Iefke Drion

Clinical evaluation of analytical variations in serum creatinine measurements: why laboratories should abandon Jaffe techniques

BackgroundNon-equivalence in serum creatinine (SCr) measurements across Dutch laboratories and the consequences hereof on chronic kidney disease (CKD) staging were examined.MethodsNational data from the Dutch annual external quality organization of 2009 were used. 144 participating laboratories examined 11 pairs of commutable, value-assigned SCr specimens in the range 52–262 μmol/L, using Jaffe or enzymatic techniques. Regression equations were created for each participating laboratory (by regressing values as measured by participating laboratories on the target values of the samples sent by the external quality organization); area under the curves were examined and used to rank laboratories. The 10th and 90th percentile regression equation were selected for each technique separately. To evaluate the impact of the variability in SCr measurements and its eventual clinical consequences in a real patient population, we used a cohort of 82424 patients aged 19–106 years. The SCr measurements of these 82424 patients were introduced in the 10th and 90th percentile regression equations. The newly calculated SCr values were used to calculate an estimated glomerular filtration rate (eGFR) using the 4-variable Isotope Dilution Mass Spectrometry traceable Modification of Diet in Renal Disease formula. Differences in CKD staging were examined, comparing the stratification outcomes for Jaffe and enzymatic SCr techniques.ResultsJaffe techniques overestimated SCr: 21%, 12%, 10% for SCr target values 52, 73 and 94 μmol/L, respectively. For enzymatic assay these values were 0%, -1%, -2%, respectively. eGFR using the MDRD formula and SCr measured by Jaffe techniques, staged patients in a lower CKD category. Downgrading to a lower CKD stage occurred in 1-42%, 2-37% and 12–78.9% of patients for the 10th and 90th percentile laboratories respectively in CKD categories 45–60, 60–90 and >90 ml/min/1.73 m2. Using enzymatic techniques, downgrading occurred only in 2-4% of patients.ConclusionsEnzymatic techniques lead to less variability in SCr measurements than Jaffe techniques, and therefore result in more accurate staging of CKD. Therefore the specific enzymatic techniques are preferably used in clinical practice in order to generate more reliable GFR estimates.

A prospective observational study of quality of diabetes care in a shared care setting: trends and age differences (ZODIAC-19)

Objective The Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC) study was initiated in 1998 to investigate the effects of shared care for patients with type 2 diabetes mellitus (T2DM) in the Netherlands, and to reduce the number of diabetes-related complications. Benchmarking the performance of diabetes care was and is an important aspect of this study. We aimed to investigate trends in diabetes care, within the ZODIAC study for a wide variety of quality indicators during a long follow-up period (1998–2008), with special interest for different age groups. Design Prospective observational cohort study. Setting Primary care, Zwolle, The Netherlands. Participants Patients with T2DM. Methods A dataset of quality measures was collected annually during the patients visit to the practice nurse or general practitioner. Linear time trends from 1998 to 2008 were estimated using linear mixed models in which we adjusted for age and gender. Age was included in the model as a categorical variable: for each follow-up year all participants were categorised into the categories <60, 60–75 and >75 years. Differences in trends between the age categories were investigated by adding an interaction term to the model. Results The number of patients who were reported to participate increased in the period 1998–2008 from 1622 to 27 438. All quality indicators improved in this study, except for body mass index. The prevalence albuminuria decreased in an 11-year-period from 42% to 21%. No relevant differences between the trends for the three age categories were observed. During all years of follow-up, mean blood pressure and body mass index were the lowest and highest, respectively, in the group of patients <60 years (data not shown). Conclusions Quality of diabetes care within the Dutch ZODIAC study, a shared care project, has considerably improved in the period 1998–2008. There were no relevant differences between trends across various age categories.

Device-Guided Breathing as Treatment for Hypertension in Type 2 Diabetes Mellitus A Randomized, Double-blind, Sham-Controlled Trial

IMPORTANCE Biofeedback with device-guided lowering of breathing frequency could be an alternate nonpharmacologic treatment option for hypertension. Evidence from trials with high methodologic quality is lacking. OBJECTIVE To evaluate the effects of device-guided lowering of breathing frequency on blood pressure in patients with type 2 diabetes mellitus and hypertension. DESIGN Single-center, double-blind, sham-controlled trial. SETTING A large nonacademic teaching hospital in the Netherlands. PARTICIPANTS Patients with type 2 diabetes mellitus and hypertension. INTERVENTION Fifteen-minute sessions with either the device that guides breathing through musical tones to a lower breathing frequency (aiming at <10 breaths/min) or a sham device (music without aiming at lowering of breathing frequency) for an 8-week study period. MAIN OUTCOMES AND MEASURES Systolic and diastolic blood pressure measured in the physicians office. RESULTS Forty-eight patients were randomized; 21 patients (88%) in the intervention group and 24 patients (100%) in the control group completed the study. There were no significant changes in systolic and diastolic blood pressure, with a difference in systolic blood pressure of 2.35 mm Hg (95% CI, -6.50 to 11.20) in favor of the control group and a difference in diastolic blood pressure of 2.25 mm Hg (95% CI, -2.16 to 6.67) in favor of the intervention group. Three patients in the intervention group experienced adverse events. CONCLUSIONS AND RELEVANCE This high methodologic quality study shows no significant effect of device-guided lowering of breathing frequency on office-measured blood pressure in patients with type 2 diabetes. On the basis of this study, together with results from all but one previous trial, device-guided lowering of breathing frequency does not appear to be a viable nonpharmacologic option for hypertension treatment.

Optimising drug prescribing and dispensing in subjects at risk for drug errors due to renal impairment: improving drug safety in primary healthcare by low eGFR alerts

Objectives To assess the risk of medication errors in subjects with renal impairment (defined as an estimated glomerular filtration rate (eGFR) ≤40 ml/min/1.73 m2) and the effectiveness of automatic eGFR ≤40-alerts relayed to community pharmacists. Design Clinical survey. Setting The city of Zwolle, The Netherlands, in a primary care setting including 22 community pharmacists and 65 general practitioners. Participants All adults who underwent ambulatory creatine measurements which triggered an eGFR ≤40-alert. Primary and secondary outcome measures The total number of ambulatory subjects with an eGFR ≤40-alert during the study period of 1 year and the number of medication errors related to renal impairment. The type and number of proposed drug adjustments recommended by the community pharmacist and acceptance rate by the prescribing physicians. Classification of all medication errors on their potential to cause an adverse drug event (ADE) and the actual occurrence of ADEs (limited to those identified through hospital record reviews) 1 year after the introduction of the alerts. Results Creatine measurements were performed in 25 929 adults. An eGFR ≤40-alert was indicated for 5.3% (n=1369). This group had a median (IQR) age of 78 (69, 84) years, and in 73% polypharmacy (≥5 drugs) was present. In 15% (n=211) of these subjects, a medication error was detected. The proportion of errors increased with age. Pharmacists recommended 342 medication adjustments, mainly concerning diuretics (22%) and antibiotics (21%). The physicians’ acceptance rate was 66%. Of all the medication errors, 88% were regarded as potential ADEs, with most classified as significant or serious. At follow-up, the ADE risk (n=40) appeared highest when the proposed medication adjustments were not implemented (38% vs 6%). Conclusions The introduction of automatic eGFR-alerts identified a considerable number of subjects who are at risk for ADEs due to renal impairment in an ambulatory setting. The nationwide implementation of this simple protocol could identify many potential ADEs, thereby substantially reducing iatrogenic complications in subjects with impaired renal function.

The Effects of a Mobile Phone Application on Quality of Life in Patients With Type 1 Diabetes Mellitus A Randomized Controlled Trial

Background: The combination of an increasing prevalence of diabetes mellitus and more people having access to smartphones creates opportunities for patient care. This study aims to investigate whether the use of the Diabetes Under Control (DBEES) mobile phone application, a digital diabetes diary, results in a change in quality of life for patients with type 1 diabetes mellitus (T1DM) compared with the standard paper diary. Methods: In this randomized controlled open-label trial, 63 patients with T1DM having access to a smartphone were assigned to the intervention group using the DBEES application (n = 31) or the control group using the standard paper diary (n = 32). Primary outcome was the change in quality of life, as measured by the RAND-36 questionnaire, between both groups. Secondary outcomes included diabetes-related distress (PAID), HbA1c, frequency of self-monitoring blood glucose, and the usability of the diabetes application (SUS). Results: Patients had a median age (IQR) of 33 (21) years, diabetes duration of 17 (16) years, and an HbA1c of 62 ± 16 mmol/mol. No significant differences in the QOL, using the RAND-36, within and between both groups were observed after 3 months. Glycemic control, diabetes-related emotional distress, and frequency of self-monitoring of blood glucose remained within and between groups. Users reviewed the usability of DBEES with a 72 ± 20, on a range of 0-100. Conclusions: The use of the DBEES application in the management of patients with T1DM for 3 months yields no alterations in quality of life compared to the standard paper diary.

Plasma COOH-Terminal Proendothelin-1 A marker of fatal cardiovascular events, all-cause mortality, and new-onset albuminuria in type 2 diabetes? (ZODIAC-29)

OBJECTIVE The aim of this study was to investigate the association between plasma COOH-terminal proendothelin-1 (CT-proET-1) and fatal cardiovascular events, all-cause mortality, and new-onset albuminuria in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS A total of 1,225 patients with type 2 diabetes participated in this prospective observational study of two combined cohorts. Three clinical end points were studied: fatal cardiovascular events, all-cause mortality, and new-onset albuminuria. After a median follow-up of 3 or 10 years, Cox proportional hazard modeling was used to investigate the association between CT-proET-1 and the end points. Harrell C statistic, the Groennesby and Borgan test, the integrated discrimination improvement (IDI), and the net reclassification improvement (NRI) were used to evaluate whether CT-proET-1 is of additional value compared with classic cardiovascular and renal risk factors. RESULTS During follow-up, 364 (30%) patients died, 150 (42%) of whom died of cardiovascular disease; 182 (26.7%) of 688 patients with normoalbuminuria at baseline developed albuminuria. CT-proET-1 was associated with fatal cardiovascular events, all-cause mortality, and new-onset albuminuria with hazard ratios of 1.59 (95% CI 1.15–2.20), 1.41 (95% CI 1.14–1.74), and 1.48 (95% CI 1.10–2.01), respectively. Addition of CT-proET-1 to a model containing traditional risk factors leads only to improved prediction of fatal cardiovascular events. The IDI appeared significant for fatal cardiovascular events (0.82 [0.1–1.54]) and all-cause mortality (0.4 [0.05–0.92]), but not for new-onset albuminuria. CONCLUSIONS CT-proET-1 has additional value for the prediction of fatal cardiovascular events and new-onset albuminuria in patients with type 2 diabetes, compared with conventional risk factors, but not for all-cause mortality.

The Cockcroft-Gault: A Better Predictor of Renal Function in an Overweight and Obese Diabetic Population

Background: The performance of the Cockcroft-Gault (CG) equation, the Modification of Diet in Renal Disease (MDRD) formula, and the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) was evaluated in body mass index (BMI) categories. Material and Methods: In this retrospective cohort study in diabetic patients, creatinine clearance was measured by collecting 24-hour urines. Renal function was estimated using the CG, MDRD, and CKD-EPI. The performance of the equations was evaluated using correlation, Krippendorff’s coefficient, bias, precision, andaccuracy. Results: The bias of the MDRD and CKD-EPI increased from –13.9 ml/min/1.73 m2 and –14.0 ml/min/1.73 m2 (BMI < 25 kg/m2), respectively, to –31.7 ml/min/1.73 m2 and –29.6 ml/min/1.73 m2 (BMI > 30 kg/m2), respectively. Bias of the CG decreased from –13.4 ml/min (BMI < 25 kg/m2) to –3.2 ml/min (BMI > 30 kg/m2). With an accepted 30% dispersion, CG had the largest accuracy in the overweight and obese group (76.9 and 76.8%, respectively). The MDRD and CKD-EPI had an accuracy of 45.8 and 34.0% (overweight group), respectively,and 51.9 and37.3% (obese group), respectively. Conclusions: All renal function prediction equations are biased when used in overweight or obese diabetic populations with preserved renal function. The CG provides the best estimate of kidney function. The limitations of renal function prediction equations should be kept in mind when making clinical decisions.

Glycaemic control and the risk of mortality in elderly type 2 diabetic patients (ZODIAC-20)

Aims:  Studies on macrovascular consequences of glucose control in elderly patients (> 75 years) with type 2 diabetes mellitus (T2DM) are lacking. The present study aimed to investigate the relationship between HbA1c and mortality in this specific population.

Midregional Fragment of Proadrenomedullin, New-Onset Albuminuria, and Cardiovascular and All-Cause Mortality in Patients With Type 2 Diabetes (ZODIAC-30)

OBJECTIVE The midregional fragment of proadrenomedullin (MR-proADM) is a marker of endothelial dysfunction and has been associated with a variety of diseases. Our aim was to investigate whether MR-proADM is associated with new-onset albuminuria and cardiovascular (CV) and all-cause mortality in patients with type 2 diabetes treated in primary care. RESEARCH DESIGN AND METHODS Patients with type 2 diabetes participating in the observational Zwolle Outpatient Diabetes Project Integrating Available Care (ZODIAC) study were included. Cox regression analyses were used to assess the relation of baseline MR-proADM with new-onset albuminuria and CV and all-cause mortality. Risk prediction capabilities of MR-proADM for new-onset albuminuria and CV and all-cause mortality were assessed with Harrell’s C and the integrated discrimination improvement. RESULTS In 1,243 patients (mean age 67 [±12] years), the median follow-up was 5.6 years (interquartile range 3.1–10.1); 388 (31%) patients died, with 168 (12%) CV deaths. Log2 MR-proADM was associated with CV (hazard ratio 1.96 [95% CI 1.27–3.01]) and all-cause mortality (1.78 [1.34–2.36]) after adjusting for age, sex, BMI, smoking, systolic blood pressure, cholesterol-to-HDL ratio, duration of diabetes, HbA1c, ACE inhibitor/angiotensin receptor blocker, history of CV diseases, log serum creatinine, and log albumin-to-creatinine ratio. MR-proADM slightly improved mortality risk prediction. The age- and sex-adjusted, but not multivariate-adjusted, MR-proADM levels were associated with new-onset albuminuria. CONCLUSIONS MR-proADM was associated with CV and all-cause mortality in patients with type 2 diabetes after a median follow-up of 5.6 years. There was no independent relationship with new-onset albuminuria. In the availability of an extensive set of risk factors, there was little added effect of MR-proADM in risk prediction of CV and all-cause mortality.

Association between 9p21 genetic variants and mortality risk in a prospective cohort of patients with type 2 diabetes (ZODIAC-15)

The genomic region at 9p21 chromosome near the CDKN2A/CDKN2B genes is associated with type 2 diabetes(T2D) and cardiovascular disease(CVD). The effect of the 9p21 locus on long-term mortality in patients with T2D has yet to be determined.We examined three single nucleotide polymorphisms (SNPs) on 9p21, consistently and independently associated with T2D (rs10811661) or CVD (rs10757278, rs2383206), in relation to the risk of total and cardiovascular mortality in diabetic patients. We also aimed to replicate the previously observed interaction between rs2383206 and glycemic control on mortality.Genotypes for three SNPs were determined in 914 individuals from a prospective cohort of T2D patients of Dutch origin. Associations with mortality were assessed using Cox proportional hazard analyses.After a median follow-up of 9.5 years, 358 out of 914 patients had died. The hazard ratio (HR) for total mortality among individuals homozygous for the T2D-risk allele of rs10811661 compared to non-homozygous individuals was 0.74(95%CI 0.59-0.93). For the carriers of both CVD-risk alleles of rs10757278, the HR for total mortality was 1.31(95%CI 1.01-1.70). We found a significant interaction between rs2383206 and HbA1c on mortality, which was higher among patients with two CVD-risk alleles in the two lowest HbA1c tertiles (HR 1.68(95%CI 1.08-2.63); HR 1.48(95%CI 1.01-2.18).In conclusion, common variants on 9p21 were associated with mortality in patients with T2D in a Dutch population. The T2D SNP was inversely associated with mortality, while the CVD SNP increased the risk for mortality. We confirmed a possible, although different, synergistic relationship between HbA1c and rs2383206 on total mortality.