Associations Between Albuminuria, Estimated GFR and Cardiac Phenotype in a Cohort with Chronic Kidney Disease: The CPH-CKD ECHO Study.

OBJECTIVE: Echocardiographic findings in chronic kidney disease (CKD) vary. We sought to estimate the prevalence of abnormal cardiac structure and function in patients with CKD and their association to estimated glomerular filtration rate (eGFR) and urine albumin/creatinine ratio (UACR). METHODS: We prospectively enrolled 825 outpatients with non-dialysis-dependent CKD, mean age 58± 13 yrs, and 175 matched healthy controls, mean age 60±12 yrs. Echocardiography included assessment of left ventricular (LV) hypertrophy, LV ejection fraction (LVEF), global longitudinal strain (GLS) and diastolic dysfunction according to ASE/EACVI guidelines. RESULTS: LV hypertrophy was found in 9% of patients vs. 1.7% of controls (p=0.005) was independently associated with UACR (p=0.002). Median LVEF was 59.4% (IQR 55.2, 62.8) in patients vs. 60.8% (57.7, 64.1) in controls (p=0.002). GLS was decreased in patients with eGFR <60ml/min/1.73m² (-17.6%±3.1%) vs. patients with higher eGFR (19.0%±2.2%, p<0.001), who were similar to controls. Diastolic dysfunction was detected in 55% of patients and in 34% of controls. LIMITATIONS: Non-random sampling, cross-sectional analysis. CONCLUSIONS: We report lower prevalence of hypertrophy than previous studies, but similar measurements of systolic and diastolic function. Cardiac remodeling in CKD may be influenced by treatment modalities, demographics, comorbidities and renal pathology.

Increased vulnerability to COVID-19 in chronic kidney disease.

BACKGROUND: The significance of chronic kidney disease on susceptibility to COVID-19 and subsequent outcomes remains unaddressed. OBJECTIVE: To investigate the association of estimated glomerular filtration rate (eGFR) on risk of contracting COVID-19 and subsequent adverse outcomes. METHODS: Rates of hospital-diagnosed COVID-19 were compared across strata of eGFR based on conditional logistic regression using a nested case-control framework with 1:4 matching of patients diagnosed with COVID-19 with controls from the Danish general population on age, gender, diabetes and hypertension. Risk of subsequent severe COVID-19 or death was assessed in a cohort study with comparisons across strata of eGFR based on adjusted Cox regression models with G-computation of results to determine 60-day risk standardized to the distribution of risk factors in the sample. RESULTS: Estimated glomerular filtration rate was inversely associated with rate of hospital-diagnosed COVID-19: eGFR 61-90 mL/min/1.73m2 HR 1.13 (95% CI 1.03-1.25), P = 0.011; eGFR 46-60 mL/min/1.73m2   HR 1.26 (95% CI 1.06-1.50), P = 0.008; eGFR 31-45 mL/min/1.73m2 HR 1.68 (95% CI 1.34-2.11), P < 0.001; and eGFR ≤ 30 mL/min/1.73m2 3.33 (95% CI 2.50-4.42), P < 0.001 (eGFR > 90 mL/min/1.73m2 as reference), and renal impairment was associated with progressive increase in standardized 60-day risk of death or severe COVID-19; eGFR > 90 mL/min/1.73m2 13.9% (95% CI 9.7-15.0); eGFR 90-61 mL/min/1.73m2 16.1% (95% CI 14.5-17.7); eGFR 46-60 mL/min/1.73m2 17.8% (95% CI 14.7-21.2); eGFR 31-45 mL/min/1.73m2 22.6% (95% CI 18.2-26.2); and eGFR ≤ 30 mL/min/1.73m2 23.6% (95% CI 18.1-29.1). CONCLUSIONS: Renal insufficiency was associated with progressive increase in both rate of hospital-diagnosed COVID-19 and subsequent risk of adverse outcomes. Results underscore a possible vulnerability associated with impaired renal function in relation to COVID-19.

Prevalence of impaired renal function in virologically suppressed people living with HIV compared with controls: the Copenhagen Comorbidity in HIV Infection (COCOMO) study.

OBJECTIVES: While renal impairment is reported more frequently in people living with HIV (PLWH) than in the general population, the PLWH samples in previous studies have generally been dominated by those at high renal risk. METHODS: Caucasian PLWH who were virologically suppressed on antiretroviral treatment and did not have injecting drug use or hepatitis C were recruited from the Copenhagen Comorbidity in HIV Infection (COCOMO) study. Sex- and age-matched controls were recruited 1:4 from the Copenhagen General Population Study up to November 2016. We defined renal impairment as one measurement of estimated glomerular filtration rate ≤ 60 mL/min/1.73 m2 , and assessed associated factors using adjusted logistic regression models. The impact of HIV-related factors was explored in a subanalysis. RESULTS: Among 598 PLWH and 2598 controls, the prevalence of renal impairment was 3.7% [95% confidence interval (CI) 2.3-5.5%] and 1.7% (95% CI 1.2-2.2%; P = 0.0014), respectively. After adjustment, HIV status was independently associated with renal impairment [odds ratio (OR) 3.4; 95% CI 1.8-6.3]. In addition, older age [OR 5.4 (95% CI 3.9-7.5) per 10 years], female sex [OR 5.0 (95% CI 2.6-9.8)] and diabetes [OR 2.9 (95% CI 1.3-6.7)] were strongly associated with renal impairment. The association between HIV status and renal impairment became stronger with older age (P = 0.02 for interaction). Current and nadir CD4 counts, duration of HIV infection and previous AIDS-defining diagnosis were not associated with renal impairment among virologically suppressed PLWH. CONCLUSIONS: The prevalence of renal impairment is low among low-risk virologically suppressed Caucasian PLWH, but remains significantly higher than in controls. Renal impairment therefore remains a concern in all PLWH and requires ongoing attention.

Continuation of lithium after a diagnosis of chronic kidney disease.

OBJECTIVE: To investigate whether continued lithium or anticonvulsant treatment after a first diagnosis of chronic kidney disease (CKD) was associated with progression to irreversible end-stage kidney disease. METHODS: Nationwide cohort study including all individuals in Denmark in a period from 1995 to 2012 with a diagnosis of CKD and (i) a history of lithium treatment (N = 754, among whom 238 patients had a diagnosis of bipolar disorder) or (ii) a history of anticonvulsant treatment (N = 5.004, among whom 199 patients had a diagnosis of bipolar disorder). End-stage CKD was defined as chronic dialysis or renal transplantation. RESULTS: Continuing lithium (HR = 0.58 (95% CI: 0.37-0.90) and continuing anticonvulsants (HR = 0.53 (95% CI: 0.44-0.64) were associated with decreased rates of end-stage CKD. In the subcohorts of patients with a diagnosis of bipolar disorder, continuing lithium was associated with decreased end-stage CKD (HR = 0.40 (95% CI: 0.17-0.98), whereas continuing anticonvulsants was not (HR = 0.70 (95% CI: 0.21-2.37). There were no interactions of continuing lithium and anticonvulsants. CONCLUSION: After an initial diagnosis of CKD, patients who are selected by their physicians to continue lithium treatment may not necessarily have an increased risk of developing end-stage CKD. Shifting to an anticonvulsant per se may not be associated with an advantage; however, this requires further investigation.

Effects of insulin detemir and NPH insulin on renal handling of sodium, fluid retention and weight in type 2 diabetic patients.

AIMS/HYPOTHESIS: In type 2 diabetic patients, insulin detemir (B29Lys(ε-tetradecanoyl),desB30 human insulin) induces less weight gain than NPH insulin. Due to the proposed reduction of tubular action by insulin detemir, type 2 diabetic patients should have increased urinary sodium excretion, thereby reducing extracellular volume and body weight when changed from NPH insulin to insulin detemir. METHODS: In a randomised, open-labelled, two-way crossover study of 24 patients with type 2 diabetes, patients were first treated with NPH insulin or insulin detemir for 8 weeks. Thereafter, they were changed to the other insulin for 8 weeks. In a third 1 week period, they were changed back to the first insulin. RESULTS: At the end of 8 weeks, body weight was reduced by 0.8 ± 0.2 kg (mean ± SEM) on insulin detemir compared with NPH insulin (p < 0.01). After insulin detemir treatment, we also observed a significant reduction of lean body mass (0.8 ± 0.2 kg, p < 0.05) and a non-significant reduction of extracellular volume (0.8 ± 0.5 l/1.73 m², p = 0.14). The weight loss occurred after as early as 1 week (0.8 ± 0.2 kg, p < 0.001), with a simultaneous and transient increase of urinary sodium excretion (p = 0.07). CONCLUSIONS/INTERPRETATION: Insulin detemir induces significant and sustained weight loss, which is first observed at 1 week after changing from NPH insulin. The initial weight loss seems to be related to changes in fluid volume and may reflect changed insulin action in the kidneys.

Rapid decline in glomerular filtration rate during the first weeks following heart transplantation.

We hypothesized that a decrease in renal function is seen immediately after heart transplantation (HTX) with little recovery over time. Twelve consecutive patients had their glomerular filtration rate (GFR) measured using (51)Cr-ethylenediaminetetraacetic acid (EDTA) measured GFR (mGFR) before transplantation and at 1, 2, 3, and 26 weeks after transplantation. The mGFR decreased by 28% and 24% during the first 3 and 26 weeks, respectively, with mean blood cyclosporine concentration as an independent risk factor for the decrease in mGFR. The identification of cyclosporine A (CsA) as the most important risk factor for the rapid and sustained decrease in renal function supports the need for more studies on renoprotective strategies immediately after HTX.

Increased urinary orosomucoid excretion predicts preeclampsia in pregnant women with pregestational type 1 diabetes.

AIMS: We evaluated the urinary orosomucoid excretion (UOE) as a biomarker of preeclampsia and preterm delivery in pregnant women with type 1 diabetes. METHODS: Singleton pregnant women with pregestational type 1 diabetes were included provided one urine sample had been collected before 17 gestational weeks. Serum and urinary orosomucoid were analysed by immunoturbidimetry. Primary outcome measurements were development of preeclampsia (blood pressure>140/90mmHg and proteinuria) and preterm delivery before 37 weeks. RESULTS: In total 173 women were included. The UOE increased during pregnancy. Preeclampsia developed in 20 women and 65 women delivered preterm. Using logistic regression analysis we found that UOE>1.37mg/l (OR: 6.85 (95% CI: 1.97-23.88; p<0.003)), nulliparity (3.88 (1.10-13.72); p<0.04), systolic blood pressure>120mmHg (4.12 (1.35-12.59); p<0.02) and duration of diabetes>20 years (3.69 (1.18-11.52); p<0.03) independently predicted the development of preeclampsia. Independent predictors of preterm delivery were duration of diabetes and HbA1c>7%. The remaining covariates included in the regression models were BMI, serum creatinine, smoking and microalbuminuria. CONCLUSIONS: Increased UOE early in pregnancy predicted preeclampsia in women with pregestational type 1 diabetes independently of albuminuria and other known risk factors. No association to preterm delivery was found.

Rapid decline in 51Cr-EDTA measured renal function during the first weeks following lung transplantation.

We previously described a 54% decline in renal function at 6 months after lung transplantation (LTx). We hypothesized that this decline is a very early event following LTx. Thirty-one consecutive patients (16 females/15 males), mean age 49 (+/-13) years, with emphysema, cystic fibrosis/bronchiectasis or idiopathic pulmonary fibrosis were included in an analysis of renal function before and after LTx. The glomerular filtration rate (GFR) was measured using the (51)Cr-ethylenediaminetetra acetic acid plasma clearance single injection technique (mGFR) at baseline before transplantation and at 1, 2, 3 and 12 weeks postoperatively. Mean mGFR declined from 103 +/- 18 to 65 +/- 22, 53 +/- 16 and 57 +/- 18 mL/min/1.73m(2) at 1-, 3- and 12-weeks post-LTx (p < 0.0001), respectively. In a time-dependent repeated measures ANOVA, risk factors for a decline in mGFR posttransplant included: time (p < 0.0001), acute renal failure within 2 weeks post-LTx (p = 0.0003), use of heart and lung machine (p = 0.04), and the use of ephedrine (p = 0.048), as well as increasing age, older than 18 years at LTx (p = 0.006). These data demonstrate that renal function, measured with an isotope method, decreases dramatically during the first week after LTx.

Increased urinary orosomucoid excretion: a proposed marker for inflammation and endothelial dysfunction in patients with type 2 diabetes.

OBJECTIVE: In a previous study, urinary orosomucoid excretion rate (UOER) independently predicted cardiovascular mortality in patients with type 2 diabetes. The aim of the present study was to determine whether increased UOER is associated with cardiovascular risk factors such as inflammation, impaired left ventricular function and endothelial dysfunction in patients with type 2 diabetes. MATERIAL AND METHODS: We performed a cross-sectional study of 41 patients with type 2 diabetes (17 patients with normal UOER and 24 with increased UOER) with no history of cardiovascular disease and 21 healthy controls. Urinary orosomucoid was measured using a particle-enhanced immunoturbidimetric assay. Plasma interleukin-6 (IL-6), tissue plasminogen activator (tPA) and soluble intercellular adhesion molecule-1 (sICAM) were measured using ELISA. Endothelial function measured as vasodilatory capacity of the brachial artery and echocardiography were done in all participants. RESULTS: Patients with diabetes and increased UOER had subclinically increased serum orosomucoid (p<0.001), C-reactive protein (CRP) (p<0.001), IL-6 (p<0.001), tPA (p<0.003) and sICAM (p<0.003) compared with healthy controls. In patients with type 2 diabetes, UOER was independently associated with increasing values of IL-6 (1.43 (1.06-1.93)) and tPA (1.82 (1.20-2.77)). Measurements by echocardiography showed no signs of cardiac dysfunction. CONCLUSIONS: Asymptomatic patients with type 2 diabetes and increased UOER displayed signs of chronic low-grade inflammation and endothelial dysfunction. UOER was independently related to markers of proinflammation and endothelial dysfunction in patients with type 2 diabetes. The previously shown relation between increased UOER and cardiovascular mortality is proposed to be caused by chronic low-grade inflammation and early endothelial dysfunction.

Hypothyroidism is associated with signs of endothelial dysfunction despite 1-year replacement therapy with levothyroxine.

OBJECTIVE: Hypothyroidism is associated with elevated cardiovascular risk, not fully explained by classical risk factors. Instead, endothelial dysfunction may link hypothyroidism to atherosclerosis. The effect of levothyroxine substitution on endothelial function has been sparsely studied and the results are unclear. This study tested endothelial function as estimated by concomitant measurements of endothelial dependent vascular dilatory capacity and plasma concentration of von Willebrand factor antigen in patients with hypothyroidism and further examined the impact of subsequent levothyroxine substitution. DESIGN AND PATIENTS: Sixteen consecutive patients (13 women, 3 men, aged 46 +/- 11 years) with hypothyroidism were included and compared to 16 matched healthy controls (13 women, 3 men, aged 49 +/- 11 years). Patients with hypothyroidism were reexamined after 3, 6 and 12 months of levothyroxine substitution. MEASUREMENTS: Dilatory responses of the brachial artery to post-ischaemic increased blood flow (endothelium-dependent flow-associated dilatation) and to nitroglycerin (endothelium-independent nitroglycerin induced dilatation) were measured by ultrasound. Plasma concentrations of von Willebrand factor antigen were measured by ELISA. RESULTS: Flow-associated dilatation was impaired in patients with hypothyroidism as compared to controls (102.7 +/- 3.6 vs. 105.6 +/- 3.8%, P = 0.04) whereas no differences in plasma concentration of von Willebrand factor antigen were found. One year levothyroxine substitution did not improve flow-associated dilatation and was associated with an increase of the plasma von Willebrand factor antigen concentration. CONCLUSIONS: Hypothyroid patients are characterized by endothelial dysfunction sustained despite long-term levothyroxine substitution and potentially increasing the risk of atherosclerosis. Different estimates of endothelial dysfunction seem unequally influenced by hypothyroidism.

Diabetic patients treated with dialysis: complications and quality of life.

AIMS/HYPOTHESIS: The aim of this study was to describe the prevalence of complications, health-related quality of life (HRQOL) and the influence of beliefs about control over health in diabetic dialysis patients. METHODS: Of 53 eligible diabetic patients on chronic dialysis during January 2004 in our clinic, 38 (76%) completed a kidney-specific (Kidney Disease Quality of Life) and a generic (SF-36) questionnaire and were characterised in terms of cardiovascular diseases and diabetic complications. Matched groups of non-diabetic dialysis patients (n = 40) and diabetic patients with a long duration of diabetes and normal kidney function (n = 38) served as controls. Generic HRQOL was compared with matched data from a survey on the Danish general population (n = 2248). RESULTS: Micro- and macrovascular complications were significantly more frequent in diabetic dialysis patients than in diabetic patients without renal disease. Self-rated physical health was significantly worse (p < 0.01) in diabetic dialysis patients (35 +/- 9 [mean +/- SD]) compared with non-diabetic dialysis patients (41 +/- 10), diabetic patients with normal kidney function (45 +/- 12) and the matched general population (47 +/- 19). The diabetic dialysis patients had similar levels of kidney-specific quality of life and mental health compared with the control groups. Reduced physical health was predicted by the presence of end-stage renal disease, diabetes and short time spent in education. Among the diabetic patients, those who believed more on their own ability to control their diabetes and less on chance reported better mental health and were less likely to be on dialysis. CONCLUSIONS/INTERPRETATIONS: Diabetic dialysis patients are characterised by a high prevalence of diabetic complications, reduced self-rated physical health but relatively good mental health.

Improved survival rate in patients with diabetes and end-stage renal disease in Denmark.

AIMS/HYPOTHESIS: We investigated the survival rate of Danish diabetic patients with end-stage renal disease (ESRD) between 1990 and 2005 and evaluated possible predictors of survival rate. MATERIALS AND METHODS: Data were obtained from the Danish National Register on Dialysis and Transplantation and from the Scandiatransplant database. Survival rates in different patient groups and association with age, sex, calendar time, waiting-list status and renal transplantation were evaluated using a multivariate Cox regression model. RESULTS: During the study period 8,421 patients (13% type 1 diabetic, 9% type 2 diabetic and 78% non-diabetic) started renal replacement therapy. The overall survival rate improved by 15% per five calendar years (hazard ratio [HR]=0.85, 95% CI: 0.81-0.88). The percentage of patients within each group who received renal transplantation was: type 1 diabetic: 26%, type 2 diabetic: 5%, non-diabetic: 24%. The survival rate of transplanted patients with diabetes mellitus (types 1 and 2) compared with non-diabetic patients at 1 year was: 95 vs 93%, at 5 years: 80 vs 85% and at 10 years: 52 vs 71%. Among diabetic patients survival rate was better in transplanted than in waiting-list patients (HR = 0.21, 95% CI 0.13-0.34), whereas the survival rate in waiting-list patients seemed to be superior to the survival rate among non-transplantation candidates (HR = 0.75, 95% CI 0.53-0.1.02, p = 0.07). CONCLUSIONS/INTERPRETATION: The survival rate of diabetic patients with ESRD has improved during the last 15 years. Although some selection bias may exist, significantly improved survival rate was observed among transplanted patients compared with dialysis patients on the waiting-list for transplantation. Renal transplantation should therefore be offered to diabetic patients with ESRD whenever possible.

Darbepoetin alfa once every 2 weeks for treatment of anemia in dialysis patients: a combined analysis of eight multicenter trials.

AIM: Darbepoetin alfa has a longer half-life than epoetin-(EPO) alfa or beta, allowing administration at less frequent intervals for the treatment of renal anemia. The aim of the present analysis was to evaluate the efficacy and tolerability of an every-2-week (Q2W) schedule of darbepoetin alfa in a large cohort of dialysis patients. METHODS: Data were combined from eight similarly designed 24-week phase 3b European studies, in which patients receiving EPO alfa or beta once-weekly were converted to Q2W darbepoetin alfa. Darbepoetin alfa dosage was titrated to maintain hemoglobin (Hb) between 10 and 13 g/dl and efficacy was evaluated during a 4-week evaluation period. RESULTS: In the 1,101 patients assigned to Q2W darbepoetin alfa (i.v., n = 196, s.c., n = 905), mean (SD) Hb levels were 11.53 (0.77) g/dl at baseline and 11.35 (1.04) g/dl at evaluation (mean change in Hb -0.27 g/dl, 95% confidence interval 0.34, -0.20). Hb levels were maintained between 10 and 13 g/dl during evaluation in 85% of patients. Darbepoetin alfa doses were similar at baseline and evaluation, and the i.v. and s.c. routes were associated with similar efficacy and dose requirements. Darbepoetin alfa was well-tolerated. CONCLUSIONS: Q2W darbepoetin alfa is effective in maintaining Hb levels in dialysis patients switched from weekly rHuEPO, regardless of the route of administration and with no notable increase in the weekly equivalent dose.

Is there a need to optimize glycemic control in hemodialyzed diabetic patients?

The report of Williams et al. gives rise to at least two important questions regarding diabetic patients on maintenance hemodialysis: (1) Does glycemic control play a significant role? (2) Is HbA1c a reliable measure of glycemic control? These questions are discussed. It is recommended that you treat ESRD patients with diabetes according to guidelines given for patients without ESRD.

Stabilized incidence of diabetic patients referred for renal replacement therapy in Denmark.

Despite an improvement in diabetes care during the last 20 years, the number of diabetic patients starting renal replacement therapy (RRT) has continued to increase in the Western world. The aim was to study the incidence of patients starting RRT in Denmark from 1990 to 2004. Data were obtained from The Danish National Registry; Report on Dialysis and Transplantation, where all patients actively treated for end-stage renal disease have been registered since 1990. The incidence of end-stage renal disease increased until 2001. Thereafter the incidence stabilized on 130 per million people (pmp). The number of diabetic patients starting RRT increased steadily from: 52 (number of patients) in 1990, 113 in 1995, 150 in 2000, 168 in 2001, and 183 in 2002. However, during the years 2003 and 2004 this number was significantly reduced by 15% to 156 and 155, respectively. This was mainly due to a 22% reduction in the number of non-insulin- treated (type II) diabetic patients (number of patients): 98, 82, and 76 in 2002, 2003, and 2004, respectively. The mean age in the background population, the mean age in diabetic patients starting RRT and the incidence of type I and type II diabetes increased during the study period. The encouraging stabilization in the incidence of diabetic patients referred for RRT observed in Denmark could be the result of implementation of a multifactorial and more intensive renoprotective intervention in patients with diabetes and chronic progressive renal disease.

Impaired vascular function during short-term poor glycaemic control in Type 1 diabetic patients.

AIM: To study the effects of short-term poor glycaemic control on vascular function in Type 1 diabetic patients. METHODS: Ten Type 1 diabetic patients, with diabetes duration of less than 10 years and normal urinary albumin excretion and ophthalmoscopy, were studied. All patients were examined after 48 h of good vs. poor glycaemic control within a 3-week period. Blood glucose was measured seven times daily for 2 days before each examination. External ultrasound was used to measure the dilatory response of the brachial artery to post-ischaemic increased blood flow (endothelium-dependent dilation) and to nitroglycerin (endothelium-independent dilation). Plasma concentration of von Willebrand factor antigen, adhesion molecules, vascular endothelial growth factor, homocystein and cholesterol were also measured. RESULTS: The median blood glucose levels in the 48 h before the examinations were [median (range), good vs. poor control]: 6.3 (5.0-7.6) vs. 15.9 (11.3-17.8) (mmol/l). The flow-associated vasodilation (% of baseline) was reduced during poor control: 102.7 (94.7-110.8) vs. 104.0 (99.6-118.5) (P < 0.05) as were the nitroglycerin-induced dilation (% of baseline): 114.5 (103.3-127.9) vs. 120.2 (106.8-148.0) (P < 0.05). P-von Willebrand factor antigen was high during poor control (kIU/l): 1.14 (0.73-1.84) vs. 0.86 (0.72-1.39) (P < 0.05) and so was P-vascular endothelial growth factor (ng/l): 288 (133-773) vs. 254 (90-383) (P < 0.05). CONCLUSIONS: Short-term (48 h) hyperglycaemia in Type 1 diabetic patients may disturb vascular function, possibly mediated through smooth muscle cell dysfunction as well as endothelial dysfunction. We suggest that prolonged and repeated episodes of hyperglycaemia could possibly lead to permanent vascular dysfunction and thereby development and progression of vascular complications in diabetes.

Orosomucoid in urine is a powerful predictor of cardiovascular mortality in normoalbuminuric patients with type 2 diabetes at five years of follow-up.

AIMS/HYPOTHESIS: To study whether urinary orosomucoid excretion rate (UOER) predicts mortality in normoalbuminuric patients with diabetes at 5 years of follow-up, and to investigate the relationship between orosomucoid in serum and urine. METHODS: A cohort of 578 patients with diabetes (430 type 2, 148 type 1) was followed prospectively for an average of 5 years. UOER was measured in timed overnight urine samples. RESULTS: Eighty-two patients with type 2 diabetes and 17 patients with type 1 diabetes died. Among patients with type 2 diabetes, 251 (58%) had normoalbuminuria; increased UOER independently predicted cardiovascular mortality (OR 4.94, 95% CI 1.60-15.22; p<0.006) in those with normoalbuminuria and in the entire cohort of patients with type 2 diabetes (odds ratio 3.63, 95% CI 1.50-8.81; p<0.005). Patients with increased UOER had a higher all-cause mortality than those with normal UOER (log-rank test, p<0.001 for type 2 patients; p<0.04 for type 1 patients). In patients with type 1 diabetes, there were five cardiovascular deaths and no significant predictive value of UOER. Patients with increased UOER had a subclinical increase in serum orosomucoid. CONCLUSION/INTERPRETATION: Increased UOER was an independent, powerful predictor of cardiovascular mortality in normoalbuminuric patients with type 2 diabetes and in the entire cohort of patients with type 2 diabetes. There were indications of UOER as being a valuable marker in type 1 diabetes that showed differences in survival between patients with normal versus increased UOER. Serum orosomucoid was associated with UOER; UOER may be a marker of low-grade inflammation in patients with diabetes.