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1.
Am J Cardiol ; 100(1): 7-12, 2007 Jul 01.
Article in English | MEDLINE | ID: mdl-17599432

ABSTRACT

Effects of cardiovascular dysfunction on renal function have been poorly characterized. Therefore, we investigated the relation between a first ischemic cardiac event and long-term renal function changes in the general population from the PREVEND study. We studied 6,360 subjects with a total follow-up duration of 27.017 subject-years. The estimated mean proportional increase in serum creatinine after a first ischemic cardiac event was 3.1% compared with 0.4% per year of follow-up in subjects without such an event (p = 0.005). This represented a significantly larger decrease in estimated glomerular filtration rate after the event in subjects with an event versus the decrease in subjects without a first ischemic cardiac event (2.2 vs 0.5 ml/min/1.73 m(2)/year of follow-up, p = 0.006). In multivariate analysis with adjustment for renal risk factors, this event showed an independent association with serum creatinine change. In conclusion, a first ischemic cardiac event appears to enhance the natural decrease in renal function. Because even mild renal dysfunction should be considered a major cardiovascular risk factor after myocardial infarction, increased renal function loss after an ischemic cardiac event could add to the risk for subsequent cardiovascular morbidity, thus closing a vicious circle.


Subject(s)
Myocardial Ischemia/complications , Renal Insufficiency/etiology , Adult , Aged , Creatinine/blood , Female , Follow-Up Studies , Glomerular Filtration Rate , Humans , Male , Middle Aged , Renal Insufficiency/blood , Risk Factors
2.
J Am Soc Nephrol ; 18(5): 1540-6, 2007 May.
Article in English | MEDLINE | ID: mdl-17409317

ABSTRACT

Albuminuria reduction could be renoprotective in hypertensive patients with diabetic nephropathy. However, the current use of renin-angiotensin-system intervention is targeted to BP only. Therefore, this study investigated the adequacy of this approach in 1428 patients with hypertension and diabetic nephropathy from the placebo-controlled Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study. Investigated were the extent of discordance in treatment effects on systolic BP (SBP) and albuminuria and its association with renal outcome in a multivariate Cox model. Among patients with a reduced SBP during treatment, a lack of albuminuria reduction was observed in 37, 26, and 51% (total, losartan, and placebo, respectively) at month 6. SBP or albuminuria reduction was associated with a lower risk for ESRD, whereas combined SBP and albuminuria reduction was associated with the lowest risk for events. Across all categories of SBP change, a progressively lower ESRD hazard ratio was observed with a larger albuminuria reduction. A lower residual level of albuminuria was also associated with lower ESRD risk. In conclusion, changes in albuminuria are not concordant in a substantial proportion of patients when titrated for BP. Meanwhile, the ESRD risk showed a clear dependence on albuminuria reduction. The ESRD risk also showed dependence on the residual level of albuminuria, even in patients who reached the current SBP target. Antihypertensive treatment that is aimed at improving renal outcomes in patients with diabetic nephropathy may therefore require a dual strategy, targeting both SBP and albuminuria reduction.


Subject(s)
Albuminuria/etiology , Angiotensin II/antagonists & inhibitors , Blood Pressure , Diabetes Mellitus, Type 2/drug therapy , Diabetic Nephropathies/drug therapy , Hypertension/drug therapy , Losartan/therapeutic use , Aged , Albuminuria/physiopathology , Albuminuria/prevention & control , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/physiopathology , Diabetes Mellitus, Type 2/urine , Diabetic Nephropathies/physiopathology , Diabetic Nephropathies/urine , Double-Blind Method , Female , Humans , Hypertension/etiology , Male , Middle Aged , Placebos
3.
J Hypertens ; 25(4): 871-6, 2007 Apr.
Article in English | MEDLINE | ID: mdl-17351381

ABSTRACT

OBJECTIVE: To investigate whether a threshold exists for cardiovascular risk in type 2 diabetic patients with hypertension, the association between renal function and cardiovascular risk was examined across the entire physiological range of serum creatinine. DESIGN AND METHODS: The RENAAL and LIFE studies enrolled 1513 and 1195 patients with type 2 diabetes and hypertension, respectively. The relationship between baseline serum creatinine and the risk for a composite outcome of myocardial infarction, stroke or cardiovascular death was examined using Cox regression models. To adjust for heterogeneity between studies and treatment groups, these factors were included as strata when applicable. The analyses were conducted with adjustment for age, gender, smoking, alcohol use, blood pressure, heart rate, total and high-density lipoprotein (HDL) cholesterol, hemoglobin, albuminuria and prior cardiovascular disease. RESULTS: The hazard ratios across the baseline serum creatinine categories < 0.9 mg/dl, 0.9-1.2 mg/dl, 1.2-1.6 mg/dl, 1.6-2.8 mg/dl and >or= 2.8 mg/dl were 0.51 (95% confidence interval 0.34, 0.74), 0.74 (0.55, 1.00), 1.00 (reference), 1.24 (0.96, 1.59) and 1.67 (1.17, 2.91), respectively. Baseline serum creatinine (per mg/dl) strongly predicted the composite cardiovascular endpoint in LIFE [2.82(1.74,4.56), P < 0.001], RENAAL [1.41(1.12,1.79), P < 0.001], as well as the combined studies [1.51(1.21,1.87), P < 0.001]. CONCLUSION: A progressively higher risk for the composite cardiovascular endpoint was observed with incremental baseline serum creatinine in type 2 diabetic patients with hypertension, even within the normal range. Thus, there appears to be no serum creatinine threshold level for an increased cardiovascular risk. Baseline serum creatinine was a major independent risk factor for cardiovascular disease (www.ClinicalTrials.gov number NCT00308347).


Subject(s)
Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/metabolism , Diabetes Mellitus, Type 2/metabolism , Hypertension/metabolism , Kidney/metabolism , Aged , Albuminuria/metabolism , Biomarkers/blood , Biomarkers/urine , Blood Pressure , Cardiovascular Diseases/physiopathology , Creatinine/blood , Creatinine/urine , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/physiopathology , Diabetes Mellitus, Type 2/urine , Double-Blind Method , Female , Follow-Up Studies , Glomerular Filtration Rate , Humans , Hypertension/blood , Hypertension/physiopathology , Hypertension/urine , Kidney/physiopathology , Male , Middle Aged , Predictive Value of Tests , Proportional Hazards Models , Randomized Controlled Trials as Topic , Research Design , Risk Factors
4.
J Am Soc Nephrol ; 17(11): 3059-66, 2006 Nov.
Article in English | MEDLINE | ID: mdl-17005935

ABSTRACT

Recently, it was shown that myocardial infarction aggravates preexistent mild renal damage that is elicited by unilateral nephrectomy in rats. The mechanism behind this cardiorenal interaction likely involves the renin-angiotensin-aldosterone-system and/or vasoactive peptides that are metabolized by neutral endopeptidase (NEP). The renoprotective effect of angiotensin-converting enzyme inhibition (ACEi) as well as combined ACE/NEP inhibition with a vasopeptidase inhibitor (VPI) was investigated in the same model to clarify the underlying mechanism. At week 17 after sequential induction of unilateral nephrectomy and myocardial infarction, treatment with lisinopril (ACEi), AVE7688 (VPI), or vehicle was initiated for 6 wk. Proteinuria and systolic BP (SBP) were evaluated weekly. Renal damage was assessed primarily by proteinuria, interstitial alpha-smooth muscle actin (alpha-SMA) staining, and the incidence of focal glomerulosclerosis (FGS). At start of treatment, proteinuria had increased progressively to 167 +/- 20 mg/d in the entire cohort (n = 42). Both ACEi and VPI provided a similar reduction in proteinuria, alpha-SMA, and FGS compared with vehicle at week 23 (proteinuria 76 +/- 6 versus 77 +/- 4%; alpha-SMA 60 +/- 6 versus 77 +/- 3%; FGS 52 +/- 14 versus 61 +/- 10%). Similar reductions in systolic BP were observed in both ACEi- and VPI-treated groups (33 +/- 3 and 37 +/- 2%, respectively). Compared with ACEi, VPI-treated rats displayed a significantly larger reduction of plasma (41 +/- 5 versus 61 +/- 4%) and renal (53 +/- 6 versus 74 +/- 4%) ACE activity. It is concluded that both ACEi and VPI intervention prevent renal damage in a rat model of cardiorenal interaction. VPI treatment seemed to provide no additional renoprotection compared with sole ACEi after 6 wk of treatment in this model, despite a more pronounced ACE-inhibiting effect of VPI.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Heterocyclic Compounds, 3-Ring/therapeutic use , Kidney Diseases/etiology , Kidney Diseases/prevention & control , Lisinopril/therapeutic use , Myocardial Infarction/complications , Neprilysin/antagonists & inhibitors , Renin-Angiotensin System/drug effects , Renin-Angiotensin System/physiology , Animals , Male , Rats , Rats, Wistar
5.
J Am Soc Nephrol ; 15(12): 3103-10, 2004 Dec.
Article in English | MEDLINE | ID: mdl-15579513

ABSTRACT

Studied were the effects of myocardial infarction (MI) on mild renal function loss in unilateral nephrectomized (UnX) rats. UnX was performed, followed after 1 wk by a variable MI (UnX + MI; n = 24). Rats with only UnX (n = 15) or MI (n = 9) and double sham animals (CON, n = 15) served as controls. Renal outcome was measured by proteinuria and plasma creatinine. Focal glomerulosclerosis (FGS) incidence was evaluated by renal histology. Cardiac function and systolic BP were measured. A division into small and large infarcts after UnX was made a priori, resulting in two groups, one with a mild MI (<20%; n = 15) and one with a moderate MI (>20%; n = 9). Mild proteinuria up to 55.5 mg/d was observed in the UnX + mild MI group, whereas proteinuria rose significantly higher to 124.5 mg/d in the UnX + moderate MI group. Incidence of FGS was significantly increased in both UnX + MI groups compared with all other groups. The average MI size was 18%, 17%, and 25% in the MI, UnX + mild MI, and UnX + moderate MI group, respectively. LVP in both UnX + MI groups was correlated with proteinuria, indicative of a cardio-renal interaction. Clinically, these data imply that more patients are at risk for cardiovascular events and that after such an event, their chance of more renal function loss increases. Finding the underlying mechanism will enable improved protection for both kidneys and heart.


Subject(s)
Glomerulosclerosis, Focal Segmental/complications , Glomerulosclerosis, Focal Segmental/pathology , Myocardial Infarction/complications , Myocardial Infarction/pathology , Animals , Creatinine/blood , Disease Models, Animal , Glomerulosclerosis, Focal Segmental/mortality , Heart/physiology , Kidney/pathology , Kidney/physiology , Male , Myocardial Infarction/mortality , Myocardium/pathology , Natriuretic Peptide, Brain/blood , Nephrectomy , Organ Size , Proteinuria/complications , Proteinuria/mortality , Proteinuria/pathology , Rats , Rats, Wistar , Risk Factors , Survival Rate
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