Pre-donation Assessment of Cystatin C to Improve Prediction of Pre- and Post-Donation GFR in Potential Living Kidney Donors.

BACKGROUND AND HYPOTHESIS: Accurate estimation of glomerular filtration rate (GFR) is crucial in living kidney donation. While most eGFR equations are based on plasma creatinine, its levels are strongly influenced by muscle mass. Application of cystatin C (CysC)-based estimates before donation may improve both estimation of current GFR and prediction of post-donation GFR. METHODS: We assessed the performance of CKD-EPI equations based on creatinine (eGFRcreat-2009, eGFRcreat-2021), cystatin C (eGFRCysC-2012), or both (eGFRcombined-2012, eGFRcombined-2021) for estimating pre- and post-donation measured GFR in 486 living kidney donors. We subsequently focused on a subgroup of individuals with high/low muscle mass (25% highest/lowest 24-hour urinary creatinine excretion, sex-stratified and height-indexed). RESULTS: Pre-donation eGFRcombined 2012 and eGFRcombined 2021 showed the strongest associations with pre- and post-donation mGFR. Pre-donation eGFRcombined 2021 was most accurate for estimating both pre-donation (bias 0.01±11.9 mL/min/1.73m2) and post-donation mGFR (bias 1.3±8.5 mL/min/1.73 m2). In donors with high/low muscle mass, CysC-based equations (with or without creatinine) performed better compared to equations based on only creatinine. CONCLUSIONS: In conclusion, combined eGFR equations yielded a better estimate of pre- and post-donation mGFR, compared to estimates based on creatinine or CysC only. The added value of CysC seems particularly pronounced in donors with high or low muscle mass.

Cost-effectiveness of finerenone in chronic kidney disease associated with type 2 diabetes in The Netherlands.

BACKGROUND: In the Netherlands, more than one million patients have type 2 diabetes (T2D), and approximately 36% of these patients have chronic kidney disease (CKD). Yearly medical costs related to T2D and CKD account for approximately €1.3 billion and €805 million, respectively. The FIDELIO-DKD trial showed that the addition of finerenone to the standard of care (SoC) lowers the risk of CKD progression and cardiovascular (CV) events in patients with CKD stages 2-4 associated with T2D. This study investigates the cost-effectiveness of adding finerenone to the SoC of patients with advanced CKD and T2D compared to SoC monotherapy. METHODS: The validated FINE-CKD model is a Markov cohort model which simulates the disease pathway of patients over a lifetime time horizon. The model was adapted to reflect the Dutch societal perspective. The model estimated the incremental costs, utilities, and incremental cost-effectiveness ratio (ICER). Sensitivity and scenario analyses were performed to assess the effect of parameter uncertainty on model robustness. RESULTS: When used in conjunction with SoC, finerenone extended time free of CV events and renal replacement therapy by respectively 0.30 and 0.31 life years compared to SoC alone, resulting in an extension of 0.20 quality-adjusted life years (QALYs). The reduction in renal and CV events led to a €6136 decrease in total lifetime costs per patient compared to SoC alone, establishing finerenone as a dominant treatment option. Finerenone in addition to SoC had a 83% probability of being dominant and a 93% probability of being cost-effective at a willingness-to-pay threshold of €20,000. CONCLUSION: By reducing the risk of CKD progression and CV events, finerenone saves costs to society while gaining QALYs in patients with T2D and advanced CKD in the Netherlands.

Separate and combined effects of individual and neighbourhood socio-economic disadvantage on health-related lifestyle risk factors: a multilevel analysis.

BACKGROUND: Socio-economic disadvantage at both individual and neighbourhood levels has been found to be associated with single lifestyle risk factors. However, it is unknown to what extent their combined effects contribute to a broad lifestyle profile. We aimed to (i) investigate the associations of individual socio-economic disadvantage (ISED) and neighbourhood socio-economic disadvantage (NSED) in relation to an extended score of health-related lifestyle risk factors (lifestyle risk index); and to (ii) investigate whether NSED modified the association between ISED and the lifestyle risk index. METHODS: Of 77 244 participants [median age (IQR): 46 (40-53) years] from the Lifelines cohort study in the northern Netherlands, we calculated a lifestyle risk index by scoring the lifestyle risk factors including smoking status, alcohol consumption, diet quality, physical activity, TV-watching time and sleep time. A higher lifestyle risk index was indicative of an unhealthier lifestyle. Composite scores of ISED and NSED based on a variety of socio-economic indicators were calculated separately. Linear mixed-effect models were used to examine the association of ISED and NSED with the lifestyle risk index and to investigate whether NSED modified the association between ISED and the lifestyle risk index by including an interaction term between ISED and NSED. RESULTS: Both ISED and NSED were associated with an unhealthier lifestyle, because ISED and NSED were both positively associated with the lifestyle risk index {highest quartile [Q4] ISED beta-coefficient [95% confidence interval (CI)]: 0.64 [0.62-0.66], P < 0.001; highest quintile [Q5] NSED beta-coefficient [95% CI]: 0.17 [0.14-0.21], P < 0.001} after adjustment for age, sex and body mass index. In addition, a positive interaction was found between NSED and ISED on the lifestyle risk index (beta-coefficient 0.016, 95% CI: 0.011-0.021, Pinteraction < 0.001), which indicated that NSED modified the association between ISED and the lifestyle risk index; i.e. the gradient of the associations across all ISED quartiles (Q4 vs Q1) was steeper among participants residing in the most disadvantaged neighbourhoods compared with those who resided in the less disadvantaged neighbourhoods. CONCLUSIONS: Our findings suggest that public health initiatives addressing lifestyle-related socio-economic health differences should not only target individuals, but also consider neighbourhood factors.

Malnutrition Universal Screening Tool and Patient-Generated Subjective Global Assessment Short Form and their predictive validity in hospitalized patients.

BACKGROUND AND AIMS: Malnutrition screening is a first step in the nutrition care process for hospitalized patients, to identify those at risk of malnutrition and associated worse outcome, preceding further assessment and intervention. Frequently used malnutrition screening tools including the Malnutrition Universal Screening Tool (MUST) mainly screen for characteristics of malnutrition, while the Patient-Generated Subjective Global Assessment Short Form (PG-SGA SF) additionally includes risk factors for development of malnutrition, yielding a higher percentage of patients at risk. To investigate whether this translates into higher risk of worse outcome, we aimed to determine the predictive validity of MUST and PG-SGA SF for prolonged hospitalization >8 days, readmission, and mortality <6 months after hospital discharge. METHODS: In this observational study, MUST was performed according to university hospital protocol. Additional screening using PG-SGA SF was performed within 24 h of hospital admission (high risk: MUST ≥ 2, PG_SGA SF ≥ 9). Associations of MUST and PG-SGA SF with outcomes were analyzed by logistic- and Cox PH-regression. RESULTS: Of 430 patients analyzed (age 58 ± 16 years, 53% male, BMI 26.9 ± 5.5 kg/m2), MUST and PG-SGA SF identified 32 and 80 at high risk, respectively. One-hundred-eight patients had prolonged hospitalization, 109 were readmitted and 20 died. High risk by MUST was associated with mortality (HR = 3.9; 95% CI 1.3-12.2, P = 0.02), but not with other endpoints. High risk by PG-SGA SF was associated with prolonged hospitalization (OR = 2.5; 95% CI 1.3-5.0, P = 0.009), readmission (HR = 1.9; 95% CI 1.1-3.2, P = 0.03), and mortality (HR = 34.8; 95% CI 4.2-289.3, P = 0.001), independent of age, sex, hospital ward and previous hospitalization <6 months. In the 363/430 patients classified as low risk by MUST, high risk by PG-SGA SF was independently associated with higher risk of readmission (HR = 1.9; 95% CI 1.0-3.5, P = 0.04) and mortality (HR = 19.5; 95% CI 2.0-189.4, P = 0.01). CONCLUSIONS: Whereas high malnutrition risk by MUST was only associated with mortality, PG-SGA SF was associated with higher risk of prolonged hospitalization, readmission, and mortality. In patients considered as low risk by MUST, high malnutrition risk by PG-SGA SF was also predictive of worse outcome. Our findings support the use of PG-SGA SF in routine care to identify patients at risk of malnutrition and worse outcome, and enable proactive interventions.

Barriers to and Facilitators of Sustained Employment: A Qualitative Study of Experiences in Dutch Patients With CKD.

RATIONALE & OBJECTIVE: Although patients with chronic kidney disease (CKD) are at risk for work disability and loss of employment, not all experience work disruption. We aimed to describe the barriers to and facilitators of sustained employment experienced by Dutch patients with CKD. STUDY DESIGN: Qualitative study using semistructured interviews. SETTING & PARTICIPANTS: 27 patients with CKD glomerular filtration rate categories 3b-5 (G3b-G5) from 4 nephrology outpatient clinics in The Netherlands. ANALYTICAL APPROACH: Content analyses with constant comparison of interview data based on the International Classification of Functioning, Disability and Health framework. RESULTS: Participants were 6 patients with CKD G3b-G4, 8 patients receiving maintenance dialysis, and 13 patients with functioning kidney transplants. We identified health-related barriers (symptoms, physical toll of dialysis/transplantation, limited work capacity) and facilitators (few physical symptoms, successful posttransplantation recovery, absence of comorbidities, good physical condition), personal barriers (psychological impact, limited work experience) and facilitators (positive disposition, job satisfaction, work attitude, person-job fit), and environmental barriers and facilitators. Environmental barriers were related to nephrology care (waiting time, use of a hemodialysis catheter) and work context (reorganization, temporary contract, working hours, physical demands); environmental facilitators were related to nephrology care (personalized dialysis, preemptive transplant), work context (large employer, social climate, job requiring mental rather than physical labor, flexible working hours, adjustment of work tasks, reduced hours, remote working, support at work, peritoneal dialysis exchange facility), and support at home. Occupational health services and social security could be barriers or facilitators. LIMITATIONS: The study sample of Dutch patients may limit the transferability of these findings to other countries. CONCLUSIONS: The wide range of barriers and facilitators in all International Classification of Functioning, Disability and Health components suggests great diversity among patients and their circumstances. These findings underline the importance of personalized nephrology and occupational health care as well as the importance of individually tailored workplace accommodations to promote sustained employment for patients with CKD.

Modelling the Cost-Effectiveness of Implementing a Dietary Intervention in Renal Transplant Recipients.

BACKGROUND: The Dietary Approach to Stop Hypertension (DASH) and potassium supplementation have been shown to reduce the risk of death with a functioning graft (DWFG) and renal graft failure in renal transplant recipients (RTR). Unfortunately, a key problem for patients is the adherence to these diets. The aim of this study is to evaluate the cost-effectiveness and budget impact of higher adherence to either the DASH or potassium supplementation. METHODS: A Markov model was used to simulate the life course of 1000 RTR in the Netherlands. A societal perspective with a lifetime time horizon was used. The potential effect of improvement of dietary adherence was modelled in different scenarios. The primary outcomes are the incremental cost-effectiveness ratio (ICER) and the budget impact. RESULTS: In the base case, improved adherence to the DASH diet saved 27,934,786 and gained 1880 quality-adjusted life years (QALYs). Improved adherence to potassium supplementation saved €1,217,803 and gained 2901 QALYs. Both resulted in dominant ICERs. The budget impact over a five-year period for the entire Dutch RTR population was €8,144,693. CONCLUSION: Improving dietary adherence in RTR is likely to be cost-saving and highly likely to be cost-effective compared to the current standard of care in the Netherlands.

Vitamin Status and Diet in Elderly with Low and High Socioeconomic Status: The Lifelines-MINUTHE Study.

Socioeconomic health inequalities are an important global public health problem. However, it is not well known to what extent socioeconomic inequalities culminate in impaired vitamin status and whether this is mediated by diet. We, therefore, aimed to assess vitamin status in a population already at increased risk of micronutrient deficiency, i.e., elderly with high and low socioeconomic status (SES), and to investigate whether potential differences therein were mediated by diet quality. Vitamin status in 1605 individuals (60-75 years) from the Lifelines- Micronutrients and Health inequalities in Elderly (MINUTHE) Study was assessed by measuring folic acid and the vitamins B6, B12, D, A, E, and K. Multinomial logistic and linear regression analyses were applied to test the associations between SES and vitamin status. Mediation analysis was used to explore the interrelationship between SES, diet quality, and vitamin status. Low SES was associated with poorer status of vitamin B6, vitamin B12, and, notably, folic acid. Moreover, multivitamin deficiencies were more prevalent in the low SES group. Diet quality was found to mediate the associations of SES with folic acid (for 39.1%), vitamin B6 (for 37.1%), and vitamin B12 (for 37.2%). We conclude that low SES is a risk factor for a spectrum of vitamin deficiencies. Diet quality can partially explain the socioeconomic differences in vitamin status, suggesting that policymakers can mitigate socioeconomic inequality in nutritional status through improving diet quality.

Comparison of two methods for the assessment of intra-erythrocyte magnesium and its determinants: Results from the LifeLines cohort study.

BACKGROUND: Direct methods for the assessment of intra-erythrocyte magnesium (dIEM) require extensive sample preparation, making them labor intensive. An alternative, less labor intensive method is indirect calculation of intra-erythrocyte magnesium (iIEM). We compared dIEM and iIEM and studied determinants of dIEM and iIEM, plasma magnesium and 24-h urinary magnesium excretion in a large population-based cohort study. METHODS: dIEM and iIEM were measured using a validated inductively coupled plasma mass spectrometry (ICP-MS) method in 1669 individuals from the second screening from the LifeLines Cohort Study. We used linear regression analyses to study the determinants of IEM, plasma magnesium and 24-h urinary magnesium excretion. RESULTS: Mean dIEM and iIEM were 0.20 ± 0.04 mmol/1012 cells and 0.25 ± 0.04 mmol/1012 cells, respectively. We found a strong correlation between dIEM and iIEM (r = 0.75). Passing-Bablok regression analyses showed an intercept of 0.015 (95% CI: 0.005; 0.023) and a slope of 1.157 (95% CI: 1.109; 1.210). In linear regression analyses, plasma levels of total- and LDL -cholesterol, and triglycerides were positively associated dIEM, iIEM, and plasma magnesium, while glucose and HbA1c were inversely associated with plasma magnesium. CONCLUSIONS: We observed a strong correlation between dIEM and iIEM, suggesting that iIEM is a reliable alternative for the labor intensive dIEM method.

Complementary Biomarker Assessment of Components Absorbed from Diet and Creatinine Excretion Rate Reflecting Muscle Mass in Dialysis Patients.

To prevent protein energy malnutrition (PEM) and accumulation of waste products, dialysis patients require diet adjustments. Dietary intake assessed by self-reported intakes often provides biased information and standard 24-h urinary excretion is inapplicable in dialysis patients. We aimed to assess dietary intake via a complementary, less biased biomarker method, and to compare this to dietary diaries. Additionally, we investigated the prospective association of creatinine excretion rate (CER) reflecting muscle mass with mortality. Complete intradialytic dialysate and interdialytic urinary collections were used to calculate 24-h excretion of protein, sodium, potassium, phosphate and creatinine in 42 chronic dialysis patients and compared with protein, sodium, potassium, and phosphate intake assessed by 5-day dietary diaries. Cox regression analyses were employed to investigate associations of CER with mortality. Mean age was 64 ± 13 years and 52% were male. Complementary biomarker assessed (CBA) and dietary assessed (DA) protein intake were significantly correlated (r = 0.610; p < 0.001), but there was a constant bias, as dietary diaries overestimated protein intake in most patients. Correlations were found between CBA and DA sodium intake (r = 0.297; p = 0.056), potassium intake (r = 0.312; p = 0.047) and phosphate uptake/intake (r = 0.409; p = 0.008). However, Bland-Altman analysis showed significant proportional bias. During a median follow-up of 26.6 (25.3⁻31.5) months, nine dialysis patients (23%) died. CER was independently and inversely associated with survival (HR: 0.59 (0.42⁻0.84); p = 0.003). Excretion measurements may be a more reliable assessment of dietary intake in dialysis patients, as this method is relatively free from biases known to exist for self-reported intakes. CER seems to be a promising tool for monitoring PEM.

Glycaemic control in the diabetes and Lifestyle Cohort Twente: A cross-sectional assessment of lifestyle and pharmacological management on Hba1c target achievement.

The majority of patients with type 2 diabetes do not reach target levels of glycated haemoglobin (HbA1c < 7%). We investigated the prevalence of HbA1c-target achievement and opportunities afforded by lifestyle and pharmacological treatment to increase target achievement. We performed cross-sectional analyses of baseline data from the Diabetes and Lifestyle Cohort Twente-1 (DIALECT-1). Patients were divided according to (1) HbA1c <53 and ≥53 mmol/mol (<7%) and (2) non-insulin treatment and tertiles of daily insulin use. We found that 161 (36%) patients achieved the target HbA1c level. Patients with HbA1c ≥53 mmol/mol had a longer duration of diabetes (13 [8-20] vs 9 [4-14] years; P < .001) and more frequently were insulin-users (76% vs 41%, P < .001). Patients in the highest tertile of insulin use had a higher body mass index than those in the lowest tertile (35.8 ± 5.5 vs 29.8 ± 5.5 kg/m2 ; P < .001). Achievement of target HbA1c is low in this type 2 diabetes population. High resistance to pharmacological treatment, paralleled with high body mass index, illustrates that increasing insulin sensitivity through lifestyle intervention is the best opportunity to improve HbA1c target achievement in this real-life population.

Real-life achievement of lipid-lowering treatment targets in the DIAbetes and LifEstyle Cohort Twente: systemic assessment of pharmacological and nutritional factors.

BACKGROUND/OBJECTIVES: Lowering low-density lipoprotein cholesterol (LDLc) in type 2 diabetes mellitus is of paramount importance in preventing cardiovascular disease. However, treatment targets for LDLc are often not reached. We studied the prevalence of LDLc target achievement in a real-life population of type 2 diabetes mellitus patients in secondary care, and investigated whether in those not on target, there is room for intensifying pharmacological and lifestyle management according to current treatment guidelines. SUBJECTS/METHODS: We performed a cross-sectional analysis in the DIAbetes and LifEstyle Cohort Twente-1 (DIALECT-1; n = 450, age 63 ± 9 years, 58% men, diabetes duration 11 (7-18) years). At baseline, we determined plasma LDLc concentration, pharmacological treatment (i.e., statin use), and lifestyle (physical activity and dietary intake). Patients were divided according to LDLc < 1.8, LDLc 1.8-2.5, and LDLc > 2.5 mmol/l. Dietary intake was collected from a validated Food Frequency Questionnaire (177 items) and we determined guideline adherence for different food groups. Physical activity was assessed with the Short Questionnaire to ASsess Health enhancing behavior. RESULTS: LDLc data were available in 428 type 2 diabetes mellitus patients. LDLc ≤ 2.5 mmol/l was achieved in 317 patients (76%). In total, 76% of patients used statins, in those with LDLc > 2.5 mmol/l, this was 44%. Adherence to lifestyle guidelines was not different between the LDLc groups and was as follows: body mass index 6%, physical activity 59%, vegetables 7%, fruit 28%, legumes 59%, nuts 14%, dairy 19%, fish 36%, tea 8%, fats 66%, red meat 12%, processed meat 2%, alcohol 71%, sweetened beverages 34%, and sodium 12%. CONCLUSIONS: In type 2 diabetes mellitus patients in secondary health care, the target LDLc is achieved by three quarters of patients. Increasing statin treatment could be a first step to improve LDLc. In addition, there are ample opportunities for lifestyle management through increasing adherence to lifestyle guidelines.

Combining traditional dietary assessment methods with novel metabolomics techniques: present efforts by the Food Biomarker Alliance.

FFQ, food diaries and 24 h recall methods represent the most commonly used dietary assessment tools in human studies on nutrition and health, but food intake biomarkers are assumed to provide a more objective reflection of intake. Unfortunately, very few of these biomarkers are sufficiently validated. This review provides an overview of food intake biomarker research and highlights present research efforts of the Joint Programming Initiative 'A Healthy Diet for a Healthy Life' (JPI-HDHL) Food Biomarkers Alliance (FoodBAll). In order to identify novel food intake biomarkers, the focus is on new food metabolomics techniques that allow the quantification of up to thousands of metabolites simultaneously, which may be applied in intervention and observational studies. As biomarkers are often influenced by various other factors than the food under investigation, FoodBAll developed a food intake biomarker quality and validity score aiming to assist the systematic evaluation of novel biomarkers. Moreover, to evaluate the applicability of nutritional biomarkers, studies are presently also focusing on associations between food intake biomarkers and diet-related disease risk. In order to be successful in these metabolomics studies, knowledge about available electronic metabolomics resources is necessary and further developments of these resources are essential. Ultimately, present efforts in this research area aim to advance quality control of traditional dietary assessment methods, advance compliance evaluation in nutritional intervention studies, and increase the significance of observational studies by investigating associations between nutrition and health.

Consumption of whole grains, fruit and vegetables is not associated with indices of renal function in the population-based longitudinal Doetinchem study.

Emerging evidence suggests that diet and renal function are related. Little is known, however, about the association of consumption of whole grains, fruit and vegetables with urinary albumin:creatinine ratio (ACR) and changes in estimated glomerular filtration rate (eGFR). We investigated this in a population-based cohort aged 26-65 years. Data were from 3787 participants from the Doetinchem cohort study, who were examined ≥3 times, 5 years apart. Consumption of food groups was assessed at each round with a validated FFQ. GFR was estimated at each round from routinely measured cystatin C and creatinine using the Chronic Kidney Disease-Epidemiology (CKD-EPI) equation. ACR was measured at the last round. Generalised estimated equation models were performed to examine associations with changes in eGFR. Linear regression was used to examine associations with ACR. Adjustments were made for covariates related to lifestyle, biological factors and diet. Mean baseline eGFR was 104·5 (sd 13·7) and mean annual decline was -0·95 (sd 0·67) ml/min per 1·73 m2 over a 15-year follow-up. A trend was observed towards slightly less annual decline in eGFR among those with higher consumption of whole grains (P=0·06). This association, however, was attenuated and no longer significant in multivariate models (P=0·29). Consumption of fruit and vegetables was not associated with changes in eGFR and urinary ACR. In conclusion, consumption of whole grains, fruit and vegetables is not associated with changes in eGFR and mean ACR. As this was the first longitudinal study into this association in the general population, and as results are only partially in line with related studies, further research is recommended.

Integrated Assessment of Pharmacological and Nutritional Cardiovascular Risk Management: Blood Pressure Control in the DIAbetes and LifEstyle Cohort Twente (DIALECT).

Cardiovascular risk management is an integral part of treatment in Type 2 Diabetes Mellitus (T2DM), and requires pharmacological as well as nutritional management. We hypothesize that a systematic assessment of both pharmacological and nutritional management can identify targets for the improvement of treatment quality. Therefore, we analysed blood pressure (BP) management in the DIAbetes and LifEstyle Cohort Twente (DIALECT). DIALECT is an observational cohort from routine diabetes care, performed at the ZGT Hospital (Almelo and Hengelo, The Netherlands). BP was measured for 15 minutes with one minute intervals. Sodium and potassium intake was derived from 24-hour urinary excretion. We determined the adherence to pharmacological and non-pharmacological guidelines in patients with BP on target (BP-OT) and BP not on target (BP-NOT). In total, 450 patients were included from August 2009 until January 2016. The mean age was 63 ± 9 years, and the majority was male (58%). In total, 53% had BP-OT. In those with BP-NOT, pharmacological management was suboptimal (zero to two antihypertensive drugs) in 62% of patients, and nutritional guideline adherence was suboptimal in 100% of patients (only 8% had a sodium intake on target, 66% had a potassium intake on target, 3% had a sodium-to-potassium ratio on target, and body mass index was <30 kg/m² in 35%). These data show pharmacological undertreatment and a low adherence to nutritional guidelines. Uncontrolled BP is common in T2DM, and our data show a window of opportunity for improving BP control, especially in nutritional management. To improve treatment quality, we advocate to incorporate the integrated monitoring of nutritional management in quality improvement cycles in routine care.

Design of stepwise screening for prediabetes and type 2 diabetes based on costs and cases detected.

OBJECTIVES: To provide insight into the trade-off between cost per case detected (CPCD) and the detection rate in questionnaire-based stepwise screening for impaired fasting glucose and undiagnosed type 2 diabetes. STUDY DESIGN AND SETTING: We considered a stepwise screening in which individuals whose risk score exceeds a predetermined cutoff value are invited for further blood glucose testing. Using individual patient data to determine questionnaire sensitivity and specificity and external sources to determine screening costs and patient response rates, we rolled back a decision tree to estimate the CPCD and the detection rate for all possible cutoffs on the questionnaire. RESULTS: We found a U-shaped relation between CPCD and detection rate, with high costs per case detected at very low and very high detection rates. Changes in patient response rates had a large impact on both the detection rate and the CPCD, whereas screening costs and questionnaire accuracy mainly impacted the CPCD. CONCLUSION: Our applied method makes it possible to identify a range of efficient cutoffs where higher detection rates can be achieved at an additional cost per detected patient. This enables decision makers to choose an optimal cutoff based on their willingness to pay for additional detected patients.

Assessment of Cotinine Reveals a Dose-Dependent Effect of Smoking Exposure on Long-term Outcomes After Renal Transplantation.

BACKGROUND: Smoking is a risk factor for poor late outcomes in renal transplant recipients (RTR). Smoking exposure can be assessed by self-report and cotinine measurements. We investigated whether use of cotinine as a biomarker for smoking exposure can serve as an alternative for self-report and to compare associations of smoking exposure by self-report and cotinine with outcomes in RTR and assess dose dependency. METHODS: Renal transplant recipients were classified as never, former, light (≤10 cigarettes/day), and heavy smokers (>10 cigarettes/day) according to self-report and analogous categories for urine and plasma cotinine. First, we assessed agreement of self-reported smoking exposure with smoking exposure according urine and plasma cotinine. Second, we compared the associations with graft failure and mortality. RESULTS: Of 603 RTR (age 51.5 ± 12.1 years, 55% men), 36.0% RTR were never, 42.3% former, 10.6% light, and 11.1% heavy smokers according to self-report. The majority (98.6%) of never smokers had nondetectable cotinine. However, 14 and 13 RTR reporting no active smoking had respective urine or plasma cotinine consistent with active smoking. Cotinine-based measurements were dose-dependently associated with mortality and graft failure. CONCLUSIONS: Plasma and urine cotinine can serve as an alternative to self-report and were dose-dependently associated with poor late outcomes in RTR.

Diagnosis and Prediction of CKD Progression by Assessment of Urinary Peptides.

Progressive CKD is generally detected at a late stage by a sustained decline in eGFR and/or the presence of significant albuminuria. With the aim of early and improved risk stratification of patients with CKD, we studied urinary peptides in a large cross-sectional multicenter cohort of 1990 individuals, including 522 with follow-up data, using proteome analysis. We validated that a previously established multipeptide urinary biomarker classifier performed significantly better in detecting and predicting progression of CKD than the current clinical standard, urinary albumin. The classifier was also more sensitive for identifying patients with rapidly progressing CKD. Compared with the combination of baseline eGFR and albuminuria (area under the curve [AUC]=0.758), the addition of the multipeptide biomarker classifier significantly improved CKD risk prediction (AUC=0.831) as assessed by the net reclassification index (0.303±-0.065; P<0.001) and integrated discrimination improvement (0.058±0.014; P<0.001). Correlation of individual urinary peptides with CKD stage and progression showed that the peptides that associated with CKD, irrespective of CKD stage or CKD progression, were either fragments of the major circulating proteins, suggesting failure of the glomerular filtration barrier sieving properties, or different collagen fragments, suggesting accumulation of intrarenal extracellular matrix. Furthermore, protein fragments associated with progression of CKD originated mostly from proteins related to inflammation and tissue repair. Results of this study suggest that urinary proteome analysis might significantly improve the current state of the art of CKD detection and outcome prediction and that identification of the urinary peptides allows insight into various ongoing pathophysiologic processes in CKD.

One risk assessment tool for cardiovascular disease, type 2 diabetes, and chronic kidney disease.

OBJECTIVE: Individuals at high risk for chronic cardiometabolic disease (cardiovascular disease [CVD], type 2 diabetes, and chronic kidney disease [CKD]) share many risk factors and would benefit from early intervention. We developed a nonlaboratory-based risk-assessment tool for identification of people at high cardiometabolic disease risk. RESEARCH DESIGN AND METHODS: Data of three population-based cohorts from different regions of the Netherlands were merged. Participants were 2,840 men and 3,940 women, white, aged 28-85 years, free from CVD, type 2 diabetes, and CKD diagnosis at baseline. The outcome was developing cardiometabolic disease during 7 years follow-up. RESULTS: Age, BMI, waist circumference, antihypertensive treatment, smoking, family history of myocardial infarction or stroke, and family history of diabetes were significant predictors, whereas former smoking, history of gestational diabetes, and use of lipid-lowering medication were not. The models showed acceptable calibration (Hosmer and Lemeshow statistics, P > 0.05) and discrimination (area under the receiver operating characteristic [ROC] curve 0.82 [95% CI 0.81-0.83] for women and 0.80 [0.78-0.82] for men). Discrimination of individual outcomes was lowest for diabetes (area under the ROC curve 0.70 for men and 0.73 for women) and highest for CVD mortality (0.83 for men and 0.85 for women). CONCLUSIONS: We demonstrate that a single risk stratification tool can identify people at high risk for future CVD, type 2 diabetes, and/or CKD. The present risk-assessment tool can be used for referring the highest risk individuals to health care for further (multivariable) risk assessment and may as such serve as an important part of prevention programs targeting chronic cardiometabolic disease.

Urinary creatinine excretion reflecting muscle mass is a predictor of mortality and graft loss in renal transplant recipients.

BACKGROUND: Insulin resistance has been implicated to underlie both excess cardiovascular disease and chronic transplant dysfunction after renal transplantation. Skeletal muscle mainly determines peripheral insulin resistance, and could therefore affect outcome. METHODS: All transplant recipients at our outpatient clinic with a functioning graft more than 1 year were invited to participate between 2001 and 2003. Mortality and death censored graft loss were recorded until August 2007. We used 24 hr urine creatinine excretion as measure of muscle mass. Cox regression was used to analyze the prospective data. RESULTS: Six hundred four renal transplant recipients (age 51+/-12 years, 55% men) were studied. Creatinine excretion was 10.1+/-2.6 mmol/24 hr in women and 13.6+/-3.4 mmol/24 hr in men. During follow-up of 5.3 (4.7-5.7) years, 95 recipients died and 42 suffered graft loss. Determinants of creatinine excretion were weight, sex, age, height, cumulative prednisolone doses, and diabetes (r2=0.45). Creatinine excretion was associated with both mortality (3rd vs. 1st tertile Hazard ratio: 0.4 [95% confidence interval 0.2-0.7], P=0.003) and graft loss (3rd vs. 1st tertile Hazard ratio: 0.4 [95% confidence interval 0.1-0.9], P=0.03) independent of age, sex, serum creatinine, proteinuria, insulin resistance related factors, time after transplantation, and duration of dialysis. CONCLUSIONS: Creatinine excretion as measure of muscle mass is associated with mortality and graft loss after renal transplantation, independent of insulin resistance and its related factors. We speculate that preservation of muscle mass by stimulating exercise, sufficient diet, and less use of corticosteroids may be relevant for improving prognosis in renal transplant recipients.