A European Research Agenda for Geriatric Emergency Medicine: a modified Delphi study.

PURPOSE: Geriatric Emergency Medicine (GEM) focuses on delivering optimal care to (sub)acutely ill older people. This involves a multidisciplinary approach throughout the whole healthcare chain. However, the underpinning evidence base is weak and it is unclear which research questions have the highest priority. The aim of this study was to provide an inventory and prioritisation of research questions among GEM professionals throughout Europe. METHODS: A two-stage modified Delphi approach was used. In stage 1, an online survey was administered to various professionals working in GEM both in the Emergency Department (ED) and other healthcare settings throughout Europe to make an inventory of potential research questions. In the processing phase, research questions were screened, categorised, and validated by an expert panel. Subsequently, in stage 2, remaining research questions were ranked based on relevance using a second online survey administered to the same target population, to identify the top 10 prioritised research questions. RESULTS: In response to the first survey, 145 respondents submitted 233 potential research questions. A total of 61 research questions were included in the second stage, which was completed by 176 respondents. The question with the highest priority was: Is implementation of elements of CGA (comprehensive geriatric assessment), such as screening for frailty and geriatric interventions, effective in improving outcomes for older patients in the ED? CONCLUSION: This study presents a top 10 of high-priority research questions for a European Research Agenda for Geriatric Emergency Medicine. The list of research questions may serve as guidance for researchers, policymakers and funding bodies in prioritising future research projects.

Isolated microalbuminuria indicates a poor medical prognosis.

BACKGROUND: Microalbuminuria is often regarded as a sign of end-organ damage due to diabetes and/or hypertension, and as such to be associated with an increased risk for cardiovascular events. It has been questioned whether isolated microalbuminuria, that is microalbuminuria in the absence of a cardiovascular disease (CVD) history, hypertension and diabetes has clinical relevance. METHODS: Included were 8356 subjects who participated in the first four screening rounds of the PREVEND study, a prospective, community-based, observational cohort study. Isolated microalbuminuria was defined as microalbuminuria (30-300 mg/24 h), in the absence of a CVD history, hypertension (blood pressure<140/90 mmHg, not using blood pressure-lowering drugs) and diabetes (fasting glucose<7.0 mmol/L, not using glucose-lowering drugs). RESULTS: Three hundred subjects met the definition of isolated microalbuminuria, in which 2250 person-years of follow-up were available. In subjects with isolated microalbuminuria, the incidence rates of cardiovascular events and mortality, hypertension and diabetes were 15.3, 28.9 and 8.9 per 1000 person-year follow-up, respectively. Subjects with isolated microalbuminuria had an increased risk for cardiovascular events and mortality [crude HR 2.23 (1.63-3.07); P<0.001], hypertension [OR 1.95 (1.47-2.59); P<0.001] and diabetes [OR 4.69 (2.92-7.51); P<0.001] compared with subjects without microalbuminuria, CVD history, hypertension and/or diabetes. This increased risk remained significant after adjustment for age and gender. The relative risk held by isolated microalbuminuria was similar to the relative risk held by microalbuminuria in subjects that did have a CVD history, hypertension and/or diabetes. CONCLUSIONS: Isolated microalbuminuria indicates a poor prognosis and warrants medical attention.

Do albuminuria and hs-CRP add to the International Diabetes Federation definition of the metabolic syndrome in predicting outcome?

BACKGROUND: To investigate the added value of elevated urinary albumin excretion (UAE) and high high-sensitive C-reactive protein (hs-CRP) in predicting new-onset type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD) and chronic kidney disease (CKD) in addition to the present metabolic syndrome (MetS) defining criteria. METHODS: The PREVEND Study is a prospective population-based cohort study in the Netherlands, including 8592 participants. The MetS was defined according to the 2004 International Diabetes Federation criteria, elevated UAE as albuminuria ≥ 30 mg/24 h and high hs-CRP as ≥ 3 mg/L. RESULTS: At follow-up, subjects without MetS when compared to subjects with MetS had a lower incidence of T2DM, CVD as well as CKD (2.5 versus 15.5; 4.1 versus 10.3 and 5.8 versus 11.2%, all P < 0.001). In subjects with MetS, the incidence of all three outcomes was higher among subjects with elevated albuminuria versus subjects with normoalbuminuria (all P < 0.01). The incidence of all outcomes was also higher among subjects with high hs-CRP versus subjects without elevated hs-CRP but only significant for CKD (P = 0.002). Multivariate analysis including elevated UAE, hs-CRP and the variables defining the MetS showed that elevated albuminuria was independently associated with the risk for new-onset T2DM, CVD and CKD, whereas high hs-CRP was only independently associated with new-onset CVD and CKD. CONCLUSION: Our data show that elevated UAE has added value to the present MetS defining variables in predicting new-onset T2DM, CVD and CKD, whereas hs-CRP adds to predicting new-onset CVD and CKD, but not T2DM.

Lower estimated glomerular filtration rate and higher albuminuria are associated with all-cause and cardiovascular mortality. A collaborative meta-analysis of high-risk population cohorts.

Screening for chronic kidney disease is recommended in people at high risk, but data on the independent and combined associations of estimated glomerular filtration rate (eGFR) and albuminuria with all-cause and cardiovascular mortality are limited. To clarify this, we performed a collaborative meta-analysis of 10 cohorts with 266,975 patients selected because of increased risk for chronic kidney disease, defined as a history of hypertension, diabetes, or cardiovascular disease. Risk for all-cause mortality was not associated with eGFR between 60-105 ml/min per 1.73 m², but increased at lower levels. Hazard ratios at eGFRs of 60, 45, and 15 ml/min per 1.73 m² were 1.03, 1.38 and 3.11, respectively, compared to an eGFR of 95, after adjustment for albuminuria and cardiovascular risk factors. Log albuminuria was linearly associated with log risk for all-cause mortality without thresholds. Adjusted hazard ratios at albumin-to-creatinine ratios of 10, 30 and 300 mg/g were 1.08, 1.38, and 2.16, respectively compared to a ratio of five. Albuminuria and eGFR were multiplicatively associated with all-cause mortality, without evidence for interaction. Similar associations were observed for cardiovascular mortality. Findings in cohorts with dipstick data were generally comparable to those in cohorts measuring albumin-to-creatinine ratios. Thus, lower eGFR and higher albuminuria are risk factors for all-cause and cardiovascular mortality in high-risk populations, independent of each other and of cardiovascular risk factors.

Lower estimated GFR and higher albuminuria are associated with adverse kidney outcomes. A collaborative meta-analysis of general and high-risk population cohorts.

Both a low estimated glomerular filtration rate (eGFR) and albuminuria are known risk factors for end-stage renal disease (ESRD). To determine their joint contribution to ESRD and other kidney outcomes, we performed a meta-analysis of nine general population cohorts with 845,125 participants and an additional eight cohorts with 173,892 patients, the latter selected because of their high risk for chronic kidney disease (CKD). In the general population, the risk for ESRD was unrelated to eGFR at values between 75 and 105 ml/min per 1.73 m(2) but increased exponentially at lower levels. Hazard ratios for eGFRs averaging 60, 45, and 15 were 4, 29, and 454, respectively, compared with an eGFR of 95, after adjustment for albuminuria and cardiovascular risk factors. Log albuminuria was linearly associated with log ESRD risk without thresholds. Adjusted hazard ratios at albumin-to-creatinine ratios of 30, 300, and 1000 mg/g were 5, 13, and 28, respectively, compared with an albumin-to-creatinine ratio of 5. Albuminuria and eGFR were associated with ESRD, without evidence for multiplicative interaction. Similar associations were found for acute kidney injury and progressive CKD. In high-risk cohorts, the findings were generally comparable. Thus, lower eGFR and higher albuminuria are risk factors for ESRD, acute kidney injury and progressive CKD in both general and high-risk populations, independent of each other and of cardiovascular risk factors.

Lower estimated glomerular filtration rate and higher albuminuria are associated with mortality and end-stage renal disease. A collaborative meta-analysis of kidney disease population cohorts.

We studied here the independent associations of estimated glomerular filtration rate (eGFR) and albuminuria with mortality and end-stage renal disease (ESRD) in individuals with chronic kidney disease (CKD). We performed a collaborative meta-analysis of 13 studies totaling 21,688 patients selected for CKD of diverse etiology. After adjustment for potential confounders and albuminuria, we found that a 15 ml/min per 1.73 m² lower eGFR below a threshold of 45 ml/min per 1.73 m² was significantly associated with mortality and ESRD (pooled hazard ratios (HRs) of 1.47 and 6.24, respectively). There was significant heterogeneity between studies for both HR estimates. After adjustment for risk factors and eGFR, an eightfold higher albumin- or protein-to-creatinine ratio was significantly associated with mortality (pooled HR 1.40) without evidence of significant heterogeneity and with ESRD (pooled HR 3.04), with significant heterogeneity between HR estimates. Lower eGFR and more severe albuminuria independently predict mortality and ESRD among individuals selected for CKD, with the associations stronger for ESRD than for mortality. Thus, these relationships are consistent with CKD stage classifications based on eGFR and suggest that albuminuria provides additional prognostic information among individuals with CKD.

Influence of age and measure of eGFR on the association between renal function and cardiovascular events.

BACKGROUND AND OBJECTIVES: This study investigates whether the association between estimated GFR (eGFR) and cardiovascular (CV) outcome differs for different measures of eGFR and different age groups. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Between 1997 and 1998, 8047 participants visited our outpatient clinic for measurement of serum creatinine, serum cystatin C, urinary creatinine, and urinary albumin excretion. GFR was estimated by the Modification of Diet in Renal Disease formula, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula, a cystatin C-based formula, a formula combining serum creatinine and cystatin C, and 24-hour creatinine clearance. Subjects had follow-up on CV events until 2005. RESULTS: During follow-up, 530 subjects had a CV event. The association between eGFR and CV events was significantly modified by age, except when GFR was estimated by 24-hour creatinine clearance. In subjects <60 years of age, all measures of eGFR were independently and significantly associated with CV events, whereas in subjects ≥60 years of age only 24-hour creatinine clearance had a weak but significant association with CV events. For all measures and all levels of eGFR, subjects with elevated levels of albuminuria were at higher risk of CV events compared with subjects with normoalbuminuria. CONCLUSIONS: In the general population, all measures of eGFR are independently and significantly associated with CV events in individuals <60 years of age, but in subjects ≥60 years of age, only 24-hour creatinine clearance is. In general, the association between eGFR and risk of CV events is weaker in elderly subjects than in younger subjects.

Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis.

BACKGROUND: Substantial controversy surrounds the use of estimated glomerular filtration rate (eGFR) and albuminuria to define chronic kidney disease and assign its stages. We undertook a meta-analysis to assess the independent and combined associations of eGFR and albuminuria with mortality. METHODS: In this collaborative meta-analysis of general population cohorts, we pooled standardised data for all-cause and cardiovascular mortality from studies containing at least 1000 participants and baseline information about eGFR and urine albumin concentrations. Cox proportional hazards models were used to estimate hazard ratios (HRs) for all-cause and cardiovascular mortality associated with eGFR and albuminuria, adjusted for potential confounders. FINDINGS: The analysis included 105,872 participants (730,577 person-years) from 14 studies with urine albumin-to-creatinine ratio (ACR) measurements and 1,128,310 participants (4,732,110 person-years) from seven studies with urine protein dipstick measurements. In studies with ACR measurements, risk of mortality was unrelated to eGFR between 75 mL/min/1.73 m(2) and 105 mL/min/1.73 m(2) and increased at lower eGFRs. Compared with eGFR 95 mL/min/1.73 m(2), adjusted HRs for all-cause mortality were 1.18 (95% CI 1.05-1.32) for eGFR 60 mL/min/1.73 m(2), 1.57 (1.39-1.78) for 45 mL/min/1.73 m(2), and 3.14 (2.39-4.13) for 15 mL/min/1.73 m(2). ACR was associated with risk of mortality linearly on the log-log scale without threshold effects. Compared with ACR 0.6 mg/mmol, adjusted HRs for all-cause mortality were 1.20 (1.15-1.26) for ACR 1.1 mg/mmol, 1.63 (1.50-1.77) for 3.4 mg/mmol, and 2.22 (1.97-2.51) for 33.9 mg/mmol. eGFR and ACR were multiplicatively associated with risk of mortality without evidence of interaction. Similar findings were recorded for cardiovascular mortality and in studies with dipstick measurements. INTERPRETATION: eGFR less than 60 mL/min/1.73 m(2) and ACR 1.1 mg/mmol (10 mg/g) or more are independent predictors of mortality risk in the general population. This study provides quantitative data for use of both kidney measures for risk assessment and definition and staging of chronic kidney disease. FUNDING: Kidney Disease: Improving Global Outcomes (KDIGO), US National Kidney Foundation, and Dutch Kidney Foundation.

Comparison of the yield of different screening approaches to detect chronic kidney disease.

BACKGROUND: Screening for chronic kidney disease (CKD) has been advised in high-risk populations. The present study aims to compare the yields of four approaches to select high-risk subjects for CKD screening, which are defined as follows: Approach 1, history of cardiovascular (CV) disease, diabetes mellitus or hypertension (=high CV risk); Approach 2, high CV risk or age >55 years; Approach 3, urinary albumin concentration (UAC) ≥20 mg/L; or Approach 4, UAC ≥10 mg/L at pre-screening. METHODS: The study population is a sample of the general population of Groningen, the Netherlands (n = 3398). UAC was measured (nephelometry) in a first morning void urine sample collected at home and sent to a laboratory by post. Information on demographics and the presence of CV risk factors was obtained by a questionnaire. The presence of CKD was determined during examination at an outpatient clinic. RESULTS: At baseline, 12% of the subjects met the criteria of Approach 1, 33% of Approach 2, 8% of Approach 3 and 25% of Approach 4. CKD was diagnosed in 370 subjects (11%). Approach 2 detected the most CKD patients (sensitivity 65%), while Approach 3 resulted in the lowest number needed to screen (1.9). During a follow-up of 7 years, only the UAC pre-screening approaches detected CKD patients who had both significantly accelerated renal function loss and increased CV risk compared to subjects without CKD. Only 28% of CKD patients detected by the UAC approaches used antihypertensive/angiotensin-converting enzyme inhibitor treatment prior to screening. CONCLUSIONS: This study suggests that pre-screening based on UAC should be favoured in comparison to screening based on CKD risk factors to detect CKD patients at high renal and CV risk.

Screening for albuminuria identifies individuals at increased renal risk.

It is unknown whether screening for albuminuria in the general population identifies individuals at increased risk for renal replacement therapy (RRT) or accelerated loss of renal function. Here, in a general population-based cohort of 40,854 individuals aged 28 to 75 yr, we collected a first morning void for measurement of urinary albumin. In a subset of 6879 individuals, we measured 24-h urinary albumin excretion and estimated GFR at baseline and during 6 yr of follow-up. Linkage with the national RRT registry identified 45 individuals who started RRT during 9 yr of follow-up. The quantity of albuminuria was associated with increased renal risk: the higher the level of albuminuria, the higher the risk of need for renal replacement therapy and the more rapid renal function decline. A urinary albumin concentration of > or =20 mg/L identified individuals who started RRT during follow-up with 58% sensitivity and 92% specificity. Of the identified individuals, 39% were previously unknown to have impaired renal function, and 50% were not being medically treated. Restricting screening to high-risk groups (e.g., known hypertension, diabetes, cardiovascular disease [CVD], older age) reduced the sensitivity of the test only marginally but failed to identify 45% of individuals with micro- and macroalbuminuria. In conclusion, individuals with elevated levels of urinary albumin are at increased risk for RRT and accelerated loss of renal function. Screening for albuminuria identifies patients at increased risk for progressive renal disease, 40 to 50% of whom were previously undiagnosed or untreated.

Screening for chronic kidney disease: where does Europe go?

This review discusses various screening approaches for chronic kidney disease that are used in Europe. The criterion for defining chronic kidney disease in the various programs differs but is frequently limited to estimated glomerular filtration rate, thus offering only data on chronic kidney disease stages 3 and higher; however, screening should not be limited to measuring only estimated glomerular filtration rate but should also include a measure of microalbuminuria, because this will offer identification of chronic kidney disease stages 1 and 2. Defining these earlier stages is of importance because the risk for developing end-stage renal disease that is associated with stages 1 and 2 is nearly equal to the risk that is associated with stage 3. Moreover, the risk for cardiovascular events in stages 1 and 2 is equal to that in stage 3. Various reports argue that costs of screening programs in general practitioner or outpatient offices are high and that they are cost-effective only for preventing end-stage renal disease when they are limited to target groups, such as patients with diabetes or hypertension and elderly. The benefits of screening programs, however, should not be evaluated only with respect to the prevention of renal events but should also include the benefits of preventing cardiovascular events. The use of preselection based on either an impaired estimated glomerular filtration rate or on protein-dipstick positivity or elevated albuminuria in a morning urine void has been found effective in various European countries as an alternative for targeted screening.

New onset hyperglycemia and diabetes are associated with increased cardiovascular risk after kidney transplantation.

BACKGROUND: Post-transplant diabetes (PTDM) is a common and serious complication of kidney transplantation. The implications of developing hyperglycemia of lesser severity are not well understood. METHODS: In this study we used American Diabetes Association (ADA) criteria to assess the incidence of abnormal glycemia post-transplant, the variables that relate to this complication, and the relationship between hyperglycemia and cardiovascular (CV) disease. Included in the study were 490 kidney recipients, transplanted from 1998 to 2003, without a history of diabetes, and with a pretransplant fasting glucose <126 mg/dL. RESULTS: Within one week post-transplant, 45% of recipients had impaired fasting glycemia (IFG, glucose 100-125 mg/dL), and 21% PTDM (glucose > or =126). One year post-transplant, 33% of patients had IFG, and 13% PTDM. Risk factors for hyperglycemia at one year included: older recipient, male gender, higher BMI, higher pretransplant glucose, and higher glucose one week post-transplant (all P < 0.002 by multivariable analyses). During a follow-up period of 40 +/- 14 months, 12% of recipients had CV events (cardiac, CVA, and/or peripheral). Increasing fasting glucose levels at one, four, and/or 12 months post-transplant were significantly related to CV events. Furthermore, these relationships were independent of other CV risk factors, including: older age, CV events pretransplant, male gender, dyslipidemia, and transplant year. Fasting glucose levels >100 mg/dL were associated with higher incidence of post-transplant cardiac (P= 0.001) and peripheral vascular disease events (P= 0.003). CONCLUSION: The incidence of post-transplant hyperglycemia and its CV impact have been underestimated. Pretransplant characteristics and, particularly, the glycemia during the first month post-transplant identified patients at risk of PTDM. Increasing glucose levels greater than 100 mg/dL, any time after the first month post-transplant, are associated with increasing CV risk. We postulate that aggressive detection and treatment of post-transplant hyperglycemia may significantly reduce CV morbidity and mortality after kidney transplantation.