Baseline Urinary Albumin Excretion Research Articles

Microalbuminuria during acute coronary syndrome: Association with 22-year mortality and causes of death. The ABC-8* study on heart disease. (*ABC is an acronym for Adria, Bassano, Conegliano, and Padova Hospitals)

BackgroundMicroalbuminuria is associated with adverse outcomes in acute coronary syndrome (ACS) patients. MethodsTo evaluate the very long-term association between Microalbuminuria and the overall mortality and causes of death in this clinical setting, we prospectively studied 579 unselected ACS patients admitted to three hospitals. The baseline albumin-to-creatinine ratio (ACR) was measured on days 1, 3, and 7 in 24-h urine samples. Patients were followed for 22 years or until death. ResultsVirtually all patients completed follow-up; 449(78%) had died: 41% due to non-sudden cardiac death (non-SCD), 19% sudden cardiac death (SCD), 40% due to non-cardiac (non-CD) death.Using unadjusted Cox regression analysis, ACR was a significant predictor of all-cause mortality (hazard ratio [HR] 1.26;95%confidence interval [CI] 1.22–1.31; p˂0.0001) and the three causes of death (HR 1.40;95%CI 1.32–1.48; p˂0.0001), (HR 1.22;95%CI 1.12–1.32; p˂0.0001) and (HR 1.16;95%CI 1.09–1.23; p˂0.0001) for non-SCD, SCD and non-CD respectively.Using a fully adjusted model, ACR was a significant independent predictor of all-cause mortality (HR 1.12; 95%CI 1.08–1.16; p˂0.0001) and only non-SCD (HR 1.21; 95%CI 1.14–1.29; p˂0.0001).There was a positive interaction between ACR level and history of AMI (HR 1.15; 95%CI 1.03–1.29; p = 0.01) and the presence of heart failure at admission (HR 1.11; 95%CI 1.01–1.24; p = 0.04), and negative interaction with higher than median LVEF (HR 0.89; 95%CI 0.80–0.99; p = 0.03) for all-cause mortality at the multivariable level. ConclusionBased on the present analysis, baseline urinary albumin excretion during ACS is a strong independent predictor of the very long-term mortality risk, chiefly due to non-sudden cardiac death.

MO504: Urinary Albumin Excretion and Cancer Risk

Abstract BACKGROUND AND AIMS Accumulating evidence has shown that chronic kidney disease (CKD) is associated with cancer development. However, the main focus in these studies was on patients with moderately or severely impaired kidney function, rather than on patients with milder CKD defined by higher albuminuria. We hypothesized that albuminuria may have an association with cancer risk that is independent of kidney function. This study examined therefore the association between urinary albumin excretion (UAE), considered the gold standard for albuminuria assessment, and the risk of cancer incidence, independent of estimated glomerular filtration rate (eGFR). METHOD We included 8490 subjects in the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study, a prospective, population-based cohort of Dutch men and women. UAE was measured in two 24-h urine specimens at baseline (1997–8). Cancer incidence was ascertained by record linkage with the nationwide network and registry of histo and cytopathology in the Netherlands (PALGA). Non-melanoma skin cancer was excluded from analyses. eGFR was calculated by the 2012 CKD-EPI creatinine-cystatin C equation. Cox proportional hazards regression models were used to calculate hazard ratios [HRs, [95% confidence intervals (95% CIs)] crude and additionally adjusted for age, sex, BMI, smoking, alcohol, educational level, diabetes and baseline eGFR. To detect potential reverse causation, we excluded subjects with a follow-up time of <1 year and recalculated the fully adjusted models. RESULTS Overall, 50% of the included subjects were female, and the mean age was 49.8 ± 12.7 years old. Median baseline UAE was 9.4 (IQR: 6.3–17.8) mg/24 h, and the mean baseline eGFR was 94.6 ± 17.3 mL/min/1.73 m2. At baseline, subjects who had higher UAE were more likely to be male, older, have lower eGFR and to have hypertension or diabetes. During a median follow-up of 17.7 (IQR: 17.67–17.71) years, 1789 subjects developed a de novo cancer. In the age- and sex-adjusted model, every doubling of UAE was associated with a 7% (HR: 1.07, 95% CI 1.04–1.10) higher risk of overall cancer. This association remained essentially unchanged after additional multivariable adjustments, including eGFR (HR: 1.06, 95% CI 1.02–1.09). UAE was also independently associated with an increased risk of development of several site-specific cancers including urothelial cell carcinoma (HR: 1.13, 95% CI 1.02–1.25), as well as lung cancer (HR: 1.13, 95% CI 1.04–1.22), haematological cancer (HR: 1.12, 95% CI 1.00–1.25), and head and neck cancer (HR: 1.29, 95% CI 1.06–1.57). We did not observe significant associations of UAE with melanoma, breast, prostate and colorectal cancers. Additionally, the associations of UAE with overall cancer, UCC, lung cancer and head and neck cancer remained significant in the fully adjusted models after we excluded subjects with a follow-up time of <1 year. CONCLUSION Higher albuminuria, assessed in 24-h urine, is associated with an increased risk of overall cancer and several site-specific cancers, independent of baseline eGFR. Future studies are warranted to corroborate these findings and to examine mechanisms underlying these associations.

The association of low-grade albuminuria with incident non-alcoholic fatty liver disease and non-invasive markers of liver fibrosis by glycaemia status.

Low-grade albuminuria, as an early marker of endothelial dysfunction and kidney damage, has been recognized as a risk factor for metabolic disorders. Epidemiological studies manifesting the association of low-grade albuminuria with the risk of incident NAFLD and fibrosis were not available. We aimed to investigate the association of low-grade albuminuria with incident NAFLD and fibrosis by glycaemia status. A prospective population-based study was performed in 3308 participants without NAFLD at recruitment. Baseline urinary albumin excretion was obtained by a first-voided early morning spot urine sample. At follow-up visit, incident NAFLD was diagnosed by hepatic ultrasound after excluding alcohol abuse and other cause of hepatic diseases. Fatty liver index (FLI) was employed to reflect liver fat content. Liver fibrosis was evaluated by NAFLD fibrosis score (NFS), fibrosis-4 score (FIB-4) and Hepamet fibrosis score (HFS) respectively. After 4.3years of follow-up, 622 (18.8%) were detected as incident NAFLD. Participants with low-grade albuminuria imposed a 40.4% [1.404 (1.112-1.772)] greater risk on incident NAFLD, and 52.0% [1.520 (1.141-2.026)], 87.4% [1.874 (1.291-2.720)] and 40.4% [1.404 (1.038-1.898)] higher risks on newly onset higher values of FLI, NFS and FIB-4 respectively. The effect of low-grade albuminuria was stronger in the subgroup of non-diabetic population. Low-grade albuminuria was independently associated with incident NAFLD and a higher probability of fibrosis, especially among non-diabetic individuals.

Chymase inhibition retards albuminuria in type 2 diabetes.

Chymase released from mast cells produces pro‐fibrotic, inflammatory, and vasoconstrictor agents. Studies were performed to test the hypothesis that chronic chymase inhibition provides a renal protective effect in type 2 diabetes. Diabetic (db/db) and control mice (db/m) were chronically infused with a chymase‐specific inhibitor or vehicle for 8 weeks. Baseline urinary albumin excretion (UalbV) averaged 42 ± 3 and 442 ± 32 microg/d in control (n = 22) and diabetic mice (n = 27), respectively (p < .05). After administration of chymase inhibitor to diabetic mice, the change in UalbV was significantly lower (459 ± 57 microg/d) than in vehicle‐treated diabetic mice (645 ± 108 microg/d). UNGALV was not different at baseline between diabetic mice that would receive the chymase inhibitor (349 ± 56 ng/d, n = 6) and vehicle (373 ± 99 ng/d, n = 6) infusions, but increased significantly only in the vehicle‐treated diabetic mice (p < .05). Glomeruli of diabetic kidneys treated chronically with chymase inhibition demonstrated reduced mesangial matrix expansion compared to glomeruli from untreated diabetic mice. Plasma angiotensin II levels were not altered by chymase inhibitor treatment. In summary, chronic chymase inhibition slowed the progression of urinary albumin excretion in diabetic mice. In conclusion, renal chymase may contribute to the progression of albuminuria in type 2 diabetes renal disease.

Association of urinary albumin excretion with central foveal thickness and intravitreal conbercept treatment frequency in patients with diabetic macular edema.

To investigate the effect of albuminuria on diabetic macular edema (DME) and the possible association between baseline urinary albumin excretion (UAE) and intravitreal conbercept (IVC) treatment frequency in DME patients. In this hospital-based retrospective study, a total of 350 in-patients with type 2 diabetes mellitus were recruited and their clinical records were reviewed. Thereafter, 52 patients identified with severe non-proliferative diabetic retinopathy (NPDR) combined with albuminuria were divided into the microalbuminuria (UAE 30-300 mg/24h) and macroalbuminuria (UAE>300 mg/24h) groups, which were compared and analyzed by both independent sample t-test and Chi-square test. Correlations between the systemic variables and the central foveal thickness (CFT) were evaluated using Spearman's correlation and linear regression analyses. Of the 52 patients with center-involved DME, 43 received an initial combined injection of conbercept (0.5 mg/0.05 mL) and triamcinolone acetonide (1 mg/0.05 mL), followed by an IVC injection, as needed. The relationship between baseline UAE and number of IVC injections during the first year of treatment was analyzed using Spearman's partial correlation. Of 350 patients, a higher incidence of DME was observed in severe non-proliferative retinopathy (NPDR) patients than that observed in other groups. By dividing the 52 patients with severe NPDR into the micro- and macro-albuminuria subgroups, significant differences in CFT, systolic blood pressure, total cholesterol and serum creatinine levels, and UAE were revealed. Furthermore, a positive liner correlation between the UAE and CFT was found. Finally, the partial correlation coefficient adjusted for either the CFT or UAE indicated that both parameters directly correlated with the number of IVC injections administered during the 12mo of follow-up. Generally, macular edema occurred in patients with severe NPDR, for whom the UAE is an independent risk predictor of DME. The baseline UAE and CFT predicted the treatment frequency of IVC injections administered in the first year for eyes with DME.

Dietary Protein Intake Is Not Associated with Progression of Diabetic Nephropathy in Patients without Macroalbuminuria

Background/Aims: Diabetic nephropathy is an important problem in patients with diabetes. However, little is known about the effect of dietary protein intake on albuminuria in patients with diabetes. Thus, the aim of this study was to clarify the association between dietary protein intake and change in urinary albumin excretion (UAE) or estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes. Methods: In this retrospective cohort study, we included 143 patients (71 men, average 64.0 (10.5) years, and median 14.5 (6.7-38.5) mg/gCr) without macroalbuminuria (UAE over 300 mg/gCr). Change in UAE or eGFR was defined as increase of UAE or GFR/follow-up duration (year). Habitual protein intake was estimated by a self-administered diet history questionnaire. Results: Median follow-up duration was 5 years. Logistic regression analyses showed that baseline UAE was associated with change in UAE (β = 0.217, p = 0.012), but the protein intake was not (β = -0.064, p = 0.454) (Table). In addition, baseline Cr was associated with change in eGFR (β = 0.344, p = 0.001), but the protein intake was not (β = 0.001, p = 0.988). Conclusions: Dietary protein intake was not associated with change in UAE or eGFR. This result suggests that protein restriction is not necessary in patients without macroalbuminuria. Multiple regression analysis on δUAE or δeGFRδUAEstandardized regression coefficientp valueδeGFRstandardized regression coefficientp valueLog (UAE+1)0.2170.012Log (UAE+1)0.0490.560Protein intake (g/kg/day)-0.0640.454Protein intake (g/kg/day)-0.0330.698Usage of RAS inhibitor0.1140.193Usage of RAS inhibitor-0.2020.021Creatinine0.0470.646Creatinine0.398&amp;lt;0.001Age-0.0030.977Age0.0610.490BMI0.1190.184BMI-0.0420.634Men-0.1430.163Men0.1210.237 Disclosure A. Kaji: None. Y. Hashimoto: Research Support; Self; Asahi Kasei Corporation, Fuji Foundation for Protein Research, Japan Society for the Promotion of Science, MSD K.K.. R. Sakai: None. T. Okamura: None. M. Yamazaki: None. M. Fukui: Research Support; Self; Grant-in-Aid for Scientific Research (C), Ono Pharmaceutical Co., Ltd., AstraZeneca, Astellas Pharma US, Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Kyowa Hakko Kirin Co., Ltd., Kissei Pharmaceutical Co., Ltd., MSD K.K., Novo Nordisk Foundation.

Serum uric acid and progression of diabetic nephropathy in type 1 diabetes

AimsUric acid (UA) is a risk factor for CKD. We evaluated UA in relation to change in GFR in patients with type 1 diabetes. MethodsPost hoc analysis of a trial of losartan in diabetic nephropathy, mean follow-up 3 years (IQR 1.5–3.5). UA was measured at baseline. Primary end-point was change in measured GFR. UA was tested in a linear regression model adjusted for known progression factors (gender, HbA1c, systolic blood pressure, cholesterol, baseline GFR and baseline urinary albumin excretion rate (UAER)). ResultsBaseline UA was 0.339 mmol/l (SD ±0.107), GFR 87 ml/min/1.73 m2 (±23), geometric mean UAER 1023 mg/24 h (IQR, 631 – 1995). Mean rate of decline in GFR was 4.6 (3.7) ml/min/year. In the upper quartile of baseline UA the mean decline in GFR from baseline to the end of the study was 6.2 (4.9) ml/min/1.73 m2 and 4.1 (3.1) ml/min/1.73 m2 in the three lower quartiles of UA, (p = 0.088). In a linear model including baseline covariates (UAER, GFR, total cholesterol, HDL cholesterol) UA was associated with decline in GFR (r2 = 0.45, p < 0.001). ConclusionUric acid was weakly associated with decline in GFR in type 1 diabetic patients with overt nephropathy.

Prognostic impact of baseline urinary albumin excretion rate in patients with resistant hypertension: a prospective cohort study.

Moderately increased albuminuria, defined as urinary albumin excretion rate (UAER) between 30 and 300-mg/24-h is a well-known cardiovascular risk factor, especially in diabetic and hypertensive patients. This study aim to analyze the prognostic value of baseline UAER in a still understudied group, patients with resistant hypertension (RHT). This is a prospective observational study, which had enrolled 1048 outpatients with RHT, who were submitted to a clinical-laboratory assessment and ambulatory blood pressure monitoring (ABPM) during the follow-up. Primary endpoints were a composite of fatal and non-fatal cardiovascular events, all-cause mortality and cardiovascular mortality. Survival analysis by multiple Cox regression assessed the associations among endpoints, baseline UAER, glomerular filtration rate (GFR), and ABPM control. After a mean 7.5 years follow-up, 233 patients died, 120 from cardiac death; 215 cardiovascular events occurred, 90 strokes and 116 coronary diseases. UAER above 30-mg/24-h increased above 40% the risk of fatal and non-fatal cardiovascular events, and of all-cause mortality. At these UAER levels, secondary outcomes were associated to increased risk of stroke and risk of end-stage renal disease, but did not affect coronary events. Both the GFR below 60-mL/min and uncontrolled ABPM were related to nearly two-fold raised risk of fatal and non-fatal cardiovascular events, when coupled with UAER above 30-mg/24-h. In conclusion, moderately increased albuminuria predicts cardiovascular events and all-cause mortality in RHT, and its prognostic impact is enhanced in association with a GFR under 60-mL/min and uncontrolled baseline ABPM.

Elevated urinary albumin excretion complements the Framingham Risk Score for the prediction of cardiovascular risk — response to treatment in the PREVEND IT trial

BackgroundThe PREVEND IT trial reported on a high cardiovascular (CV) event rate in subjects with a baseline urinary albumin excretion (UAE) rate of ≥ 50 mg/24 h. Here, we report on the observed 10-year CV outcome of this population and compare this with the predicted Framingham Risk Score (FRS). In addition, we evaluated the effect of four years of fosinopril treatment on this relation. Methods and resultsFrom the PREVEND IT cohort, 833 subjects without history of CV disease, randomized to fosinopril (N = 412) or placebo (N = 421), were studied. The primary endpoint included CV mortality and adjudicated hospitalization for CV disease during a 10-year follow-up period. Mean age was 51 ± 12 years and 65% were males, while prevalence of diabetes (2.6%) and use of CV drugs (3.5%) was low. Subjects were categorized to high UAE (≥ 50 mg/24 h) or low UAE (< 50 mg/24 h). After 10 years of follow-up, the event rate in the high UAE group was almost twice as high as predicted by the FRS (29.5% vs. 17.2%). Treatment for four years with fosinopril reduced the event rate to comparable levels of that predicted by FRS. The addition of UAE ≥ 50 mg/24 h to the FRS improved the Integrated Discrimination Improvement (P = 0.033) and increased the area under the curve by 0.54% (P = 0.024). ConclusionsThe 10-year CV risk of subjects with an elevated UAE (≥ 50 mg/24 h) is substantially underestimated by the FRS. Treatment with fosinopril successfully reduced this increased event rate to FRS-predicted CV risk.

Association of a Reduction in Central Obesity and Phosphorus Intake With Changes in Urinary Albumin Excretion: The PREMIER Study

Excess adiposity and dietary factors may be important determinants of urinary albumin excretion (UAE). Observational analysis of PREMIER, a randomized trial designed to lower blood pressure using behavioral interventions (counseling on weight loss, healthy diet, and exercise). 481 participants with normal kidney function who provided adequate 24-hour urine collections at baseline and 6 months. Change in waist circumference; 24-hour urine sodium, potassium, and phosphorus excretion; and protein intake estimated from urea nitrogen. The primary outcome was change in log-transformed 24-hour UAE over 6 months. After 6 months, the proportion of individuals with UAE ≥10 mg/d decreased from 18.7% to 12.7% (P < 0.001). Changes in mean waist circumference (-4.2 ± 6.6 [SD] cm), 24-hour excretion of sodium (-28.2 ± 71.7 mmol/d), potassium (+8.4 ± 27.8 mmol/d), phosphorus (-27.7 ± 314.1 mg/d), and protein intake (-1.7 ± 19.4 g/d) were observed. After adjustment for relevant covariates, the following variables were associated significantly with reduction in ln(UAE) in separate models: decrease in waist circumference (P = 0.001), decrease in 24-hour urine phosphorus excretion (P < 0.001), and decrease in protein intake (P = 0.01). In a multivariable model including these 3 predictors, decreases in waist circumference (P = 0.002) and 24-hour urine phosphorus excretion (P = 0.03), but not change in protein intake (P = 0.5), remained associated significantly with reduction in ln(UAE). These associations remained significant even after adjustment for changes in blood pressure and insulin resistance. Baseline UAE and metabolic syndrome modified the relationship of waist circumference with ln(UAE); specifically, individuals with higher UAE and baseline metabolic syndrome experienced greater reductions in ln(UAE) from decreases in waist circumference. Observational study with potential for confounding. In adults with normal kidney function, decreases in waist circumference and 24-hour urine phosphorus excretion are associated with reductions in UAE. These findings support the rationale for clinical trials to determine whether reducing dietary phosphorus intake or waist circumference could prevent chronic kidney disease or slow its progression.

High-normal diastolic blood pressure is a risk for development of microalbuminuria in the general population

Although hypertension is a well known risk factor for microalbuminuria, it is unclear whether blood pressure less than 140/90 mmHg could be a risk for microalbuminuria. We assessed the relationship between baseline blood pressure and the future onset of microalbuminuria in the general population. We studied 2603 town inhabitants of Watari, located in the southeastern part of Miyagi prefecture, Japan. Demographic data, medical history, sitting blood pressure, fasting blood chemistry, and urinary albumin-creatinine ratio were measured at baseline and were followed annually during the next 3 years. Among 2338 individuals who were normoalbuminuric at baseline (albumin-creatinine ratio <30 mg/g Cr), 161 developed microalbuminuria (albumin-creatinine ratio 30-299 mg/g Cr) during a mean follow-up period of 2.4 years. Incident microalbuminuria patients were older (63.7 ± 8.6 vs. 61.4 ± 10.5 years; P < 0.01), included fewer men (31.1 vs. 40.1%; P < 0.05), had a greater BMI (23.8 ± 3.6 vs. 23.1 ± 3.1 kg/m²; P < 0.01), higher blood pressures (133.5 ± 18.1/75.8 ± 11.9 vs. 127.6 ± 18.1/73.4 ± 11.0 mmHg; P < 0.01 for both systolic and diastolic), higher triglycerides (median 1.18 vs. 1.02 mmol/l; P < 0.01), higher fasting blood glucose (median 5.05 vs. 4.94 mmol/l; P < 0.01), higher urinary albumin excretion (median 13.0 vs. 5.9 mg/g Cr; P < 0.001), and lower serum creatinine concentrations (59.2 ± 12.8 vs. 61.4 ± 13.2 μmol/l; P < 0.05) compared to persistent normoalbuminuric individuals. Multivariate Cox proportional hazards analysis including all covariates revealed that only baseline urinary albumin excretion was an independent predictor for future microalbuminuria, whereas high-normal DBP, triglyceride, and fasting blood glucose concentrations were all significant predictors in the model excluding urinary albumin excretion. High-normal DBP associated with metabolic disorders could initiate glomerular damage, leading to future microalbuminuria.

Reduction in Morning Blood Pressure Is a Key Factor for Ameliorating Urinary Albumin Excretion in Patients With Morning Hypertension Irrespective of Treatment Regimen

The Morning Hypertension and Angiotensin Receptor Blocker/Hydrochlorothiazide Combination Therapy (MAPPY) study has shown that losartan/hydrochlorothiazide (HCTZ) combination is superior to high-dose losartan in not only reducing morning systolic blood pressure (SBP) but also ameliorating urinary albumin excretion (UAE) after 3-month treatment. The purpose of the present study was to investigate factors associated with UAE reduction in on-treatment patients with morning hypertension. A total of 95 patients registered in the MAPPY study were analyzed. Patients were treated with either a losartan/HCTZ combination regimen (n=47) or a high-dose losartan regimen (n=48). Three-month treatment significantly reduced morning SBP, evening SBP, and clinic SBP (P<0.001, P<0.05, and P<0.01, respectively). UAE and serum uric acid were significantly decreased (P<0.01 for both) without the change in estimated glomerular filtration rate. Multiple linear regression analysis indicated that %morning SBP reduction and baseline UAE were independent determinants of the UAE reduction (P=0.001 for both). After adjustments for the reduction in morning-evening SBP difference, baseline UAE, and %uric acid reduction, estimated %UAE reduction level was positively correlated with the tertiles of the increasing %morning SBP reduction level (P=0.031 for trend). Moreover, subgroup analysis showed that morning SBP reduction was an independent determinant of UAE reduction in both treatment regimens. Reduction in morning SBP was a key factor in UAE reduction in patients with morning hypertension, irrespective of treatment regimen.

Relation of Reduction in Urinary Albumin Excretion to Ten-Year Cardiovascular Mortality in Patients With Type 2 Diabetes and Systemic Hypertension

Microalbuminuria is one of the strongest predictors of both adverse renal and cardiovascular disease (CVD) outcomes in patients with type 2 diabetes mellitus. Although measurement of urinary albumin excretion (UAE) is widely recommended, limited data are available to suggest that reducing UAE translates into a reduction in long-term cardiovascular mortality, particularly among patients without overt nephropathy, who constitute most patients with type 2 diabetes worldwide. We assessed whether changes in the UAE at 1 year were associated with cardiovascular mortality in 393 patients with hypertension and type 2 diabetes during a 10-year period. On univariate analysis, CVD history, age, diabetes duration, and change in UAE at 1 year were associated with cardiovascular mortality risk (hazard ratio 2.60 for those with CVD history, 95% confidence interval [CI] 1.47 to 4.62; hazard ratio 1.59 per 10 years of diabetes duration, 95% CI 1.12 to 2.25; and hazard ratio 1.49 per log UAE increase, 95% CI 1.13 to 1.96). In a stepwise Cox regression model that included baseline UAE and CVD history, the 10-year predicted mortality of those with a decrease in UAE of 2 logs at 1 year was 4.7% (95% CI 1.4% to 7.8%). For those with an increase in UAE of 2 logs at 1 year, it was 24.5% (95% CI 10.1% to 36.5%). In conclusion, these data support current guideline recommendations to screen for UAE in all patients with type 2 diabetes, even in the absence of nephropathy, and suggest that serial UAE measurements even after the initiation of antihypertensive therapy has prognostic value independent of traditional cardiovascular risk factors.

Interaction of eNOS polymorphism with MTHFR variants increases the risk of diabetic nephropathy and its progression in type 2 diabetes mellitus patients

Long-term effects of angiotensin-converting enzyme inhibition and metabolic control in hypertensive type 2 diabetic patients.In hypertensive type 2 diabetic patients, treatment with angiotensin-converting enzyme (ACE) inhibitors is associated with a lower incidence of cardiovascular events than those treated with calcium channel-blocking agents. However, the long-term renal effects of ACE inhibitors in these patients remain inconclusive. In 1989, we commenced a placebo-controlled, double-blind, randomized study to examine the anti-albuminuric effects of enalapril versus nifedipine (slow release) in 102 hypertensive, type 2 diabetic patients. These patients have been followed up for a mean trial duration of 5.5 ± 2.2 years. We examined the determinants, including the effect of ACE inhibition on clinical outcomes in these patients.After a six-week placebo-controlled, run-in period, 52 patients were randomized double-blind to receive nifedipine (slow release) and 50 patients to receive enalapril. After the one-year analysis, which confirmed the superior anti-albuminuric effects of enalapril (-54%) over nifedipine (+11%), all patients were continued on their previously assigned treatment with informed consent. They were subdivided into normoalbuminuric (N = 43), microalbuminuric (N = 34), and macroalbuminuric (N = 25) groups based on two of three 24-hour urinary albumin excretion (UAE) measurements during the run-in period. Renal function was shown by the 24-hour UAE, creatinine clearance (CCr), and the regression coefficient of the yearly plasma creatinine reciprocal (β-1/Cr). Clinical endpoints were defined as death, cardiovascular events, and/or renal events (need for renal replacement therapy or doubling of baseline plasma creatinine).In the whole group, patients treated with enalapril were more likely to revert to being normoalbuminuric (23.8 vs. 15.4%), and fewer of them developed macroalbuminuria (19.1 vs. 30.8%) compared with the nifedipine-treated patients (P < 0.05). In the microalbuminuric group, treatment with enalapril (N = 21) was associated with a 13.0% (P < 0.01) reduction in 24-hour UAE compared with a 17.3% increase in the nifedipine group (N = 13). In the macroalbuminuric patients, enalapril treatment (N = 11) was associated with stabilization compared with a decline in renal function in the nifedipine group, as shown by the β-1/Cr (0.65 ± 4.29 vs. -1.93 ± 2.35 1/μmol × 10-3, P < 0.05) after adjustment for baseline values. Compared with the normoalbuminuric and microalbuminuric patients, those with macroalbuminuria had the lowest mean CCr (75.5 ± 24.1 vs. 63.5 ± 21.3 vs. 41.9 ± 18.5 mL/min, P < 0.001) and the highest frequency of clinical events (4.7 vs. 5.9 vs. 52%, P < 0.001). On multivariate analysis, β-1/Cr (R2 = 0.195, P < 0.001) was independently associated with baseline HbA1c (β = -0.285, P = 0.004), whereas clinical outcomes (R2 = 0.176, P < 0.001) were independently related to the mean low-density lipoprotein cholesterol (β = 2.426, P = 0.018), high-density lipoprotein cholesterol (β = -8.797, P = 0.03), baseline UAE (β = 0.002, P = 0.04), and mean CCr during treatment (β = -0.211, P = 0.006).In this prospective cohort analysis involving 102 hypertensive, type 2 diabetic patients with varying degrees of albuminuria followed up for a mean duration of five years, we observed the importance of good metabolic and blood pressure control on the progression of albuminuria and renal function. Treatment with enalapril was associated with a greater reduction in albuminuria than with nifedipine in the entire patient group, and especially in those with microalbuminuria. In the macroalbuminuric patients, the rate of deterioration in renal function was also attenuated by treatment with enalapril.

Synergistic effects of the MTHFR C677T and A1298C polymorphisms on the increase risk of micro- and macro-albuminuria and progression of diabetic nephropathy among Iranians with type 2 diabetes mellitus

Long-term effects of angiotensin-converting enzyme inhibition and metabolic control in hypertensive type 2 diabetic patients.In hypertensive type 2 diabetic patients, treatment with angiotensin-converting enzyme (ACE) inhibitors is associated with a lower incidence of cardiovascular events than those treated with calcium channel-blocking agents. However, the long-term renal effects of ACE inhibitors in these patients remain inconclusive. In 1989, we commenced a placebo-controlled, double-blind, randomized study to examine the anti-albuminuric effects of enalapril versus nifedipine (slow release) in 102 hypertensive, type 2 diabetic patients. These patients have been followed up for a mean trial duration of 5.5 ± 2.2 years. We examined the determinants, including the effect of ACE inhibition on clinical outcomes in these patients.After a six-week placebo-controlled, run-in period, 52 patients were randomized double-blind to receive nifedipine (slow release) and 50 patients to receive enalapril. After the one-year analysis, which confirmed the superior anti-albuminuric effects of enalapril (-54%) over nifedipine (+11%), all patients were continued on their previously assigned treatment with informed consent. They were subdivided into normoalbuminuric (N = 43), microalbuminuric (N = 34), and macroalbuminuric (N = 25) groups based on two of three 24-hour urinary albumin excretion (UAE) measurements during the run-in period. Renal function was shown by the 24-hour UAE, creatinine clearance (CCr), and the regression coefficient of the yearly plasma creatinine reciprocal (β-1/Cr). Clinical endpoints were defined as death, cardiovascular events, and/or renal events (need for renal replacement therapy or doubling of baseline plasma creatinine).In the whole group, patients treated with enalapril were more likely to revert to being normoalbuminuric (23.8 vs. 15.4%), and fewer of them developed macroalbuminuria (19.1 vs. 30.8%) compared with the nifedipine-treated patients (P < 0.05). In the microalbuminuric group, treatment with enalapril (N = 21) was associated with a 13.0% (P < 0.01) reduction in 24-hour UAE compared with a 17.3% increase in the nifedipine group (N = 13). In the macroalbuminuric patients, enalapril treatment (N = 11) was associated with stabilization compared with a decline in renal function in the nifedipine group, as shown by the β-1/Cr (0.65 ± 4.29 vs. -1.93 ± 2.35 1/μmol × 10-3, P < 0.05) after adjustment for baseline values. Compared with the normoalbuminuric and microalbuminuric patients, those with macroalbuminuria had the lowest mean CCr (75.5 ± 24.1 vs. 63.5 ± 21.3 vs. 41.9 ± 18.5 mL/min, P < 0.001) and the highest frequency of clinical events (4.7 vs. 5.9 vs. 52%, P < 0.001). On multivariate analysis, β-1/Cr (R2 = 0.195, P < 0.001) was independently associated with baseline HbA1c (β = -0.285, P = 0.004), whereas clinical outcomes (R2 = 0.176, P < 0.001) were independently related to the mean low-density lipoprotein cholesterol (β = 2.426, P = 0.018), high-density lipoprotein cholesterol (β = -8.797, P = 0.03), baseline UAE (β = 0.002, P = 0.04), and mean CCr during treatment (β = -0.211, P = 0.006).In this prospective cohort analysis involving 102 hypertensive, type 2 diabetic patients with varying degrees of albuminuria followed up for a mean duration of five years, we observed the importance of good metabolic and blood pressure control on the progression of albuminuria and renal function. Treatment with enalapril was associated with a greater reduction in albuminuria than with nifedipine in the entire patient group, and especially in those with microalbuminuria. In the macroalbuminuric patients, the rate of deterioration in renal function was also attenuated by treatment with enalapril.

Long-term effects of fosinopril and pravastatin on cardiovascular events in subjects with microalbuminuria: Ten years of follow-up of Prevention of Renal and Vascular End-stage Disease Intervention Trial (PREVEND IT)

The PREVEND IT investigated whether treatment targeted at lowering urinary albumin excretion (UAE) would reduce adverse cardiovascular events. We obtained extended follow-up data to approximately 10 years to investigate the long-term effects of fosinopril 20 mg and pravastatin 40 mg on cardiovascular outcomes in subjects with UAE >15 mg per 24 hours.The original PREVEND IT consisted of 864 participants and 839 survivors after 4 years. For every survivor, the primary end point determined by the combined incidence of cardiovascular mortality and hospitalization for cardiovascular morbidity was registered in several national databases and electronic hospital systems.Mean total follow-up of the extended PREVEND IT was 9.5 years (range 9.4-10.7 years). Four years of treatment with fosinopril was not associated with a reduction in the primary end point compared with placebo (hazard ratio 0.87, 95% CI 0.61-1.24 [P = .42]) during long-term follow-up. After 9.5 years, subjects with a baseline UAE in the upper quintile (>50 mg/24 hours) had a total event rate of 29.5% and were at a higher risk for developing cardiovascular disease compared with less UAE (hazard ratio 2.03, 95% CI 1.38-2.97 [P ≤ .01]). In addition, 4 years of fosinopril treatment resulted in a risk reduction of 45% (95% CI 6%-75% [P = .04]) in this group compared with placebo. Subjects originally assigned to pravastatin had no overall risk reduction in the primary end point (P = .99).Elevated UAE is associated with increased cardiovascular mortality and morbidity after 9.5 years of follow-up, with a doubling of the risk if the UAE is >50 mg per 24 hours. In this group, the benefits of 4-year treatment with fosinopril were sustained during posttrial follow-up for cardiovascular mortality and morbidity. We propose that UAE be used to estimate risk in the general population and that large clinical trials be designed to confirm the hypothesis that angiotensin-converting enzyme-inhibitor treatment may be beneficial in patients with mildly elevated UAE despite the absence of other comorbidities.

Potential Benefit of Statin Therapy for Dyslipidemia with Chronic Kidney Disease: Fluvastatin Renal Evaluation Trial (FRET)

Dyslipidemia is a common complication of chronic kidney disease (CKD) and contributes to cardiovascular morbidity and mortality of CKD patients. The aim of the present study was to determine whether fluvastatin, which is mostly characterized by its pleiotropic anti-oxidant effects, has renoprotective effects in dyslipidemic patients with CKD. In 43 dyslipidemic patients with CKD taking fluvastatin 10 mg/day, 20 mg/day or 30 mg/day, renal functions as well as lipid profiles were assessed. After 3 months of treatment with fluvastatin, LDL-cholesterol level significantly decreased. Serum creatinine level, estimated glomerular filtration rate (eGFR), urinary albumin excretion (UAE), urinary liver-type fatty acid binding protein (L-FABP) level and urinary 8-hydroxydeoxyguanosine (8-OHdG) level did not change in overall patients. However, in patients with microalbuminuria (baseline UAE ≥ 30 mg/g·creatinine; n = 23), the UAE significantly decreased [2.43 ± 0.67 to 1.98 ± 0.80 log(mg/g·creatinine), p = 0.01]. In patients with high L-FABP group (baseline L-FABP ≥ 11 µg/g·creatinine; n = 18), the urinary L-FABP level was significantly decreased (1.52 ± 0.45 to 1.26 ± 0.43 µg/g·creatinine, p < 0.01). In the limited 23 patients with microalbuminuria, the L-FABP level was significantly decreased [1.20 ± 0.62 to 1.03 ± 0.49 log(µg/g·creatinine), p = 0.042], although the LDL-cholesterol level (139 ± 28 to 129 ± 23 mg/dL, p = 0.08) only showed a tendency to decrease. The 8-OHdG level also was significantly decreased (13.6 ± 9.6 to 9.8 ± 3.8 ng/g·creatinine, p = 0.043). In the overall patients, changes in the values for UAE and urinary L-FABP were not correlated with the changes in LDL-levels. Fluvastatin reduces both UAE and the urinary L-FABP level, and thus, has renoprotective effects, independent of its lipid lowering effects in dyslipidemic patients with CKD.

Pathogenesis and Treatment of Microalbuminuria in Patients With Diabetes: The Road Ahead

The incidence of type 2 diabetes is increasing in the United States, which is expected to result in an increased prevalence of microalbuminuria and higher cardiovascular risk. Microalbuminuria is an indication that a low-level inflammatory process is ongoing. In patients with hypertension, with or without diabetes, increasing urinary albumin excretion (UAE) is associated with elevated levels of inflammatory markers, endothelial dysfunction, and platelet activation. Microalbuminuria is associated with an increased incidence of cardiovascular disease (CVD) morbidity and mortality in patients with hypertension and in those with diabetes with or without hypertension. Antihypertensive agents that modulate the renin-angiotensin-aldosterone system (RAAS) can delay the onset and reduce progression of microalbuminuria and decrease CVD morbidity and mortality in patients with diabetes. Clinical trials provide a spectrum of results regarding the protective effects of RAAS-blocking agents. Consideration of baseline blood pressure (BP), UAE and CVD risk, and the extent of BP lowering with treatment is necessary when interpreting clinical trial results in patients with microalbuminuria. It remains to be determined whether targeting the underlying inflammatory process can retard or prevent microalbuminuria progression or whether treatment of microalbuminuria can prevent end-stage renal disease or death.

Albuminuria within the normal range and ultrasound‐assessed atherosclerosis in the AIR study: a 9‐year follow‐up of 58‐year‐old clinically healthy men

Background:Microalbuminuria, traditionally defined as 30–300 mg urinary albumin/24 h, predicts renal impairment and cardiovascular disease. Studies suggest that also a far lower urinary albumin excretion (UAE) can predict clinical outcome. Intima media thickness (IMT) is an established estimate of atherosclerosis. In this study, we investigated the predictive value of UAE within the normal rate (UAE–n) for the progression of IMT in the carotid and femoral arteries. Methods: We included 325 clinically healthy men with normoalbuminuria. Anthropometrics, urine and blood samples were taken and IMT in the carotid and femoral arteries were assessed by B–mode ultrasound at baseline and after 3 and 9 years. The annual progression rate of IMT (r–IMT) was calculated. Results: UAE–n correlated with carotid IMT at baseline and after 3 and 9 years, but not with r–IMT. In a regression analysis, only HDL and baseline IMT remained as statistically significant co–variates to mean IMT at 9 years. IMT in the femoral artery and r–IMT at any time–point did not correlate to baseline UAE. Conclusion: UAE–n was associated with carotid IMT after 3 and 9 years but not r–IMT or with femoral artery IMT. Carotid IMT after 9 years' follow–up was independently related to baseline IMT and HDL cholesterol. In this cohort of 58–year–old men, our interpretation is that UAE–n is not associated with the increase in carotid and femoral artery IMT observed after 9 years.

Association between serum uric acid, metabolic syndrome and microalbuminuria in previously untreated essential hypertensive patients

Background and objective The aim of the study was to assess the association of serum uric acid levels with microalbuminuria —urinary albumin excretion (UAE)≥ 30 mg/24 h—. Patients and method Cross-sectional study in 429 (220 women) hypertensive, non diabetic, never treated patients (mean age: 47 years) with glomerular filtration rate ≥60 ml/min/1.73 m 2. Results The prevalence of microalbuminuria was 20.5%; 18% had hyperuricemia and 47% fulfilled the criteria for metabolic syndrome (MS). Baseline UAE correlated in the unvaried analysis to diastolic blood pressure, waist circumference, high-density lipoprotein cholesterol and uric acid. In multiple linear regression models, only MS (beta=0.113; p=0.03), and serum uric acid values (beta=0.04; p=0.05) were independently associated with logUAE, after adjustment for age and sex. Hyperuricemia (serum uric acid level ≥7.0 mg/dl for men and ≥6.5 mg/dl for women; odds ratio=2.18; 95% confidence interval, 1.21–3.92; p=0.010), and MS (odds ratio=2.16; 95% confidence interval, 1.32–3.53; p=0.002) were independently associated with a higher risk of microalbuminuria in multiple logistic regression analyses. The prevalence of microalbuminuria was 45.8% in patients with coexistent MS and hyperuricemia, as compared to 13.6% in hypertensive patients without it ( p<0.001). In patients with concomitant MS and hyperuricemia the probability of being microalbuminuric was 3.7 times higher than in patients without those factors. Conclusion Serum uric acid level is associated with microalbuminuria. Coexistence of MS and hyperuricemia in hypertensive patients increases almost 4 times the odds of being microalbuminuric.