Past Decline Versus Current eGFR and Subsequent Mortality Risk.

A single determination of eGFR associates with subsequent mortality risk. Prior decline in eGFR indicates loss of kidney function, but the relationship to mortality risk is uncertain. We conducted an individual-level meta-analysis of the risk of mortality associated with antecedent eGFR slope, adjusting for established risk factors, including last eGFR, among 1.2 million subjects from 12 CKD and 22 other cohorts within the CKD Prognosis Consortium. Over a 3-year antecedent period, 12% of participants in the CKD cohorts and 11% in the other cohorts had an eGFR slope <-5 ml/min per 1.73 m(2) per year, whereas 7% and 4% had a slope >5 ml/min per 1.73 m(2) per year, respectively. Compared with a slope of 0 ml/min per 1.73 m(2) per year, a slope of -6 ml/min per 1.73 m(2) per year associated with adjusted hazard ratios for all-cause mortality of 1.25 (95% confidence interval [95% CI], 1.09 to 1.44) among CKD cohorts and 1.15 (95% CI, 1.01 to 1.31) among other cohorts during a follow-up of 3.2 years. A slope of +6 ml/min per 1.73 m(2) per year also associated with higher all-cause mortality risk, with adjusted hazard ratios of 1.58 (95% CI, 1.29 to 1.95) among CKD cohorts and 1.43 (95% CI, 1.11 to 1.84) among other cohorts. Results were similar for cardiovascular and noncardiovascular causes of death and stronger for longer antecedent periods (3 versus <3 years). We conclude that prior decline or rise in eGFR associates with an increased risk of mortality, independent of current eGFR.

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.

Comparison of methods for renal risk prediction in patients with type 2 diabetes (ZODIAC-36).

BACKGROUND: Patients with diabetes are at high risk of death prior to reaching end-stage renal disease, but most models predicting the risk of kidney disease do not take this competing risk into account. We aimed to compare the performance of Cox regression and competing risk models for prediction of early- and late-stage renal complications in type 2 diabetes. METHODS: Patients with type 2 diabetes participating in the observational ZODIAC study were included. Prediction models for (micro)albuminuria and 50% increase in serum creatinine (SCr) were developed using Cox regression and competing risk analyses. Model performance was assessed by discrimination and calibration. RESULTS: During a total follow-up period of 10 years, 183 out of 640 patients (28.6%) with normoalbuminuria developed (micro)albuminuria, and 22 patients (3.4%) died without developing (micro)albuminuria (i.e. experienced the competing event). Seventy-nine out of 1,143 patients (6.9%) reached the renal end point of 50% increase in SCr, while 219 (19.2%) died without developing the renal end point. Performance of the Cox and competing risk models predicting (micro)albuminuria was similar and differences in predicted risks were small. However, the Cox model increasingly overestimated the risk of increase in SCr in presence of a substantial number of competing events, while the performance of the competing risk model was quite good. CONCLUSIONS: In this study, we demonstrated that, in case of substantial numbers of competing events, it is important to account for the competing risk of death in renal risk prediction in patients with type 2 diabetes.

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.

[SGLT-2 inhibitors: diabetes treatment by glycosuria; literature review on the effect of dapagliflozin]. / SGLT-2-remmers: glucosurie als diabetesbehandeling; literatuurstudie naar het effect van dapagliflozine.

OBJECTIVE: To describe the efficacy and safety of dapagliflozin, the first sodium-glucose co-transporter-2 (SGLT-2) inhibitor for the treatment of diabetes mellitus type 2 (DM2) to be registered in the Netherlands. DESIGN: Literature review. METHOD: We searched the Medline database for articles on the use of dapagliflozin in patients with DM2. We included randomised studies with a minimum duration of 12 weeks and systematic reviews published up to 19 October 2012. Two assessors selected the articles on the basis of title, abstract and if necessary, the complete text. RESULTS: Eleven articles were suitable for analysis. On comparison with placebo, the use of dapagliflozin gave a drop in HbA1c-value of approximately 0.5-0.8 percentage points (6-9 mmol/mol). The body weight of patients who used dapagliflozin dropped between 1.0-2.4 kg on comparison with the placebo and metformin control groups. Urinary tract infections occurred twice as often and genital infections three to four times more often. There were no data on the effect on micro- and macrovascular complications or on mortality. CONCLUSION: Dapagliflozin regulates the blood glucose levels less effectively than currently used medications, although the small number of studies that compare dapagliflozin with metformin or glipizide show no differences in the drop in HbA1c between the study groups. Dapagliflozin use leads to minor, clinically non-relevant weight loss. There are as yet no data on its long term efficacy and safety.

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 physician's 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 m(2)) 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.

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.

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

BACKGROUND: Non-equivalence in serum creatinine (SCr) measurements across Dutch laboratories and the consequences hereof on chronic kidney disease (CKD) staging were examined. METHODS: National 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. RESULTS: Jaffe 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. CONCLUSIONS: Enzymatic 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 patient's 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.

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.

Chronic kidney disease and mortality risk among older patients with type 2 diabetes mellitus (ZODIAC-24).

OBJECTIVE: to investigate the association between a decreased estimated glomerular filtration rate (eGFR), albuminuria and mortality in elderly patients with type 2 diabetes mellitus (T2DM). DESIGN: prospective observational cohort study. SETTING: primary care. SUBJECTS: eight hundred and ten patients, ≥65 years with T2DM. Analyses were performed in age strata: 65-75 (n = 471), >75 (n = 339) years. METHODS: Cox proportional hazard modelling was used to investigate the association between eGFR, albuminuria and all-cause and cardiovascular mortality after a median follow-up of 9.8 years. RESULTS: an eGFR <45 and 45-60 ml/min/1.73 m(2) is associated with increased cardiovascular mortality in patients of 65-75 years, hazard ratio (HR): 3.29 (1.58-6.86) and 1.78 (1.09-2.90), respectively; in those >75 years increased cardiovascular mortality was observed when eGFR was <45 ml/min/1.73 m(2): 2.42 (1.47-3.69). Compared with patients of 65-75 years, an eGFR >60 ml/min/1.73 m(2) and normo-albuminuria, fully adjusted HRs for cardiovascular mortality were 2.26 (1.04-4.92) and 4.86 (2.33-10.15) for those aged 65-75 years, an eGFR of 45-60 ml/min/1.73 m(2) and normo-albuminuria or albuminuria, respectively; HRs were 1.33 (0.67-2.66) and 2.01 (1.02-3.94), respectively, for those >75 years. CONCLUSIONS: an eGFR of 45-60 ml/min/1.73 m(2) in T2DM patients is associated with increased mortality in patients aged 65-75 years but not in those >75 years. Albuminuria is associated with increased mortality in patients >65 years.

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, and accuracy. RESULTS: The bias of the MDRD and CKD-EPI increased from -13.9 ml/min/1.73 m(2) and -14.0 ml/min/1.73 m(2) (BMI < 25 kg/m(2)), respectively, to -31.7 ml/min/1.73 m(2) and -29.6 ml/min/1.73 m(2) (BMI > 30 kg/m(2)), respectively. Bias of the CG decreased from -13.4 ml/min (BMI < 25 kg/m(2)) to -3.2 ml/min (BMI > 30 kg/m(2)). 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 and 37.3% (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.

[Employing age-related cut-off values results in fewer patients with renal impairment in secondary care]. / Consequenties van leeftijdsgebonden afkappunten voor nierfunctie op de belasting van de eerste- en tweedelijnsgezondheidszorg.

OBJECTIVE: To describe the consequences on the burden for primary and secondary care in the Netherlands, of using age-related cut-off values for renal function which follow the Dutch national transmural agreement (LTA) for 'Chronic renal impairment', rather than the 'Kidney disease outcome quality initiative' (K/DOQI) guidelines. DESIGN: Observational cross-sectional study. METHODS: 82,424 patients whose serum creatinine had been determined in 2009 were identified from the laboratory registry of the Isala Clinics in Zwolle, the Netherlands. The glomerular filtration rate was estimated using the abbreviated Modification of Diet in Renal Disease (MDRD) equation (eGFR). Burden of care was defined as the necessity for referral or consultation in secondary care. The number of people that would have been referred using the K/DOQI guideline that refers all those with an eGFR < 60 ml/min/1.73 m², was compared to a situation using age-related cut-off values in the referral policy. RESULTS: The study population contained 82,424 people; 45.3% were men; age range was 19-106 years; 38.7% were > 65 years. 19% of the population (n = 15,637) had an eGFR < 60 ml/min/1.73 m2 and would have been referred had the K/DOQI guidelines been applied; 11,935 of those 15,637 were > 65 years. The use of the LTA for 'Chronic renal impairment', that includes age as one of the criteria, would have resulted in the referral of 3,303/15,637 patients (2,011 of those 3,303 were > 65 years), and resulted in consultation with a nephrologist for 5,748/15,637 patients (3,338/5,748 were > 65 years). The majority of patients aged > 65 years and with an eGFR < 60 ml/min/1.73 m2 (55%) could be treated in primary care without consultation of secondary care or referral. CONCLUSION: The categorization applied by the current LTA for 'Chronic renal impairment', whereby age-related cut-off values are used in the referral policy, will result in more targeted referral to secondary care, especially in the elderly patient group, when compared to application of the K/DOQI guidelines.