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.

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.

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.

Clinical and patient-reported trajectories at end-of-life in older patients with advanced CKD.

BACKGROUND: We explore longitudinal trajectories of clinical indicators, patient-reported outcomes, and hospitalizations, in the years preceding death in a population of older patients with advanced chronic kidney disease (CKD). METHODS: The EQUAL study is a European observational prospective cohort study with an incident eGFR <20 ml/min per 1.73 m2 and ≥65 years of age. The evolution of each clinical indicator was explored using generalized additive models during the 4 years preceding death. RESULTS: We included 661 decedents with a median time to death of 2.0 years (IQR 0.9-3.2). During the years preceding death, eGFR, Subjective Global Assessment score, and blood pressure declined, with accelerations seen at 6 months preceding death. Serum hemoglobin, hematocrit, cholesterol, calcium, albumin, and sodium values declined slowly during follow-up, with accelerations observed between 6 and 12 months preceding death. Physical and mental quality of life declined linearly throughout follow-up. The number of reported symptoms was stable up to 2 years prior to death, with an acceleration observed at 1 year prior to death. The rate of hospitalization was stable at around one hospitalization per person year, increasing exponentially at 6 months preceding death. CONCLUSIONS: We identified clinically relevant physiological accelerations in patient trajectories that began ∼6 to 12 months prior to death, which are likely multifactorial in nature, but correlate with a surge in hospitalizations. Further research should focus on how to effectively use this knowledge to inform patient and family expectations, to benefit the planning of (end-of-life) care, and to establish clinical alert systems.

Serum Potassium and Risk of Death or Kidney Replacement Therapy in Older People With CKD Stages 4-5: Eight-Year Follow-up.

RATIONALE & OBJECTIVE: Hypokalemia may accelerate kidney function decline. Both hypo- and hyperkalemia can cause sudden cardiac death. However, little is known about the relationship between serum potassium and death or the occurrence of kidney failure requiring replacement therapy (KRT). We investigated this relationship in older people with chronic kidney disease (CKD) stage 4-5. STUDY DESIGN: Prospective observational cohort study. SETTING & PARTICIPANTS: We followed 1,714 patients (≥65 years old) from the European Quality (EQUAL) study for 8 years from their first estimated glomerular filtration rate (eGFR)<20mL/min/1.73m2 measurement. EXPOSURE: Serum potassium was measured every 3 to 6 months and categorized as≤3.5,>3.5-≤4.0,>4.0-≤4.5,>4.5-≤5.0 (reference),>5.0-≤5.5, >5.5-≤6.0, and>6.0mmol/L. OUTCOME: The combined outcome death before KRT or start of KRT. ANALYTICAL APPROACH: The association between categorical and continuous time-varying potassium and death or KRT start was examined using Cox proportional hazards and restricted cubic spline analyses, adjusted for age, sex, diabetes, cardiovascular disease, renin-angiotensin-aldosterone system (RAAS) inhibition, eGFR, and subjective global assessment (SGA). RESULTS: At baseline, 66% of participants were men, 42% had diabetes, 47% cardiovascular disease, and 54% used RAAS inhibitors. Their mean age was 76±7 (SD) years, mean eGFR was 17±5 (SD) mL/min/1.73m2, and mean SGA was 6.0±1.0 (SD). Over 8 years, 414 (24%) died before starting KRT, and 595 (35%) started KRT. Adjusted hazard ratios for death or KRT according to the potassium categories were 1.6 (95% CI, 1.1-2.3), 1.4 (95% CI, 1.1-1.7), 1.1 (95% CI, 1.0-1.4), 1 (reference), 1.1 (95% CI, 0.9-1.4), 1.8 (95% CI, 1.4-2.3), and 2.2 (95% CI, 1.5-3.3). Hazard ratios were lowest at a potassium of about 4.9mmol/L. LIMITATIONS: Shorter intervals between potassium measurements would have allowed for more precise estimations. CONCLUSIONS: We observed a U-shaped relationship between serum potassium and death or KRT start among patients with incident CKD 4-5, with a nadir risk at a potassium level of 4.9mmol/L. These findings underscore the potential importance of preventing both high and low potassium in patients with CKD 4-5. PLAIN-LANGUAGE SUMMARY: Abnormal potassium blood levels may increase the risk of death or kidney function decline, especially in older people with chronic kidney disease (CKD). We studied 1,714 patients aged≥65 years with advanced CKD from the European Quality (EQUAL) study and followed them for 8 years. We found that both low and high levels of potassium were associated with an increased risk of death or start of kidney replacement therapy, with the lowest risk observed at a potassium level of 4.9 mmol/L. In patients with CKD, the focus is often on preventing high blood potassium. However, this relatively high optimum potassium level stresses the potential importance of also preventing low potassium levels in older patients with advanced CKD.

Association between CKD-MBD and mortality in older patients with advanced CKD-results from the EQUAL study.

BACKGROUND: Chronic kidney disease-mineral and bone disorder (CKD-MBD) is a common complication of CKD; it is associated with higher mortality in dialysis patients, while its impact in non-dialysis patients remains mostly unknown. We investigated the associations between parathyroid hormone (PTH), phosphate and calcium (and their interactions), and all-cause, cardiovascular (CV) and non-CV mortality in older non-dialysis patients with advanced CKD. METHODS: We used data from the European Quality study, which includes patients aged ≥65 years with estimated glomerular filtration rate ≤20 mL/min/1.73 m2 from six European countries. Sequentially adjusted Cox models were used to assess the association between baseline and time-dependent CKD-MBD biomarkers and all-cause, CV and non-CV mortality. Effect modification between biomarkers was also assessed. RESULTS: In 1294 patients, the prevalence of CKD-MBD at baseline was 94%. Both PTH [adjusted hazard ratio (aHR) 1.12, 95% confidence interval (CI) 1.03-1.23, P = .01] and phosphate (aHR 1.35, 95% CI 1.00-1.84, P = .05), but not calcium (aHR 1.11, 95% CI 0.57-2.17, P = .76), were associated with all-cause mortality. Calcium was not independently associated with mortality, but modified the effect of phosphate, with the highest mortality risk found in patients with both hypercalcemia and hyperphosphatemia. PTH level was associated with CV mortality, but not with non-CV mortality, whereas phosphate was associated with both CV and non-CV mortality in most models. CONCLUSIONS: CKD-MBD is very common in older non-dialysis patients with advanced CKD. PTH and phosphate are independently associated with all-cause mortality in this population. While PTH level is only associated with CV mortality, phosphate seems to be associated with both CV and non-CV mortality.

Symptom Burden before and after Dialysis Initiation in Older Patients.

BACKGROUND AND OBJECTIVES: For older patients with kidney failure, lowering symptom burden may be more important than prolonging life. Dialysis initiation may affect individual kidney failure-related symptoms differently, but the change in symptoms before and after start of dialysis has not been studied. Therefore, we investigated the course of total and individual symptom number and burden before and after starting dialysis in older patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The European Quality (EQUAL) study is an ongoing, prospective, multicenter study in patients ≥65 years with an incident eGFR ≤20 ml/min per 1.73 m2. Using the dialysis symptom index (DSI), 30 symptoms were assessed every 3-6 months between 2012 and 2021. Scores for symptom number range from zero to 30 and, for burden, from zero to 150, with higher scores indicating more severity. Using mixed effects models, we studied symptoms during the year preceding and the year after dialysis initiation. RESULTS: We included 456 incident patients on dialysis who filled out at least one DSI during the year before or after dialysis. At dialysis initiation, mean (SD) participant age was 76 (6) years, 75% were men, mean (SD) eGFR was 8 (3) ml/min per 1.73 m2, 44% had diabetes, and 46% had cardiovascular disease. In the year before dialysis initiation, symptom number increased +3.6 (95% confidence interval [95% CI], +2.5 to +4.6) and symptom burden increased +13.3 (95% CI, +9.5 to +17.0). In the year after, symptom number changed -0.9 (95% CI, -3.4 to +1.5) and burden decreased -5.9 (95% CI, -14.9 to -3.0). At dialysis initiation, "fatigue," "decreased interest in sex," and "difficulty becoming sexually aroused" had the highest prevalence of 81%, 69%, and 68%, respectively, with a burden of 2.7, 2.4, and 2.3, respectively. "Fatigue" somewhat improved after dialysis initiation, whereas the prevalence and burden of sexual symptoms further increased. CONCLUSIONS: Symptom burden worsened considerably before and stabilized after dialysis initiation. "Fatigue," "decreased interest in sex," and "difficulty becoming sexually aroused" were considered most burdensome, of which only "fatigue" somewhat improved after dialysis initiation.

Predicting Kidney Failure, Cardiovascular Disease and Death in Advanced CKD Patients.

Introduction: Predicting the timing and occurrence of kidney replacement therapy (KRT), cardiovascular events, and death among patients with advanced chronic kidney disease (CKD) is clinically useful and relevant. We aimed to externally validate a recently developed CKD G4+ risk calculator for these outcomes and to assess its potential clinical impact in guiding vascular access placement. Methods: We included 1517 patients from the European Quality (EQUAL) study, a European multicentre prospective cohort study of nephrology-referred advanced CKD patients aged ≥65 years. Model performance was assessed based on discrimination and calibration. Potential clinical utility for timing of referral for vascular access placement was studied with diagnostic measures and decision curve analysis (DCA). Results: The model showed a good discrimination for KRT and "death after KRT," with 2-year concordance (C) statistics of 0.74 and 0.76, respectively. Discrimination for cardiovascular events (2-year C-statistic: 0.70) and overall death (2-year C-statistic: 0.61) was poorer. Calibration was fairly accurate. Decision curves illustrated that using the model to guide vascular access referral would generally lead to less unused arteriovenous fistulas (AVFs) than following estimated glomerular filtration rate (eGFR) thresholds. Conclusion: This study shows moderate to good predictive performance of the model in an older cohort of nephrology-referred patients with advanced CKD. Using the model to guide referral for vascular access placement has potential in combating unnecessary vascular surgeries.

Soluble suppression of tumorigenesis-2 is a strong predictor of all-cause, cardiovascular and infection-related mortality risk in haemodialysis patients with diabetes mellitus.

Background: Soluble suppression of tumorigenesis-2 (sST2) is a strong prognostic biomarker of cardiovascular (CV) disease. End-stage kidney disease (ESKD) patients are at high risk of CV events and infections. Herein we investigated the utility of sST2 to predict all-cause and cause-specific mortality in haemodialysis (HD) patients with diabetes mellitus. Methods: sST2 concentrations were measured in plasma samples of 1196 participants of the German Diabetes and Dialysis (4D) study who had type 2 diabetes mellitus and received maintenance HD for ESKD. Hazard ratios (HRs) for prespecified, adjudicated endpoints were determined according to sST2 levels at baseline by multivariate Cox proportional hazards analysis. Results: Participants (mean age 66 years, 54% male) had a median sST2 concentration of 25 ng/mL and were followed up for 4 years. After adjustment for possible confounders, participants with sST2 concentrations in the highest (>32.6 ng/mL) compared with the lowest (<20.1 ng/mL) quartile exhibited a 2-fold higher all-cause mortality risk {[HR 2.06 95% confidence interval (CI) 1.61-2.61]; P < .001}. High sST concentrations (fourth versus first quartile) were strongly associated with the risk of cardiac death [HR 2.29 (95% CI 1.55-3.39); P < .001]. Analysis of individual components of cardiac causes of death showed an increased risk of sudden death [HR 2.24 (95% CI 1.33-3.77); P < .001], death due to myocardial infarction [HR 2.12 (95% CI 0.9-5.0); P = .087] and heart failure [HR 3.34 (95% CI 1.15-9.75); P = .027] in participants with sST2 levels in the highest compared with the lowest quartile. Likewise, participants with the highest sST2 levels had an increased risk of fatal stroke [HR 1.92 (95% CI 1.17-3.14); P = .009] and fatal infections [HR 2.01 (95% CI 1.2-3.37); P = .008]. In contrast to fatal CV events, sST2 was not associated with the risk of non-fatal myocardial infarction [HR 0.68 (95% CI 0.41-1.12); P = .132] or non-fatal stroke [HR 1.28 (95% CI 0.64-2.53); P = .485]. Conclusions: In HD patients with diabetes mellitus, high concentrations of sST2 were strongly and independently associated with an increased risk of all-cause mortality, CV mortality and death due to infection but not non-fatal CV events.

The association between TMAO, CMPF, and clinical outcomes in advanced chronic kidney disease: results from the European QUALity (EQUAL) Study.

BACKGROUND: Trimethylamine N-oxide (TMAO), a metabolite from red meat and fish consumption, plays a role in promoting cardiovascular events. However, data regarding TMAO and its impact on clinical outcomes are inconclusive, possibly due to its undetermined dietary source. OBJECTIVES: We hypothesized that circulating TMAO derived from fish intake might cause less harm compared with red meat sources by examining the concomitant level of 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF), a known biomarker of fish intake, and investigated the association between TMAO, CMPF, and outcomes. METHODS: Patients were recruited from the European QUALity (EQUAL) Study on treatment in advanced chronic kidney disease among individuals aged ≥65 y whose estimated glomerular filtration rate (eGFR) had dropped for the first time to ≤20 mL/min per 1.73 m2 during the last 6 mo. The association between TMAO, CMPF, and outcomes including all-cause mortality and kidney replacement therapy (KRT) was assessed among 737 patients. Patients were further stratified by median cutoffs of TMAO and CMPF, suggesting high/low red meat and fish intake. RESULTS: During a median of 39 mo of follow-up, 232 patients died. Higher TMAO was independently associated with an increased risk of all-cause mortality (multivariable HR: 1.46; 95% CI: 1.17, 1.83). Higher CMPF was associated with a reduced risk of both all-cause mortality (HR: 0.79; 95% CI: 0.71, 0.89) and KRT (HR: 0.80; 95% CI: 0.71, 0.90), independently of TMAO and other clinically relevant confounders. In comparison to patients with low TMAO and CMPF, patients with low TMAO and high CMPF had reduced risk of all-cause mortality (adjusted HR: 0.49; 95% CI: 0.31, 0.73), whereas those with high TMAO and high CMPF showed no association across adjusted models. CONCLUSIONS: High CMPF conferred an independent role in health benefits and might even counteract the unfavorable association between TMAO and outcomes. Whether higher circulating CMPF concentrations are due to fish consumption, and/or if CMPF is a protective factor, remains to be verified.

Quality of Life before and after the Start of Dialysis in Older Patients.

BACKGROUND AND OBJECTIVES: In older people with kidney failure, improving health-related quality of life is often more important than solely prolonging life. However, little is known about the effect of dialysis initiation on health-related quality of life in older patients. Therefore, we investigated the evolution of health-related quality of life before and after starting dialysis in older patients with kidney failure. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The European Quality study is an ongoing prospective, multicenter study in patients aged ≥65 years with an incident eGFR ≤20 ml/min per 1.73 m2. Between April 2012 and December 2021, health-related quality of life was assessed every 3-6 months using the 36-item Short-Form Health Survey (SF-36), providing a mental component summary (MCS) and a physical component summary (PCS). Scores range from zero to 100, with higher scores indicating better health-related quality of life. With linear mixed models, we explored the course of health-related quality of life during the year preceding and following dialysis initiation. RESULTS: In total, 457 patients starting dialysis were included who filled out at least one SF-36 during follow-up. At dialysis initiation, mean ± SD age was 76±6 years, eGFR was 8±3 ml/min per 1.73 m2, 75% were men, 9% smoked, 45% had diabetes, and 46% had cardiovascular disease. Median (interquartile range) MCS was 53 (38-73), and median PCS was 39 (27-58). During the year preceding dialysis, estimated mean change in MCS was -13 (95% confidence interval, -17 to -9), and in PCS, it was -11 (95% confidence interval, -15 to -7). In the year following dialysis, estimated mean change in MCS was +2 (95% confidence interval, -7 to +11), and in PCS, it was -2 (95% confidence interval, -11 to +7). Health-related quality-of-life patterns were similar for most mental (mental health, role emotional, social functioning, vitality) and physical domains (physical functioning, bodily pain, role physical). CONCLUSIONS: Patients experienced a clinically relevant decline of both mental and physical health-related quality of life before dialysis initiation, which stabilized thereafter. These results may help inform older patients with kidney failure who decided to start dialysis.

The relationship between uremic toxins and symptoms in older men and women with advanced chronic kidney disease.

Background: Patients with stage 4/5 chronic kidney disease (CKD) suffer from various symptoms. The retention of uremic solutes is thought to be associated with those symptoms. However, there are relatively few rigorous studies on the potential links between uremic toxins and symptoms in patients with CKD. Methods: The EQUAL study is an ongoing observational cohort study of non-dialyzed patients with stage 4/5 CKD. EQUAL patients from Germany, Poland, Sweden and the UK were included in the present study (n = 795). Data and symptom self-report questionnaires were collected between April 2012 and September 2020. Baseline uric acid and parathyroid hormone and 10 uremic toxins were quantified. We tested the association between uremic toxins and symptoms and adjusted P-values for multiple testing. Results: Symptoms were more frequent in women than in men with stage 4/5 CKD, while levels of various uremic toxins were higher in men. Only trimethylamine N-oxide (TMAO; positive association with fatigue), p-cresyl sulfate (PCS) with constipation and 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (negative association with shortness of breath) demonstrated moderately strong associations with symptoms in adjusted analyses. The association of phenylacetylglutamine with shortness of breath was consistent in both sexes, although it only reached statistical significance in the full population. In contrast, TMAO (fatigue) and PCS and phenylacetylglutamine (constipation) were only associated with symptoms in men, who presented higher serum levels than women. Conclusion: Only a limited number of toxins were associated with symptoms in persons with stage 4/5 CKD. Other uremic toxins, uremia-related factors or psychosocial factors not yet explored might contribute to symptom burden.

Converting from face-to-face to postal follow-up and its effects on participant retention, response rates and errors: lessons from the EQUAL study in the UK.

BACKGROUND: Prospective cohort studies are challenging to deliver, with one of the main difficulties lying in retention of participants. The need to socially distance during the COVID-19 pandemic has added to this challenge. The pre-COVID-19 adaptation of the European Quality (EQUAL) study in the UK to a remote form of follow-up for efficiency provides lessons for those who are considering changing their study design. METHODS: The EQUAL study is an international prospective cohort study of patients ≥65 years of age with advanced chronic kidney disease. Initially, patients were invited to complete a questionnaire (SF-36, Dialysis Symptom Index and Renal Treatment Satisfaction Questionnaire) at research clinics every 3-6 months, known as "traditional follow-up" (TFU). In 2018, all living patients were invited to switch to "efficient follow-up" (EFU), which used an abbreviated questionnaire consisting of SF-12 and Dialysis Symptom Index. These were administered centrally by post. Response rates were calculated using returned questionnaires as a proportion of surviving invitees, and error rates presented as the average percentage of unanswered questions or unclear answers, of total questions in returned questionnaires. Response and error rates were calculated 6-monthly in TFU to allow comparisons with EFU. RESULTS: Of the 504 patients initially recruited, 236 were still alive at the time of conversion to EFU; 111 of these (47%) consented to the change in follow-up. In those who consented, median TFU was 34 months, ranging from 0 to 42 months. Their response rates fell steadily from 88% (98/111) at month 0 of TFU, to 20% (3/15) at month 42. The response rate for the first EFU questionnaire was 60% (59/99) of those alive from TFU. With this improvement in response rates, the first EFU also lowered errors to baseline levels seen in early follow-up, after having almost trebled throughout traditional follow-up. CONCLUSIONS: Overall, this study demonstrates that administration of shorter follow-up questionnaires by post rather than in person does not negatively impact patient response or error rates. These results may be reassuring for researchers who are trying to limit face-to-face contact with patients during the COVID-19 pandemic.

Health-Related Quality-of-Life Trajectories over Time in Older Men and Women with Advanced Chronic Kidney Disease.

BACKGROUND AND OBJECTIVES: The effect of sex on longitudinal health-related quality of life remains unknown in CKD. Here we assess differences in the sex-specific evolution of health-related quality of life in older men and women with advanced CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The European Quality Study on Treatment in Advanced Chronic Kidney Disease is a European observational prospective cohort study in referred patients with CKD and an incident eGFR<20 ml/min per 1.73 m2 who are ≥65 years of age not on dialysis. Health-related quality of life was measured using the 36-Item Short Form Survey at 3- to 6-month intervals between April 2012 and September 2020, providing Physical Component Summary and Mental Component Summary scores. Trajectories were modeled by sex using linear mixed models, and sex differences in health-related quality-of-life slope were explored. RESULTS: We included 5345 health-related quality-of-life measurements in 1421 participants. At baseline, women had considerably lower mean Physical Component Summary (42) and Mental Component Summary (60) compared with men (Physical Component Summary: 55; Mental Component Summary: 69; P<0.001). However, during follow-up, Physical Component Summary and Mental Component Summary scores declined approximately twice as fast in men (Physical Component Summary: 2.5 per year; 95% confidence interval, 1.8 to 3.1; Mental Component Summary: 2.7 per year; 95% confidence interval, 2.0 to 3.4) compared with in women (Physical Component Summary: 1.1 per year; 95% confidence interval, 0.1 to 2.0; Mental Component Summary: 1.6 per year; 95% confidence interval, 0.7 to 2.6). This difference was partly attenuated after adjusting for important covariates, notably eGFR decline. Higher serum phosphate, lower hemoglobin, and the presence of preexisting diabetes were associated with lower Physical Component Summary and Mental Component Summary scores in men but to a lesser extent in women. CONCLUSIONS: Among older men and women with advanced CKD, women had lower health-related quality of life at baseline, but men experienced a more rapid decline in health-related quality of life over time.

Patient-Reported Measures and Lifestyle Are Associated With Deterioration in Nutritional Status in CKD Stage 4-5: The EQUAL Cohort Study.

OBJECTIVE: The aim of this study was to explore the changes in nutritional status before dialysis initiation and to identify modifiable risk factors of nutritional status decline in older adults with advanced renal disease. DESIGN AND METHODS: The European Quality Study on treatment in advanced chronic kidney disease (EQUAL) is a prospective, observational cohort study involving six European countries. We included 1,103 adults >65 years with incident estimated glomerular filtration rate <20 mL/min/1.73 m2 not on dialysis, attending nephrology care. Nutritional status was assessed with the 7-point Subjective Global Assessment tool (7-p SGA), patient-reported outcomes with RAND-36 and the Dialysis Symptom Index. Logistic regression was used to estimate the associations between potential risk factors and SGA decline. RESULTS: The majority of the patients had a normal nutritional status at baseline, 28% were moderately malnourished (SGA ≤5). Overall, mean SGA decreased by -0.18 points/year, (95% confidence interval -0.21; -0.14). More than one-third of the study participants (34.9%) deteriorated in nutritional status (1 point decline in SGA) and 10.9% had a severe decline in SGA (≥2 points). The proportion of patients with low SGA (≤5) increased every 6 months. Those who dropped in SGA also declined in estimated glomerular filtration rate and mental health score. Every 10 points decrease in physical function score increased the odds of decline in SGA by 23%. Lower physical function score at baseline, gastrointestinal symptoms, and smoking were risk factors for impaired nutritional status. There was an interaction between diabetes and physical function on SGA decline. CONCLUSIONS: Nutritional status deteriorated in more than one-third of the study participants during the first year of follow-up. Lower patient-reported physical function, more gastrointestinal symptoms, and current smoking were associated with decline in nutritional status.

Altered vitamin K biodistribution and metabolism in experimental and human chronic kidney disease.

Chronic kidney disease (CKD) is accompanied with extensive cardiovascular calcification, in part correlating with functional vitamin K deficiency. Here, we sought to determine causes for vitamin K deficiency beyond reduced dietary intake. Initially, vitamin K uptake and distribution into circulating lipoproteins after a single administration of vitamin K1 plus K2 (menaquinone 4 and menaquinone 7, respectively) was determined in patients on dialysis therapy and healthy individuals. The patients incorporated very little menaquinone 7 but more menaquinone 4 into high density lipoprotein (HDL) and low-density lipoprotein particles than did healthy individuals. In contrast to healthy persons, HDL particles from the patients could not be spiked with menaquinone 7 in vitro and HDL uptake was diminished in osteoblasts. A reduced carboxylation activity (low vitamin K activity) of uremic HDL particles spiked with menaquinone 7 vs. that of controls was confirmed in a bioassay using human primary vascular smooth muscle cells. Kidney menaquinone 4 tissue levels were reduced in 5/6-nephrectomized versus sham-operated C57BL/6 mice after four weeks of a vitamin K rich diet. From the analyzed enzymes involved in vitamin K metabolism, kidney HMG-CoA reductase protein was reduced in both rats and patients with CKD. In a trial on the efficacy and safety of atorvastatin in 1051 patients with type 2 diabetes receiving dialysis therapy, no pronounced vitamin K deficiency was noted. However, the highest levels of PIVKA-II (biomarker of subclinical vitamin K deficiency) were noted when a statin was combined with a proton pump inhibitor. Thus, profound disturbances in lipoprotein mediated vitamin K transport and metabolism in uremia suggest that menaquinone 7 supplementation to patients on dialysis therapy has reduced efficacy.

Using datasets to ascertain the generalizability of clinical cohorts: the example of the European QUALity study on the treatment of advanced chronic kidney disease.

BACKGROUND: Cohort studies are among the most robust of observational studies but have issues with external validity. This study assesses threats to external validity (generalizability) in the European QUALity (EQUAL) study, a cohort study of people >65 years of age with Stage 4/5 chronic kidney disease. METHODS: Patients meeting the EQUAL inclusion criteria were identified in The Health Improvement Network database and stratified into those attending renal units, a secondary care cohort (SCC) and a not primary care cohort (PCC). Survival, progression to renal replacement therapy (RRT) and hospitalization were compared. RESULTS: The analysis included 250, 633 and 2464 patients in EQUAL, PCC and SCC. EQUAL had a higher proportion of men compared with PCC and SCC (60.0% versus 34.8% versus 51.4%). Increasing age ≥85 years {odds ratio [OR] 0.25 [95% confidence interval (CI) 0.15-0.40]} and comorbidity [Charlson Comorbidity Index ≥4, OR 0.69 (95% CI 0.52-0.91)] were associated with non-participation in EQUAL. EQUAL had a higher proportion of patients starting RRT at 1 year compared with SCC (8.1% versus 2.1%; P < 0.001). Patients in the PCC and SCC had increased risk of hospitalization [incidence rate ratio 1.76 (95% CI 1.27-2.47) and 2.13 (95% CI 1.59-2.86)] and mortality at 1 year [hazard ratio 3.48 (95% CI 2.1-5.7) and 1.7 (95% CI 1.1-2.7)] compared with EQUAL. CONCLUSIONS: This study provides evidence of how participants in a cohort study can differ from the broader population of patients, which is essential when considering external validity and application to local practice.

High Oxalate Concentrations Correlate with Increased Risk for Sudden Cardiac Death in Dialysis Patients.

BACKGROUND: The clinical significance of accumulating toxic terminal metabolites such as oxalate in patients with kidney failure is not well understood. METHODS: To evaluate serum oxalate concentrations and risk of all-cause mortality and cardiovascular events in a cohort of patients with kidney failure requiring chronic dialysis, we performed a post-hoc analysis of the randomized German Diabetes Dialysis (4D) Study; this study included 1255 European patients on hemodialysis with diabetes followed-up for a median of 4 years. The results obtained via Cox proportional hazards models were confirmed by competing risk regression and restricted cubic spline modeling in the 4D Study cohort and validated in a separate cohort of 104 US patients on dialysis after a median follow-up of 2.5 years. RESULTS: A total of 1108 patients had baseline oxalate measurements, with a median oxalate concentration of 42.4 µM. During follow-up, 548 patients died, including 139 (25.4%) from sudden cardiac death. A total of 413 patients reached the primary composite cardiovascular end point (cardiac death, nonfatal myocardial infarction, and fatal or nonfatal stroke). Patients in the highest oxalate quartile (≥59.7 µM) had a 40% increased risk for cardiovascular events (adjusted hazard ratio [aHR], 1.40; 95% confidence interval [95% CI], 1.08 to 1.81) and a 62% increased risk of sudden cardiac death (aHR, 1.62; 95% CI, 1.03 to 2.56), compared with those in the lowest quartile (≤29.6 µM). The associations remained when accounting for competing risks and with oxalate as a continuous variable. CONCLUSIONS: Elevated serum oxalate is a novel risk factor for cardiovascular events and sudden cardiac death in patients on dialysis. Further studies are warranted to test whether oxalate-lowering strategies improve cardiovascular mortality in patients on dialysis.

Triglyceride-Rich Lipoproteins, Apolipoproteins, and Atherosclerotic Cardiovascular Events Among Patients with Diabetes Mellitus and End-Stage Renal Disease on Hemodialysis.

Hypertriglyceridemia may be implicated in the high atherosclerotic cardiovascular disease (ASCVD) risk experienced by patients with end-stage renal disease (ESRD). In this post-hoc analysis of the "Die Deutsche Diabetes Dialyse Studie (4D)" clinical trial, we examined incident ASCVD events, defined as myocardial infarction, ischemic stroke, or a coronary revascularization procedure, among 1255 participants with type 2 diabetes and ESRD treated with hemodialysis. Cox-regression methods were used to evaluate the association of triglycerides, very-low density lipoprotein cholesterol (VLDL-C), and apolipoproteins B (Apo B) and C-III (Apo C-III) with ASCVD. During a median follow-up time of 2.3 years, 340 (27%) participants experienced an ASCVD event. Higher concentrations of triglycerides were not associated with ASCVD risk: Hazard ratio (HR) 0.95; 95% CI (0.83, 1.10) per doubling concentration. Similarly, VLDL-C HR 1.01; 95% CI (0.90, 1.13); Apo B HR 1.04; 95% CI (0.93, 1.16); and Apo C-III HR 0.97; 95% CI (0.86, 1.09) (per one standard deviation higher concentrations), were not associated with ASCVD events. These associations did not differ by allocation to treatment to atorvastatin or by concentrations of markers of inflammation or malnutrition. In conclusion, we found no evidence that triglycerides, triglyceride-rich lipoproteins, or apolipoproteins B or C-III were associated with risk of ASCVD events among patients with type 2 diabetes and ESRD on hemodialysis. These results suggest that lowering triglycerides may not decrease atherosclerotic cardiovascular risk in this population.