Chronic kidney disease and the global public health agenda: an international consensus.

Early detection is a key strategy to prevent kidney disease, its progression and related complications, but numerous studies show that awareness of kidney disease at the population level is low. Therefore, increasing knowledge and implementing sustainable solutions for early detection of kidney disease are public health priorities. Economic and epidemiological data underscore why kidney disease should be placed on the global public health agenda - kidney disease prevalence is increasing globally and it is now the seventh leading risk factor for mortality worldwide. Moreover, demographic trends, the obesity epidemic and the sequelae of climate change are all likely to increase kidney disease prevalence further, with serious implications for survival, quality of life and health care spending worldwide. Importantly, the burden of kidney disease is highest among historically disadvantaged populations that often have limited access to optimal kidney disease therapies, which greatly contributes to current socioeconomic disparities in health outcomes. This joint statement from the International Society of Nephrology, European Renal Association and American Society of Nephrology, supported by three other regional nephrology societies, advocates for the inclusion of kidney disease in the current WHO statement on major non-communicable disease drivers of premature mortality.

Sodium Glucose Co-transporter 2 Inhibitors and Major Adverse Cardiovascular Outcomes: A SMART-C Collaborative Meta-Analysis.

BACKGROUND: Sodium glucose co-transporter 2 inhibitors (SGLT2i) consistently improve heart failure and kidney-related outcomes; however, effects on major adverse cardiovascular events (MACE) across different patient populations are less clear. METHODS: This was a collaborative trial-level meta-analysis from the SGLT2i meta-analysis cardio-renal trialists consortium, which includes all phase 3, placebo-controlled, outcomes trials of SGLT2i across three patient populations (diabetes at high risk for atherosclerotic cardiovascular disease [ASCVD], heart failure [HF], or chronic kidney disease [CKD]). The outcomes of interest were MACE (composite of CV death, myocardial infarction [MI], or stroke), individual components of MACE (inclusive of fatal and non-fatal events), all-cause mortality, and death subtypes. Effect estimates for SGLT2i vs. placebo were meta-analyzed across trials and examined across key subgroups (established ASCVD, prior MI, diabetes, prior HF, albuminuria, CKD stages and risk groups). RESULTS: A total of 78,607 patients across 11 trials were included: 42,568 (54.2%), 20,725 (26.4%), and 15,314 (19.5%) were included from trials of patients with diabetes at high risk for ASCVD, HF, or CKD, respectively. SGLT2i reduced the rate of MACE by 9% (HR 0.91 [95% CI 0.87-0.96], p<0.0001) with a consistent effect across all three patient populations (I2=0%) and across all key subgroups. This effect was primarily driven by a reduction in CV death (HR 0.86 [0.81-0.92], p<0.0001), with no significant effect for MI in the overall population (HR 0.95 [0.87-1.04], p=0.29), and no effect on stroke (HR 0.99 [0.91-1.07], p=0.77). The benefit for CV death was driven primarily by reductions in HF death and sudden cardiac death (HR 0.68 [0.46-1.02] and HR 0.86 [0.78-0.95], respectively) and was generally consistent across subgroups, with the possible exception of being more apparent in those with albuminuria (Pint=0.02). CONCLUSIONS: SGLT2i reduce the risk of MACE across a broad range of patients irrespective of ASCVD, diabetes, kidney function or other major clinical characteristics at baseline. This effect is driven primarily by a reduction of CV death, particularly HF and sudden cardiac death, without a significant effect on MI in the overall population, and no effect on stroke. These data may help inform selection for SGLT2i therapies across the spectrum of cardiovascular-kidney-metabolic disease.

[InspeCKD - Analysis of the use of diagnostics in patients at high risk for chronic kidney disease in German general practitioner (GP) practices]. / InspeCKD - Analyse zur Nutzung von Labordiagnostik im Kontext der chronischen Nierenerkrankung : Daten von Risikopatientinnen und -patienten in deutschen Hausarztpraxen.

BACKGROUND: Despite the high prevalence of chronic kidney disease (CKD) in Germany, only a small proportion of patients are currently diagnosed with CKD. Patients with hypertension, diabetes mellitus, and/or cardiovascular disease have a significantly increased risk of developing CKD and rapid disease progression and should therefore be screened and monitored in accordance with the guidelines. OBJECTIVES: The aim of this retrospective, cross-sectional study was to gain insights into appropriate diagnosis of patients at risk for CKD in German general practitioner practices. METHOD: For the analysis of the use of CKD-relevant diagnostics, electronic patient records from German general practitioner practices were analyzed. Adults with hypertension and/or diabetes mellitus and/or cardiovascular disease with a documented observation period of at least one year were included in the study. RESULTS: Data from a total of 448,837 patients from 1244 general practitioner practices were analyzed. 75.8% of patients had hypertension, 35.1% had cardiovascular disease, and 32.4% had diabetes mellitus. During a mean observation period of 1.7 years, serum creatinine was assessed at least once in 45.5% of patients. A urine dipstick test for albuminuria was performed in 7.9% of patients and in 0.4% of patients, urine albumin-to-creatine ratio (UACR) was measured. Laboratory diagnostics were initiated a little more frequently in high-risk patients compared to the overall cohort. CONCLUSIONS: The study highlights that despite known risk factors, guideline compliant CKD screening is rarely performed in German general practitioner practices, which implicates the need to increase the awareness of early diagnosis of CKD in patients at risk.

Genetic variants of unknown significance in alpha-galactosidase A: Cellular delineation from Fabry disease.

Fabry disease (FD) is an X-linked multiorgan disorder caused by variants in the alpha-galactosidase A gene (GLA). Depending on the variant, disease phenotypes range from benign to life-threatening. More than 1000 GLA variants are known, but a link between genotype and phenotype in FD has not yet been established for all. p.A143T, p.D313Y, and p.S126G are frequent examples of variants of unknown significance (VUS). We have investigated the potential pathogenicity of these VUS combining clinical data with data obtained in human cellular in vitro systems. We have analyzed four different male subject-derived cell types for alpha-galactosidase A enzyme (GLA) activity and intracellular Gb3 load. Additionally, Gb3 load in skin tissue as well as clinical data were studied for correlates of disease manifestations. A reduction of GLA activity was observed in cells carrying p.A143T compared with controls (p < 0.05). In cells carrying the p.D313Y variant, a reduced GLA activity was found only in endothelial cells (p < 0.01) compared with controls. No pathological changes were observed in cells carrying the p.S126G variant. None of the VUS investigated caused intracellular Gb3 accumulation in any cell type. Our data of aberrant GLA activity in cells of p.A143T hemizygotes and overall normal cellular phenotypes in cells of p.D313Y and p.S126G hemizygotes contribute a basic science perspective to the clinically highly relevant discussion on VUS in GLA.

Interactive exploration of adverse events and multimorbidity in CKD.

BACKGROUND AND HYPOTHESIS: Persons with chronic kidney disease (CKD) are at increased risk of adverse events, early mortality, and multimorbidity. A detailed overview of adverse event types and rates from a large CKD cohort under regular nephrological care is missing. We generated an interactive tool to enable exploration of adverse events and their combinations in the prospective, observational German CKD (GCKD) study. METHODS: The GCKD study enrolled 5217 participants under regular nephrological care with an estimated glomerular filtration rate of 30-60 or >60 mL/min/1.73m2 and an overt proteinuria. Cardio-, cerebro- and peripheral vascular, kidney, infection, and cancer events, as well as deaths were adjudicated following a standard operation procedure. We summarized these time-to-event data points for exploration in interactive graphs within an R shiny app. Multivariable adjusted Cox models for time to first event were fitted. Cumulative incidence functions, Kaplan-Meier curves and intersection plots were used to display main adverse events and their combinations by sex and CKD etiology. RESULTS: Over a median of 6.5 years, 10 271 events occurred in total and 680 participants (13.0%) died while 2947 participants (56.5%) experienced any event. The new publicly available interactive platform enables readers to scrutinize adverse events and their combinations as well as mortality trends as a gateway to better understand multimorbidity in CKD: incident rates per 1000 patient-years varied by event type, CKD etiology, and baseline characteristics. Incidence rates for the most frequent events and their recurrence were 113.6 (cardiovascular), 75.0 (kidney), and 66.0 (infection). Participants with diabetic kidney disease and men were more prone to experiencing events. CONCLUSION: This comprehensive explorative tool to visualize adverse events (https://gckd.diz.uk-erlangen.de/), their combination, mortality, and multimorbidity among persons with CKD may manifest as a valuable resource for patient care, identification of high-risk groups, health services, and public health policy planning.

Apolipoprotein A-IV concentrations and cancer in a large cohort of chronic kidney disease patients: results from the GCKD study.

BACKGROUND: Chronic kidney disease (CKD) is highly connected to inflammation and oxidative stress. Both favour the development of cancer in CKD patients. Serum apolipoprotein A-IV (apoA-IV) concentrations are influenced by kidney function and are an early marker of kidney impairment. Besides others, it has antioxidant and anti-inflammatory properties. Proteomic studies and small case-control studies identified low apoA-IV as a biomarker for various forms of cancer; however, prospective studies are lacking. We therefore investigated whether serum apoA-IV is associated with cancer in the German Chronic Kidney Disease (GCKD) study. METHODS: These analyses include 5039 Caucasian patients from the prospective GCKD cohort study followed for 6.5 years. Main inclusion criteria were an eGFR of 30-60 mL/min/1.73m2 or an eGFR > 60 mL/min/1.73m2 in the presence of overt proteinuria. RESULTS: Mean apoA-IV concentrations of the entire cohort were 28.9 ± 9.8 mg/dL (median 27.6 mg/dL). 615 patients had a history of cancer before the enrolment into the study. ApoA-IV concentrations above the median were associated with a lower odds for a history of cancer (OR = 0.79, p = 0.02 when adjusted age, sex, smoking, diabetes, BMI, albuminuria, statin intake, and eGFRcreatinine). During follow-up 368 patients developed an incident cancer event and those with apoA-IV above the median had a lower risk (HR = 0.72, 95%CI 0.57-0.90, P = 0.004). Finally, 62 patients died from such an incident cancer event and each 10 mg/dL higher apoA-IV concentrations were associated with a lower risk for fatal cancer (HR = 0.62, 95%CI 0.44-0.88, P = 0.007). CONCLUSIONS: Our data indicate an association of high apoA-IV concentrations with reduced frequencies of a history of cancer as well as incident fatal and non-fatal cancer events in a large cohort of patients with CKD.

The safety of a low protein diet in older adults with advanced chronic kidney disease.

BACKGROUND: A low protein diet (LPD) is recommended to patients with advanced chronic kidney disease (CKD), whereas geriatric guidelines recommend a higher amount of protein. The aim of this study was to evaluate the safety of LPD treatment in older adults with advanced CKD. METHODS: The EQUAL study is a prospective, observational study, including patients ≥65 years, incident estimated glomerular filtration rate <20 ml/min/1.73m², in six European countries with follow-up up till six years. Nutritional status was assessed by 7-point subjective global assessment (SGA) every 3-6 months. Prescribed diet (gram protein/kilogram/bodyweight) was recorded on every study visit; measured protein intake was available in three countries. Time to death and decline in nutritional status (SGA decrease by ≥2 points) were analysed using marginal structural models with dynamic inverse probability of treatment and censoring weights. RESULTS: Out of 1738 adults (631 prescribed LPD at any point during follow-up) there were 1319 with repeated SGA measurements of which 267 (20%) declined in SGA ≥ 2 points and 565 (32.5%) died. There was no difference in survival or decline in nutritional status for patients prescribed LPD ≤0.8 g/kg ideal bodyweight (Odds Ratio (OR) for mortality 1.15 (95% Confidence interval (CI) 0.86-1.55) and OR for decline in SGA 1.11 (95% CI 0.74-1.66) in the adjusted models. In patients prescribed LPD <0.6 g/kg ideal bodyweight, the results were similar. There was a significant interaction with LPD and higher age >75 years, lower SGA, and higher comorbidity burden for both mortality and nutritional status decline. CONCLUSIONS: In older adults with CKD approaching end-stage kidney disease, a traditional LPD prescribed and monitored according to routine clinical practice in Europe appears to be safe.

Empagliflozin and Rapid Kidney Function Decline Incidence in Type 2 Diabetes: An Exploratory Analysis From the EMPA-REG OUTCOME Trial.

Rationale & Objective: Kidney function progressively declines in most patients with type 2 diabetes (T2DM). Many develop progressive chronic kidney disease (CKD), but some experience a more rapid decline, with a greater risk of kidney failure and cardiovascular disease. In EMPA-REG OUTCOME, empagliflozin was associated with slower kidney disease progression. This post hoc analysis evaluated the effect of empagliflozin (pooled doses) on the prevalence of a "rapid decliner" phenotype, defined by an annual estimated glomerular filtration rate (eGFR) decline of >3 mL/min/1.73 m2. Study Design: This was an exploratory analysis of EMPA-REG OUTCOME, a large randomized, double-blind, placebo-controlled trial in adults with T2DM, established cardiovascular disease and an eGFR of ≥30 mL/min/1.73 m2. Setting & Participants: Analysis was undertaken on 6,967 participants (99.2%) in whom serial eGFR data was available. Interventions: Patients were randomized (1:1:1) to empagliflozin 10 mg, 25 mg, or placebo in addition to standard of care. Outcomes: Annual change in eGFR over the maintenance phase of treatment (week 4 to last value on treatment) was calculated using linear regression models. Logistic regression analysis was used to investigate differences in rapid decline between the treatment groups. Results: Over the study period, a rapid decliner phenotype was observed in 188 (9.5%) participants receiving placebo and 134 (3.4%) receiving empagliflozin. After adjusting for other risk factors, this equated to a two-third reduction in odds (OR, 0.32; 95% CI, 0.25-0.40; P < 0.001) among participants receiving empagliflozin versus placebo. A comparable risk reduction was observed using a threshold of eGFR decline of >5 mL/min/1.73 m2/y (empagliflozin vs placebo, 43 [1.1%] vs 44 [2.2%] participants; OR, 0.47; 95% CI, 0.31-0.72; P < 0.001). Limitations: This is a post hoc analysis of a trial undertaken in participants with T2DM and CVD. Generalization of findings to other settings remains to be established. Conclusions: Patients receiving empagliflozin were significantly less likely to experience a rapid decline in eGFR over a median of 2.6 years of exposure to the study drug. Funding: The Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance. Trial Registration: clinicaltrials.gov ID: NCT01131676.

In most people with type 2 diabetes, their kidney function starts to decline over time. However, in some people, this can happen more rapidly, which can increase their risk of kidney or cardiovascular disease. A major study, EMPA-REG OUTCOME, has shown that empagliflozin, which helps to control blood sugar in people with type 2 diabetes, also reduced the risk of cardiovascular disease events and slowed the progression of kidney disease, when compared with people in the study who received placebo. In this new research from the same major study empagliflozin, compared with a placebo, was shown to reduce the risk of people having a rapid decline in their kidney function over the 3 years of the study.

A European Renal Association (ERA) synopsis for nephrology practice of the 2023 European Society of Hypertension (ESH) Guidelines for the Management of Arterial Hypertension.

In June 2023, the European Society of Hypertension (ESH) presented and published the new 2023 ESH Guidelines for the Management of Arterial Hypertension, a document that was endorsed by the European Renal Association (ERA). Following the evolution of evidence in recent years, several novel recommendations relevant to the management of hypertension in patients with chronic kidney disease (CKD) appeared in these Guidelines. These include recommendations for target office BP < 130/80 mmHg in most and against target office BP < 120/70 mmHg in all patients with CKD; recommendations for use of spironolactone or chlortalidone for patients with resistant hypertension with eGFR higher or lower than 30 ml/min/1.73 m2, respectively; use of an SGLT2-inhibitor for patients with CKD and eGFR ≥20 ml/min/1.73 m2; use of finerenone for patients with CKD, type 2 DM, albuminuria, eGFR ≥25 ml/min/1.73 m2 and serum potassium < 5.0 mmol/L; and revascularization in patients with atherosclerotic renovascular disease and secondary hypertension or high-risk phenotypes if stenosis ≥ 70% is present. The present report is a synopsis of sections of the ESH Guidelines that are relevant to the daily clinical practice of nephrologists, prepared by experts of ESH and ERA. The sections summarized are those referring to the role of CKD in hypertension staging and cardiovascular risk stratification, the evaluation of hypertension-mediated kidney damage and the overall management of hypertension in patients with CKD.

How do SGLT2 inhibitors protect the kidney? A mediation analysis of the EMPA-REG OUTCOME trial.

INTRODUCTION: Mechanisms underlying kidney benefits with sodium-glucose cotransporter-2 (SGLT2) inhibition in heart failure and/or type 2 diabetes (T2D) with established cardiovascular disease are currently unclear. METHODS: We evaluated post hoc the factors mediating the effect of empagliflozin on a composite kidney outcome (first sustained estimate glomerular filtration rate ≥40% reduction from baseline, initiation of renal replacement therapy, or death due to kidney disease) in EMPA-REG OUTCOME. Variables, calculated as change from baseline or updated mean, were evaluated as time-dependent covariates and using a landmark approach (at Week 12) in Cox regression analyses. In multivariable analyses, variables with the greatest mediating effect were added using a step-up procedure. RESULTS: In univariable time-dependent updated mean covariate analyses, the strongest mediator was hematocrit (99.5% mediation). Hemoglobin, uric acid, and urine albumin-to-creatinine ratio mediated 79.4%, 33.2%, and 31.0%, respectively. Multivariable analyses were not performed due to the very strong mediation effect of hematocrit. In univariable Week 12 landmark change from baseline analyses, the strongest mediators included hematocrit (40.7%), glycated hemoglobin (28.3%), systolic blood pressure (16.8%), and free fatty acids (16.5%), which yielded a combined mediation of 78.9% in multivariable analysis. CONCLUSIONS: Changes in hematocrit and hemoglobin were the strongest mediators of empagliflozin's kidney benefits in EMPA-REG OUTCOME participants with T2D and cardiovascular disease.

Early changes in estimated glomerular filtration rate post-initiation of empagliflozin in EMPEROR-Preserved.

AIMS: Renal function (estimated glomerular filtration rate [eGFR]) changes early after the introduction of empagliflozin have not been described in heart failure with preserved ejection fraction (HFpEF). The aim of this study was to describe early eGFR changes, assess its determinants and its clinical impact on cardiovascular and renal outcomes in patients with HFpEF enrolled in EMPEROR-Preserved. METHODS AND RESULTS: Estimated glomerular filtration rate changes (absolute and relative) from randomization to week 4 were calculated and landmark analyses performed. Initial eGFR change was available in 5836 patients (97.5% of the population). Empagliflozin induced a mean eGFR change of -3.2 ml/min/1.73 m2 versus placebo from baseline to week 4. After week 4, in the empagliflozin group, the risk of the primary outcome (composite of heart failure hospitalization or cardiovascular death), cardiovascular, all-cause mortality and sustained ≥50% eGFR decrease or end-stage renal disease (ESRD) did not differ by eGFR change levels. In contrast, in the placebo group, patients included in the tertile with most profound eGFR decrease (i.e. ≥5.1% from baseline) had a higher risk of the primary outcome (hazard ratio [HR] 1.46, 95% confidence interval [CI] 1.17-1.82), cardiovascular mortality (HR 1.38, 95% CI 1.01-1.89) and sustained ≥50% eGFR decrease or ESRD (HR 2.20, 95% CI 1.20-4.04) versus tertile with eGFR increase. CONCLUSION: An initial relatively small eGFR decrease may be expected after empagliflozin initiation. Such small eGFR decrease was not associated with adverse cardiovascular outcomes with empagliflozin. In contrast, eGFR decrease was associated with poor cardiovascular outcomes with placebo.

Hypoglycemia and Cardiovascular Outcomes in the CARMELINA and CAROLINA Trials of Linagliptin: A Secondary Analysis of Randomized Clinical Trials.

Importance: Previous studies have reported an association between hypoglycemia and cardiovascular (CV) events in people with type 2 diabetes (T2D), but it is unclear if this association is causal or identifies a high-risk patient phenotype. Objective: To evaluate the associations between hypoglycemia and CV outcomes. Design, Setting, and Participants: This secondary analysis was a post hoc assessment of the multinational, double-blind CARMELINA (Cardiovascular and Renal Microvascular Outcome Study With Linagliptin; 2013-2016) and CAROLINA (Cardiovascular Outcome Trial of Linagliptin vs Glimepiride in Type 2 Diabetes; 2010-2018) randomized clinical trials of the antihyperglycemic drug, linagliptin, a dipeptidyl peptidase 4 inhibitor. Participants were adults with T2D at high CV risk with or without high kidney risk. By design, participants in the CARMELINA trial had longer duration of T2D and had a higher CV risk than participants in the CAROLINA trial. Data analyses were conducted between June 2021 and June 2023. Intervention: Linagliptin or placebo in the CARMELINA trial, and linagliptin or glimepiride in the CAROLINA trial. Main Outcomes and Measures: The primary outcome for both trials was CV death, myocardial infarction (MI), or stroke (3-point major adverse CV events [3P-MACE]). For the present analyses, hospitalization for heart failure (HF) was added. Hypoglycemia was defined as plasma glucose less than 54 mg/dL or severe hypoglycemia (episodes requiring the assistance of another person). Associations between the first hypoglycemic episode and subsequent CV events and between nonfatal CV events (MI, stroke, hospitalization for HF) and subsequent hypoglycemic episodes were assessed using multivariable Cox proportional hazards regression models. Sensitivity analyses explored the risk of CV events within 60 days after each hypoglycemic episode. Results: In the CARMELINA trial (6979 patients; 4390 males [62.9%]; mean [SD] age, 65.9 [9.1] years), there was an association between hypoglycemia and subsequent 3P-MACE plus hospitalization for HF (hazard ratio [HR], 1.23; 95% CI, 1.04-1.46) as well as between nonfatal CV events and subsequent hypoglycemia (HR, 1.39; 95% CI, 1.06-1.83). In the CAROLINA trial (6033 patients; 3619 males (60.0%); mean [SD] age, 64.0 [9.5] years), there was no association between hypoglycemia and subsequent 3P-MACE plus hospitalization for HF (HR, 1.00; 95% CI, 0.76-1.32) and between nonfatal CV events and subsequent hypoglycemia (HR, 1.44; 95% CI, 0.96-2.16). In analyses of CV events occurring within 60 days after hypoglycemia, there was either no association or too few events to analyze. Conclusions and Relevance: This study found bidirectional associations between hypoglycemia and CV outcomes in the CARMELINA trial but no associations in either direction in the CAROLINA trial, challenging the notion that hypoglycemia causes adverse CV events. The findings from the CARMELINA trial suggest that both hypoglycemia and CV events more likely identify patients at high risk for both. Trial Registration: ClinicalTrials.gov Identifier: NCT01897532 (CARMELINA) and NCT01243424 (CAROLINA).

Nephrology Partnership for Advancing Technology in Healthcare (N-PATH) program: the teachers' perspective.

The N-PATH (Nephrology Partnership for Advancing Technology in Healthcare) program concluded with the 60th European Renal Association 2023 Congress in Milan, Italy. This collaborative initiative aimed to provide advanced training in interventional nephrology to young European nephrologists. Funded by Erasmus+ Knowledge Alliance, N-PATH addressed the global burden of chronic kidney disease (CKD) and the shortage of nephrologists. CKD affects >850 million people worldwide, yet nephrology struggles to attract medical talent, leading to unfilled positions in residency programs. To address this, N-PATH focused on enhancing nephrology education through four specialized modules: renal expert in renal pathology (ReMAP), renal expert in vascular access (ReVAC), renal expert in medical ultrasound (ReMUS) and renal expert in peritoneal dialysis (RePED). ReMAP emphasized the importance of kidney biopsy in nephrology diagnosis and treatment, providing theoretical knowledge and hands-on training. ReVAC centred on vascular access in haemodialysis, teaching trainees about different access types, placement techniques and managing complications. ReMUS recognized the significance of ultrasound in nephrology, promoting interdisciplinary collaboration and preparing nephrologists for comprehensive patient care. RePED addressed chronic peritoneal dialysis, offering comprehensive training in patient selection, prescription, monitoring, complications and surgical techniques for catheter insertion. Overall, N-PATH's strategy involved collaborative networks, hands-on training, mentorship, an interdisciplinary approach and the integration of emerging technologies. By bridging the gap between theoretical knowledge and practical skills, N-PATH aimed to revitalize interest in nephrology and prepare proficient nephrologists to tackle the challenges of kidney diseases. In conclusion, the N-PATH program aimed to address the shortage of nephrologists and improve the quality of nephrology care in Europe. By providing specialized training, fostering collaboration and promoting patient-centred care, N-PATH aimed to inspire future nephrology professionals to meet the growing healthcare demands related to kidney diseases and elevate the specialty's status within the medical community.

Protein Biomarkers and Major Cardiovascular Events in Older People With Advanced CKD: The European Quality (EQUAL) Study.

Rationale & Objective: Cardiovascular disease is the leading cause of morbidity and mortality in chronic kidney disease (CKD). We investigated 184 inflammatory and cardiovascular proteins to determine their potential as biomarkers for major cardiovascular events (MACEs). Study Design: The European Quality (EQUAL) is an observational cohort study that enrolled people aged ≥65 years with an estimated glomerular filtration rate ≤20 mL/min/1.73 m2. Setting & Participants: Recruited participants were split into the discovery (n = 611) and replication cohorts (n = 292). Exposure: Levels of 184 blood proteins were measured at the baseline visit, and each protein was analyzed individually. Outcome: MACE. Analytical Approach: Cox proportional hazard models adjusted for age, sex, estimated glomerular filtration rate, previous MACE, and country were used to determine the risk of MACE. Proteins with false discovery rate adjusted P values of <0.05 in the discovery cohort were tested in the replication cohort. Sensitivity analyses were performed by adjusting for traditional risk factors, CKD-specific risk factors, and level of proteinuria and segregating atherosclerotic and nonatherosclerotic MACE. Results: During a median follow-up of 2.9 years, 349 people (39%) experienced a MACE. Forty-eight proteins were associated with MACE in the discovery cohort; 9 of these were reproduced in the replication cohort. Three of these proteins maintained a strong association with MACE after adjustment for traditional and CKD-specific risk factors and proteinuria. Tenascin (TNC), fibroblast growth factor-23 (FGF-23), and V-set and immunoglobulin domain-containing protein 2 (VSIG2) were associated with both atherosclerotic and nonatherosclerotic MACE. All replicated proteins except carbonic anhydrase 1 and carbonic anhydrase 3 were associated with nonatherosclerotic MACE. Limitations: Single protein concentration measurements and limited follow-up time. Conclusions: Our findings corroborate previously reported relationships between FGF-23, vascular cell adhesion protein-1, TNC, and placental growth factor with cardiovascular outcomes in CKD. We identify 5 proteins not previously linked with MACE in CKD that may be targets for future therapies. Plain-Language Summary: Kidney disease increases the risk of heart disease, stroke, and other vascular conditions. Blood tests that predict the likelihood of these problems may help to guide treatment, but studies are needed in people with kidney disease. We analyzed blood tests from older people with kidney disease, looking for proteins associated with higher risk of these conditions. Nine proteins were identified, of which 3 showed a strong effect after all other information was considered. This work supports previous research regarding 4 of these proteins and identifies 5 additional proteins that may be associated with higher risk. Further work is needed to confirm our findings and to determine whether these proteins can be used to guide treatment.

Effects of Empagliflozin on Fluid Overload, Weight, and Blood Pressure in CKD.

SIGNIFICANCE STATEMENT: SGLT2 inhibitors reduce risk of kidney progression, AKI, and cardiovascular disease, but the mechanisms of benefit are incompletely understood. Bioimpedance spectroscopy can estimate body water and fat mass. One quarter of the EMPA-KIDNEY bioimpedance substudy CKD population had clinically significant levels of bioimpedance-derived "Fluid Overload" at recruitment. Empagliflozin induced a prompt and sustained reduction in "Fluid Overload," irrespective of sex, diabetes, and baseline N-terminal pro B-type natriuretic peptide or eGFR. No significant effect on bioimpedance-derived fat mass was observed. The effects of SGLT2 inhibitors on body water may be one of the contributing mechanisms by which they mediate effects on cardiovascular risk. BACKGROUND: CKD is associated with fluid excess that can be estimated by bioimpedance spectroscopy. We aimed to assess effects of sodium glucose co-transporter 2 inhibition on bioimpedance-derived "Fluid Overload" and adiposity in a CKD population. METHODS: EMPA-KIDNEY was a double-blind placebo-controlled trial of empagliflozin 10 mg once daily in patients with CKD at risk of progression. In a substudy, bioimpedance measurements were added to the main trial procedures at randomization and at 2- and 18-month follow-up visits. The substudy's primary outcome was the study-average difference in absolute "Fluid Overload" (an estimate of excess extracellular water) analyzed using a mixed model repeated measures approach. RESULTS: The 660 substudy participants were broadly representative of the 6609-participant trial population. Substudy mean baseline absolute "Fluid Overload" was 0.4±1.7 L. Compared with placebo, the overall mean absolute "Fluid Overload" difference among those allocated empagliflozin was -0.24 L (95% confidence interval [CI], -0.38 to -0.11), with similar sized differences at 2 and 18 months, and in prespecified subgroups. Total body water differences comprised between-group differences in extracellular water of -0.49 L (95% CI, -0.69 to -0.30, including the -0.24 L "Fluid Overload" difference) and a -0.30 L (95% CI, -0.57 to -0.03) difference in intracellular water. There was no significant effect of empagliflozin on bioimpedance-derived adipose tissue mass (-0.28 kg [95% CI, -1.41 to 0.85]). The between-group difference in weight was -0.7 kg (95% CI, -1.3 to -0.1). CONCLUSIONS: In a broad range of patients with CKD, empagliflozin resulted in a sustained reduction in a bioimpedance-derived estimate of fluid overload, with no statistically significant effect on fat mass. TRIAL REGISTRATION: Clinicaltrials.gov: NCT03594110 ; EuDRACT: 2017-002971-24 ( https://eudract.ema.europa.eu/ ).

Effect of Dialysate and Plasma Sodium on Mortality in a Global Historical Hemodialysis Cohort.

SIGNIFICANCE STATEMENT: This large observational cohort study aimed to investigate the relationship between dialysate and plasma sodium concentrations and mortality among maintenance hemodialysis patients. Using a large multinational cohort of 68,196 patients, we found that lower dialysate sodium concentrations (≤138 mmol/L) were independently associated with higher mortality compared with higher dialysate sodium concentrations (>138 mmol/L). The risk of death was lower among patients exposed to higher dialysate sodium concentrations, regardless of plasma sodium levels. These results challenge the prevailing assumption that lower dialysate sodium concentrations improve outcomes in hemodialysis patients. The study confirms that until robust evidence from randomized trials that are underway is available, nephrologists should remain cautious in reconsideration of dialysate sodium prescribing practices to optimize cardiovascular outcomes and reduce mortality in this population. BACKGROUND: Excess mortality in hemodialysis (HD) patients is largely due to cardiovascular disease and is associated with abnormal fluid status and plasma sodium concentrations. Ultrafiltration facilitates the removal of fluid and sodium, whereas diffusive exchange of sodium plays a pivotal role in sodium removal and tonicity adjustment. Lower dialysate sodium may increase sodium removal at the expense of hypotonicity, reduced blood volume refilling, and intradialytic hypotension risk. Higher dialysate sodium preserves blood volume and hemodynamic stability but reduces sodium removal. In this retrospective cohort, we aimed to assess whether prescribing a dialysate sodium ≤138 mmol/L has an effect on survival outcomes compared with dialysate sodium >138 mmol/L after adjusting for plasma sodium concentration. METHODS: The study population included incident HD patients from 875 Fresenius Medical Care Nephrocare clinics in 25 countries between 2010 and 2019. Baseline dialysate sodium (≤138 or >138 mmol/L) and plasma sodium (<135, 135-142, >142 mmol/L) concentrations defined exposure status. We used multivariable Cox regression model stratified by country to model the association between time-varying dialysate and plasma sodium exposure and all-cause mortality, adjusted for demographic and treatment variables, including bioimpedance measures of fluid status. RESULTS: In 2,123,957 patient-months from 68,196 incident HD patients with on average three HD sessions per week dialysate sodium of 138 mmol/L was prescribed in 63.2%, 139 mmol/L in 15.8%, 140 mmol/L in 20.7%, and other concentrations in 0.4% of patients. Most clinical centers (78.6%) used a standardized concentration. During a median follow-up of 40 months, one third of patients ( n =21,644) died. Dialysate sodium ≤138 mmol/L was associated with higher mortality (multivariate hazard ratio for the total population (1.57, 95% confidence interval, 1.25 to 1.98), adjusted for plasma sodium concentrations and other confounding variables. Subgroup analysis did not show any evidence of effect modification by plasma sodium concentrations or other patient-specific variables. CONCLUSIONS: These observational findings stress the need for randomized evidence to reliably define optimal standard dialysate sodium prescribing practices.

Kidney and heart failure events are bidirectionally associated in patients with type 2 diabetes and cardiovascular disease.

AIMS: This study aimed to evaluate the bidirectional relationship between kidney and cardiovascular (CV) events in trial participants with type 2 diabetes and CV disease. METHODS AND RESULTS: Post hoc analyses of EMPA-REG OUTCOME using Cox regression models were performed to assess the association of baseline factors with risk of a kidney event and bidirectional associations of incident kidney events and CV events. Among placebo-treated participants, baseline factors significantly associated with greater kidney event risk included lower baseline estimated glomerular filtration rate, albuminuria, higher uric acid, low-density lipoprotein cholesterol levels, and prior heart failure (HF). Coronary artery disease was not associated with increased risk. In placebo-treated participants, occurrence of an incident non-fatal kidney event increased the subsequent risk of hospitalization for HF (HHF) but not 3-point major adverse CV events (non-fatal stroke, non-fatal myocardial infarction, and CV death). Vice versa, HHF (but not myocardial infarction/stroke) increased the risk of subsequent kidney events. These associations were generally also seen in empagliflozin-treated participants and in the overall population. Interestingly, the risk of kidney events following HHF was not significantly increased in the relatively small number of placebo-treated participants already diagnosed with HF at baseline. CONCLUSIONS: These findings demonstrate a bidirectional inter-relationship between HHF and kidney events. Further exploration of this relationship and strategies to optimize the use of therapies to reduce both kidney and HF outcomes is warranted.

The impact of gender on the risk of cardiovascular events in older adults with advanced chronic kidney disease.

Background: Patients with chronic kidney disease (CKD) are at a higher risk of major adverse cardiovascular events (MACE) compared with the general population, but gender differences in this risk, especially in older adults, are not fully known. We aim to identify gender differences in the risk of MACE in older European CKD patients, and explore factors that may explain these differences. Methods: The European Quality study (EQUAL) is a prospective study on stage 4-5 CKD patients, ≥65 years old, not on dialysis, from Germany, Italy, the Netherlands, Poland, Sweden and the UK. Cox regression and cumulative incidence competing risk curves were used to identify gender differences in MACE risks. Mediation analysis was used to identify variables which may explain risk differences between men and women. Results: A total of 417 men out of 1134 (37%) and 185 women out of 602 women (31%) experienced at least one MACE, over a follow-up period of 5 years. Women had an 18% lower risk of first MACE compared with men (hazard ratio 0.82; 95% confidence interval 0.69-0.97; P = .02), which was attenuated after adjusting for pre-existing cardiometabolic comorbidities and cardiovascular risk factors. There were no significant gender differences in the risk of recurrent MACE or fatal MACE. The risk difference in MACE by gender was larger in patients aged 65-75 years, compared with patients over 75 years. Conclusions: In a cohort of older adults with advanced CKD, women had lower risks of MACE. These risk differences were partially explained by pre-existing cardiometabolic comorbidities and cardiovascular risk factors.