. A zero-inflated Poisson model determined the association between plasma magnesium concentration and AAC., Results: 79 out of 280 patients did not have AAC, and in patients with AAC the median calcification score was 3.5 (interquartile range: 0.0-8.6). The mean plasma magnesium concentration was 0.76 ± 0.10 mmol/L at baseline. A 0.1 mmol/L higher plasma magnesium concentration was associated with lower AAC of 0.07 point (95% CI -0.28 - 0.14). A 0.1 mmol/L higher plasma magnesium lowered the odds of detecting any AAC by 30% (OR = 0.63; 95% CI 0.29-1.37). After 1 year and 4 years (at time of X-ray) of follow-up this association was attenuated (OR = 0.93; 95% CI 0.61-1.43 and 0.93; 95% CI 0.60-1.45, respectively). None of these associations reached statistical significance., Conclusions: Plasma magnesium concentration at baseline is not associated with the risk for future AAC. Interventions increasing magnesium to avoid vascular calcification may have greatest potential in early CKD stages prior to onset of vascular calcification.

Iron is an essential element that is indispensable for life. The delicate physiological body iron balance is maintained by both systemic and cellular regulatory mechanisms. The iron-regulatory hormone hepcidin assures maintenance of adequate systemic iron levels and is regulated by circulating and stored iron levels, inflammation and erythropoiesis. The kidney has an important role in preventing iron loss from the body by means of reabsorption. Cellular iron levels are dependent on iron import, storage, utilization and export, which are mainly regulated by the iron response element-iron regulatory protein (IRE-IRP) system. In the kidney, iron transport mechanisms independent of the IRE-IRP system have been identified, suggesting additional mechanisms for iron handling in this organ. Yet, knowledge gaps on renal iron handling remain in terms of redundancy in transport mechanisms, the roles of the different tubular segments and related regulatory processes. Disturbances in cellular and systemic iron balance are recognized as causes and consequences of kidney injury. Consequently, iron metabolism has become a focus for novel therapeutic interventions for acute kidney injury and chronic kidney disease, which has fuelled interest in the molecular mechanisms of renal iron handling and renal injury, as well as the complex dynamics between systemic and local cellular iron regulation.

Background: Randomized trials of CKD treatments traditionally use clinical events late in CKD progression as end points. This requires costly studies with large sample sizes and long follow-up. Surrogate end points like GFR slope may speed up the evaluation of new therapies by enabling smaller studies with shorter follow-up., Methods: We used statistical simulations to identify trial situations where GFR slope provides increased statistical power compared with the clinical end point of doubling of serum creatinine or kidney failure. We simulated GFR trajectories based on data from 47 randomized treatment comparisons. We evaluated the sample size required for adequate statistical power based on GFR slopes calculated from baseline and from 3 months follow-up., Results: In most scenarios where the treatment has no acute effect, analyses of GFR slope provided similar or improved statistical power compared with the clinical end point, often allowing investigators to shorten follow-up by at least half while simultaneously reducing sample size. When patients' GFRs are higher, the power advantages of GFR slope increase. However, acute treatment effects within several months of randomization can increase the risk of false conclusions about therapies based on GFR slope. Care is needed in study design and analysis to avoid such false conclusions., Conclusions: Use of GFR slope can substantially increase statistical power compared with the clinical end point, particularly when baseline GFR is high and there is no acute effect. The optimum GFR-based end point depends on multiple factors including the rate of GFR decline, type of treatment effect and study design., (Copyright © 2019 by the American Society of Nephrology.)

The Kidney Disease: Improving Global Outcomes (KDIGO) initiative organized a Controversies Conference on glomerular diseases in November 2017. The conference focused on the 2012 KDIGO guideline with the aim of identifying new insights into nomenclature, pathogenesis, diagnostic work-up, and, in particular, therapy of glomerular diseases since the guideline's publication. It was the consensus of the group that most guideline recommendations, in particular those dealing with therapy, will need to be revisited by the guideline-updating Work Group. This report covers general management of glomerular disease, IgA nephropathy, and membranous nephropathy., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: It is unknown what patients in primary care with mild-to-moderate chronic kidney disease (CKD) know, think, and feel about their diagnoses and how they value the information provided. The aim of the study was to explore their knowledge, thoughts, and experiences concerning their CKD and the information given to them., Method: Qualitative interview study with patients with mild-to-moderate CKD who know their diagnoses and are treated mainly by family physicians., Results: Four themes arose: CKD literacy, coping with anxiety, prerequisites for self-management, and reciprocity in information provision. The participants filled deficiencies in their CKD knowledge with misconceptions and half-truth about causes, symptoms, and treatment. The anxiety about CKD at the time of diagnosis versus the feeling of irrelevance later on was due to the absence of CKD symptoms and their physicians' minimization of the seriousness of CKD. Participants failed to connect lifestyle and cardiovascular disease with CKD. Not all participants were well informed about the consequences that CKD might have. CKD literacy and willingness to change were both necessary to accept lifestyle changes. Further, the participants felt that it would be helpful when information comes with empathy and is tailored to patients' personal needs., Conclusions: Patients have various perceptions about their CKD. Exploring these perceptions could help match their needs with better-tailored information. Doctors should be aware that they can deliver inaccurate signals about CKD severity, so that patients fail to realize the potential impact of CKD. This makes them less open to lifestyle changes and improving their self-management., Competing Interests: Conflict of interest: none declared., (© Copyright 2018 by the American Board of Family Medicine.)

Background: Guideline adherence in chronic kidney disease management is low, despite guideline implementation initiatives. Knowing general practitioners' (GPs') perspectives of management of early-stage chronic kidney disease (CKD) and the applicability of the national interdisciplinary guideline could support strategies to improve quality of care., Method: Qualitative focus group study with 27 GPs in the Netherlands. Three analysts open-coded and comparatively analysed the data. Mind-mapping sessions were performed after data-saturation., Results: Five themes emerged: defining CKD, knowledge and awareness, patient-physician interaction, organisation of CKD care and value of the guideline. A key finding was the abstractness of the CKD concept. The GPs expressed various perspectives about defining CKD and interpreting estimated glomerular filtration rates. Views about clinical relevance influenced the decision-making, although factual knowledge seems lacking. Striving to inform well enough without creating anxiety and to explain suitably for the intellectual ability of the patient caused tension in the patient-physician interaction. Integration with cardiovascular disease-management programmes was mentioned as a way of implementing CKD care in the future. The guideline was perceived as a rough guide rather than a leading document., Conclusion: CKD is perceived as an abstract rather than a clinical concept. Abstractness plays a role in all formulated themes. Management of CKD patients in primary care is complex and is influenced by physician-bound considerations related to individual knowledge and perception of the importance of CKD. Strategies are needed to improve GPs' understanding of the concept of CKD by education, a holistic approach to guidelines, and integration of CKD care into cardiovascular programmes., Trial Registration: Not applicable.

Background: GPs insufficiently follow guidelines regarding consultation and referral for chronic kidney disease (CKD)., Objective: To identify patient characteristics and quality of care (QoC) in CKD patients with whom consultation and referral recommendations were not followed., Method: A 14 month prospective observational cohort study of primary care patients with CKD stage 3-5. 47 practices participated, serving 207469 people. 2547 CKD patients fulfilled consultation criteria, 225 fulfilled referral criteria. We compared characteristics of patients managed by GPs with patients receiving nephrologist co-management. We assessed QoC as adherence to monitoring criteria, CKD recognition and achievement of blood pressure (BP) targets., Results: Patients treated in primary care despite a consultation recommendation (94%) had higher eGFR values (OR 1.07; 95% CI: 1.05-1.09), were less often monitored for renal function (OR 0.42; 95% CI: 0.24-0.74) and potassium (OR 0.56; 95% CI: 0.35-0.92) and CKD was less frequently recognised (OR 0.46; 95% CI: 0.31-0.68) than in patients with nephrologist co-management. Patients treated in primary care despite referral recommendation (70%) were older (OR 1.03; 95% CI:1.01-1.06) and had less cardiovascular disease (OR 0.37; 95% CI: 0.19-0.73). Overall, in patients solely managed by GPs, CKD recognition was 50%, monitoring disease progression in 36% and metabolic parameters in 3%, BP targets were achieved in 51%. Monitoring of renal function and BP was positively associated with diabetes (OR 3.10; 95% CI: 2.47-3.88 and OR 7.78; 95% CI: 3.21-18.87) and hypertension (OR 3.19; 95% CI: 2.67-3.82 and OR 3.35; 95% CI: 1.45-7.77)., Conclusion: Patients remaining in primary care despite nephrologists' co-management recommendations were inadequately monitored, and BP targets were insufficiently met. CKD patients without cardiovascular comorbidity or diabetes require extra attention to guarantee adequate monitoring of renal function and BP., (© The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

In patients with chronic kidney disease (CKD), adequate renal clearance is compromised, resulting in the accumulation of a plethora of uremic solutes. These uremic retention solutes, also named uremic toxins, are a heterogeneous group of organic compounds with intrinsic biological activities, many of which are too large to be filtered and/or are protein bound. The renal excretion of protein-bound toxins depends largely on active tubular secretion, which shifts the binding and allows for active secretion of the free fraction. To facilitate this process, renal proximal tubule cells are equipped with a range of transporters that co-operate in basolateral uptake and luminal excretion. Many of these transporters have been characterized as mediators of drug disposition, but have recently been recognized for their importance in the proximal renal tubular transport of uremic toxins as well. This also indicates that during uremia, drug disposition may be severely affected as a result of drug-uremic toxin interaction. In addition, CKD patients receive various drugs to treat their complications potentially resulting in drug-drug interactions (DDIs), also for drugs that are non-renally excreted. This review discusses the current knowledge on formation, disposition and removal of protein-bound uremic toxins. Furthermore, implications associated with drug treatment in kidney failure, as well as innovative renal replacement therapies targetting the protein-bound uremic toxins are being discussed. It will become clear that the complex problems associated with uremia warrant a transdisciplinary approach that unites research experts in the area of fundamental biomedical research with their colleagues in clinical nephrology., (© 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)