Therapeutic approaches in lowering albuminuria: travels along the renin-angiotensin-aldosterone-system pathway

Achieving optimal blood pressure and albuminuria control is a major therapeutic treatment goal in patients with renal insufficiency. Angiotensin-converting enzyme-inhibitors (ACEIs) and angiotensin-receptor blockers (ARB) are the mainstay of therapy in these patients. However, despite these therapies many patients remain at high risk of renal or cardiovascular disease that shows a relationship with albuminuria. Various approaches have been tested to maximize the efficacy of ACEI and ARB. Increasing the dose of an ACEI or ARB beyond the maximal registered antihypertensive dose causes a distinct decrease in albuminuria without additional effects on blood pressure. The combination of an ACEI and ARB is another possibility to further reduce albuminuria. However, the alleged beneficial effects on hard renal and cardiovascular outcome are not unambiguously demonstrated. Adding a direct renin inhibitor to an ACEI or ARB has been shown to lower albuminuria in patients with and without diabetes. Long-term trials are currently under way to determine the effects of direct renin inhibition on clinical outcomes. Volume excess has been shown to blunt the blood pressure and albuminuria response to ACEI or ARB therapy. Intervening in volume status by means of restricting dietary sodium intake or diuretic therapy has convincingly been shown to lower blood pressure and albuminuria. Whether this strategy translates into a reduction in the risk of renal or cardiovascular events has not (yet) been investigated in prospective randomized trials. Various options are at hand which have been shown to maximize the blood pressure and albuminuria response to ACEI and ARB treatment. However, long-term studies supporting the benefits of these strategies on hard renal and cardiovascular outcomes are warranted.     

Angiotensin-converting enzyme inhibitor or angiotensin II type 1 receptor antagonist therapy is associated with prolonged patient and graft survival after renal transplantation

Angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II type 1 receptor blockers (ARB) reduce cardiovascular death in the general population, but data for renal transplant recipients remain elusive. Similarly, ACEI/ARB have been shown to reduce proteinuria, but data on graft survival are lacking. Therefore a retrospective open cohort study was conducted of 2031 patients who received their first renal allograft at the Medical University of Vienna between 1990 and 2003 and survived at least 3 mo. Patient and graft survival was compared between patients with versus without ACEI and/or ARB therapy. Data were analyzed with and without propensity score models for ACEI/ARB therapy. Medication and comorbidities were analyzed as time-dependent variables in the Cox regression analyses. Ten-year survival rates were 74% in the ACEI/ARB group but only 53% in the noACEI/ARB group (P<0.001). The hazard ratio (HR) of ACEI/ARB use for mortality was 0.57 (95% confidence interval [CI] 0.40 to 0.81) compared with nonuse. Ten-year actual graft survival rate was 59% in ACEI/ARB patients but only 41% in nonusers (P=0.002). The HR of actual graft failure for ACEI/ARB recipients was 0.55 (95% CI 0.43 to 0.70) compared with nonusers; the HR of functional graft survival was 0.56 (95% CI 0.40 to 0.78). Ten-year unadjusted functional graft survival rates were 76% among ACEI/ARB patients and 71% in noACEI/ARB recipients (P=0.57). In summary, the use of ACEI/ARB therapy was associated with longer patient and graft survival after renal transplantation. More frequent use of these medications may reduce the high incidence of death and renal allograft failure in these patients.     

Soluble adhesion molecules in end-stage renal disease: a predictor of outcome.

BACKGROUND: Inflammation is thought to contribute to initiation and aggravation of atherosclerosis through a process predominantly mediated by adhesion molecules. The aims of this study were to investigate the association between the concentrations of circulating soluble intercellular (sICAM-1) and vascular cellular (sVCAM-1) adhesion molecules and clinical outcome, and to evaluate the effect of antihypertensive drugs on sICAM-1 and sVCAM-1 concentrations in end-stage renal disease (ESRD) patients. METHODS: We prospectively investigated 310 (191 males) incident ESRD patients, 53+/-12 years old, shortly before the start of renal replacement therapy. Glomerular filtration rate (GFR) was 6.4 (range 0.8-16.5) ml/min/1.73 m(2). Plasma sICAM-1 and sVCAM-1 were measured by enzyme-linked immunosorbent assay (ELISA) kits. Survival was determined from the day of examination, with a mean follow-up period of 39 (range 1-123) months. RESULTS: In non-adjusted analysis, high sICAM-1 and sVCAM-1 levels were associated with all-cause and cardiovascular (P<0.001) mortality. After adjusting for age, gender, diabetes mellitus, serum cholesterol, C-reactive protein (CRP), subjective global assessment and angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB), the association between high sICAM-1 and mortality remained significant for all-cause (HR 1.9; CI 1.2-2.9, P = 0.004) and cardiovascular (HR 1.8; CI 1.1-3.1, P = 0.02) mortality, and a high sVCAM-1 was associated with all-cause mortality (HR 1.7; CI 1.04-2.7, P = 0.03). Furthermore, the concentration of sICAM-1, but not sVCAM-1, was lower in patients receiving ACEI/ARB (254+/-83 vs 275+/-92 ng/ml; P<0.05) or patients receiving calcium channel blockers (CCB, 251+/-75 vs 273+/-95 ng/ml; P<0.05) than in non-users. CONCLUSIONS: In ESRD patients, sICAM-1 and sVCAM-1 are independent predictors of all cause and cardiovascular death. The use of ACEI/ARB or CCB was associated with decreased concentrations of soluble adhesion molecules.     

Lower progression rate of end-stage renal disease in patients with peripheral arterial disease using statins or Angiotensin-converting enzyme inhibitors

Patients with peripheral arterial disease (PAD) are at increased risk for ESRD and cardiovascular events. The primary objective was to assess the association between ankle-brachial index (ABI) values and renal outcome. The secondary objective was to evaluate whether statins and angiotensin-converting enzyme inhibitors (ACEI) are associated with improved renal and cardiovascular outcome in patients with PAD. In a prospective observational cohort study of 1940 consecutive patients with PAD, ABI was measured and chronic statin and ACEI therapy was noted at baseline. Serial creatinine concentrations were obtained at baseline, 6 mo, and every year after enrollment. End points were ESRD, all-cause mortality, and cardiac events during a median follow-up period of 8 yr. Baseline estimated GFR <60 ml/min per 1.73 m(2) was assessed in 27% of patients. ESRD, all-cause mortality, and cardiac events occurred in 10, 46, and 31% of patients, respectively. In multivariate analysis, a lower baseline ABI was significantly associated with a higher progression rate of ESRD (hazard ratio [HR] per 0.10 decrease 1.34; 95% confidence interval [CI] 1.21 to 1.49). Chronic use of statins and ACEI were significantly associated with lower ESRD (HR 0.41 [95% CI 0.28 to 0.63] and 0.74 [95% CI 0.54 to 0.98], respectively), mortality (HR 0.66; [95% CI 0.55 to 0.82] and 0.84 [95% CI 78 to 0.95], respectively), and cardiac events (HR 0.71 [95% CI 0.56 to 0.91] and 0.81 [95% CI 0.68 to 0.96], respectively). In patients with PAD, low ABI values independently predict the onset of ESRD. Less progression toward ESRD and improved cardiovascular outcome was observed among patients who were on long-term statins and ACEI.     

No impact of hyperkalaemia with renin-angiotensin system blockades in maintenance haemodialysis patients.

BACKGROUND: Renin-angiotensin system (RAS) blockades, angiotensin converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) are well accepted for the cardiorenal-protective benefits added to antihypertensive effects in chronic kidney diseases (CKD), but associated with an increased risk of hyperkalaemia. However, few studies have investigated the effect of RAS blockades on serum potassium in dialysis patients. METHODS: Hyperkalaemia associated with RAS blockades by ACEI and/or ARB was evaluated in 69 patients on maintenance haemodialysis, who underwent a three-period crossover study in four groups (no exposure to RAS blockades, ACEI or ARB alone and ACEI plus ARB treatments), lasting one month in each period. RESULTS: Sixty-two patients completed this prospective 3-month study, and no one stopped the study because of the development of hyperkalaemia and/or complications. Mean serum K was similar among the four periods (no exposure, 5.54+/-0.67 mmol/l; ACEI alone, 5.54+/-0.75 mmol/l; ARB alone, 5.50+/-0.66 mmol/l; ACEI+ARB combination, 5.42+/-0.66 mmol/l) and was also equal when compared between the two groups with and without exposure to RAS blockades (5.48+/-0.68 vs 5.54+/-0.67 mmol/l, P=NS). The incidence of severe hyperkalaemic episodes (>6.0 mmol/l) upon monthly predialysis serum K determination was 25.8% with no exposure to RAS blockades, 29.8% for ACEI alone, 19.6% for ARB alone and 17.7% for ACEI+ARB combination without statistically significant differences among the four periods (P=NS). Among covariables, the degree of Kt/V, intakes of other medications interfering with potassium homeostasis and diabetes mellitus did not result in any significant hyperkalaemic changes during the 3-month study period except anuric patients compared with non-anuric patients (5.58+/-0.69 vs 5.19+/-0.65 mmol/l, P<0.001). CONCLUSION: Neither monotherapy (ACEI or ARB) nor combination therapy (ACEI plus ARB) is associated with the additional risk of hyperkalaemia in patients on maintenance haemodialysis. However, those patients with anuria on RAS blockades warrant the cautious monitoring of serum K to prevent hyperkalaemia.     

Use of Cardioprotective Medications in Kidney Transplant Recipients

Death with function causes half of late kidney transplant failures, and cardiovascular disease (CVD) is the most common cause of death in these patients. We examined the use of potentially cardioprotective medications in a prospective observational study at seven transplant centers in the United States and Canada. Among 935 patients, 87% received antihypertensive medications at both 1 and 6 months after transplantation. Similar antihypertensive regimens were used for patients with and without diabetes and CVD, but with wide variability among centers. In contrast, while 44% of patients were on angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) at the time of transplantation, the proportion taking these agents dropped to 12% at month 1, then increased to 24% at 6 months. Fewer than 30% with CVD or diabetes received ACEI/ARB therapy 6 months posttransplant. Aspirin use was uncommon (<40% of patients). Even among those with diabetes and/or CVD, fewer than 60% received aspirin and only half received a statin at 1 and 6 months. This study demonstrates marked variability in the use of cardioprotective medications in kidney transplant recipients, a finding that may reflect, among several possible explanations, clinical uncertainty due the lack of randomized trials for these medications in this population.     

Blood pressure, antihypertensive treatment, and graft survival in kidney transplant patients

Whether the use of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker inhibitor (ACEI/ARB) is beneficial in renal transplant recipients remains controversial. In this retrospective study on 505 renal transplant recipients, we analyzed blood pressure and graft survival according to antihypertensive treatment with ACE-I/ARB and/or calcium channel blockers (CCB) over a period of 10 years. Patients were stratified according to their blood pressure 1 year after transplantation [controlled (≤130/80 mmHg; CTR, 181 patients) and noncontrolled (>130/80 mmHg; non-CTR, 324 patients)] and according to antihypertensive treatment (ACE-I/ARB and/or CCB taken for at least 2 years). One year after transplantation, 88.4% of CTR and 96.6% of non-CTR received antihypertensive treatment ( P  < 0.05). Graft survival was longer in CTR than in non-CTR ( P  < 0.05). Importantly, graft survival was longer in patients who received long-term treatment with ACEI/ARB, CCB, or a combination of ACEI/ARB and CCB ( P  < 0.001). The beneficial effect of ACEI/ARB therapy was more pronounced in non-CTR compared with that of CTR. We conclude that blood pressure control is a key target for long-term graft survival in renal transplant patients. Long-term ACEI/ARB and CCB therapy is beneficial for graft survival, especially in patients with diabetes and/or albuminuria.     

Treatment strategies in patients with chronic renal disease: ACE inhibitors,angiotensin receptor antagonists,or both?

We discuss the evidence supporting the use of angiotensin-converting enzyme inhibitors (ACEI), angiotensin II type 1 receptor blockers (ARB), or the combination of both in children with chronic renal disease. Several large-scale, prospective, randomized studies with clinical end points have been performed in adult patients, but studies in children are relatively scarce. In adult patients with chronic renal diseases, ACEI clearly delay the progression of chronic non-diabetic renal diseases, and nephropathy in patients with type 1 diabetes. The benefits of ACEI are most apparent in glomerular diseases with marked proteinuria but extend also to kidney diseases with lower proteinuria. This notion is also supported by several smaller or retrospective trials in children. Therefore, ACEI should be given to children with chronic renal diseases, particularly if high blood pressure and/or proteinuria are present. In adults, large-scale trials have documented that ARB exert similar effects as ACEI but tend to exert fewer undesired side effects. Data on ARB in children with chronic renal disease are still very scarce, but these substances offer an alternative for patients who cannot tolerate ACEI due to unwarranted side effects. Combination therapy with ARB plus ACEI may be more effective than either drug class alone. However, we will need the results of further long-term prospective clinical studies, as well as a better understanding of the role of the AT₂ receptor, before combination therapy can be widely recommended. A trial of ARB plus ACEI is justified in selected patients if blood pressure and/or proteinuria cannot adequately be lowered by ACEI or ARB alone.     

Pulse pressure and risk of total mortality and cardiovascular events in patients on chronic hemodialysis

BACKGROUND: Pulse pressure (PP) has been shown as a risk factor for mortality or cardiovascular events in several studies. However, the impact of PP on prognosis in a cohort of chronic hemodialysis patients has not been sufficiently studied. We examined the effect of PP on total mortality and cardiovascular events in chronic hemodialysis patients, and whether PP adds useful value to systolic blood pressure (SBP) or diastolic blood pressure (DBP) for predicting total mortality and cardiovascular events in chronic hemodialysis patients. METHODS: Chronic hemodialysis patients (N=1243, 720 men, 523 women) alive on January 1, 1991 at baseline were involved in this study. Cox regression, adjusted for age, sex, and other risk factors, was used to assess the relation between blood pressure components and risk of death and cardiovascular events over a nine-year follow-up. RESULTS: The association with the risk of total mortality was positive for PP (P=0.002) and SBP (P=0.04), but not significant for DBP (P=0.4), considering each pressure individually (single blood pressure component model, SPM); of the three measurements, PP yielded the highest chi2 value. When SBP and DBP were jointly entered into the Cox regression model (dual blood pressure component model, DPM), the association with the risk of total mortality was positive for SBP (HR, 1.083; 95% CI, 1.030 to 1.137) and negative for DBP (HR, 0.886; 0.808 to 0.970). After the addition of diabetes mellitus as an adjusted variable to the model, PP was not a significant predictor for total mortality; PP was a significant predictor for total mortality in non-diabetic patients, but not in diabetic patients. PP was positively associated with the risk of stroke, and stroke and AMI; however, predictive value of PP for each endpoint was not superior to SBP and DBP in SPM. In DPM with SBP and DBP, the association with the risk of stroke and acute myocardial infarction (AMI) was positive for SBP (P=0.02) but not significant for DBP (P=0.5). In DPM with SBP and PP, the association with the risk of stroke and AMI was positive for SBP (P=0.01) but not significant for PP (P=0.5). CONCLUSIONS: In non-diabetic patients on chronic hemodialysis, PP was an independent predictor of total mortality. PP was more potent predictor of total mortality than SBP or DBP. For predicting cardiovascular events, SBP was superior to PP or DBP.     

Demographics of blood pressure and hypertension in children on renal replacement therapy in Europe

Hypertension is a well-known complication in children on renal replacement therapy and an important risk factor for cardiovascular disease in later life. In order to define the prevalence of and risk factors for hypertension among children, we enrolled 3337 pediatric patients from 15 countries in the ESPN/ERA-EDTA Registry of whom 464 were on hemodialysis, 851 on peritoneal dialysis, and 2023 had received a renal allograft. Hypertension was defined as either systolic or diastolic blood pressures in the 95th percentile or greater for age, height, and gender or use of antihypertensive medication. Analyses were adjusted for age, gender, duration, and modality of renal replacement therapy. In 10 countries in which information on the use of antihypertensive medication was available, hypertension was present in over two-thirds of hemodialysis, peritoneal dialysis, or transplant patients. Blood pressure values above the 95th percentile were significantly more prevalent in very young patients (under 3 years) compared to 13- to 17-year olds (odds ratio 2.47), during the first year compared to over 5 years of renal replacement therapy (odds ratio 1.80), and in patients on hemodialysis compared to transplant recipients or those on peritoneal dialysis (odds ratios of 2.48 and 1.59, respectively). Over time, mean blood pressures decreased in both hemodialysis and transplant patients, but not in peritoneal dialysis patients. Hence, our findings highlight the extent of the problem of hypertension in children with end-stage renal disease in Europe.     

Ankle-brachial blood pressure index predicts all-cause and cardiovascular mortality in hemodialysis patients

A reduction in ankle-brachial BP index (ABPI) is associated with generalized atherosclerotic diseases and predicts cardiovascular mortality and morbidity in several patient populations. However, a large-scale analysis of ABPI is lacking for hemodialysis (HD) patients, and its use in this population is not fully validated. A cohort of 1010 Japanese patients undergoing chronic hemodialysis was studied between November 1999 and May 2002. Mean age at entry was 60.6 +/- 12.5 yr, and duration of follow-up was 22.3 +/- 5.6 mo. Patients were stratified into five groups (< 0.9, > or = 0.9 to < 1.0, > or = 1.0 to < 1.1, > or = 1.1 to < 1.3, and > or = 1.3) by ABPI measured at entry by an oscillometric method. The frequency distribution of ABPI was 16.5% of patients < 0.9, 8.6% of patients > or = 0.9 to < 1.0, 16.9% of patients 1.0 > or = to < 1.1, and 47.0% of patients > or 1.1 to < 1.3, whereas 10.9% of patients had an abnormally high ABPI (> or = 1.3). The relative risk of a history of diabetes mellitus (DM), cardiovascular, and cerebrovascular disease was significantly higher in patients with lower ABPI than those with ABPI > or = 1.1 to <1.3. During the study period, 77 cardiovascular and 41 noncardiovascular fatal events occurred. On the basis of Cox proportional hazards regression analysis, ABPI emerged as a strong independent predictor of all-cause and cardiovascular mortality. After adjustment for confounding variables, the hazard ratio (HR) for ABPI < 0.9 was 4.04 (95% confidence interval, 2.38 to 6.95) for all-cause mortality and 5.90 (2.83 to 12.29) for cardiovascular mortality. Even those with modest reductions in the ABPI (> or = 0.9 to <1.1) appeared to be at increased risk. Patients having abnormally high ABPI (> or = 1.3) also had poor prognosis (HR, 2.33 [1.11 to 4.89] and 3.04 [1.14 to 8.12] for all-cause and cardiovascular mortality, respectively). Thus, the present findings validate ABPI as a powerful and independent predictor for all-cause and cardiovascular mortality among hemodialysis patients.     

ACE inhibitor or angiotensin II receptor blocker use is a risk factor for contrast-induced nephropathy

Background: The aim of the present study was to assess the influence of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) use on the incidence of contrast-induced nephropathy (CIN) in patients undergoing coronary angiography. Methods: A retrospective case control study was conducted on a total of 201 patients divided into 2 groups (CIN group and control group). CIN was defined as an increase in serum creatinine by more than 25% from baseline within 48 hours of radiocontrast exposure. The CIN group had 96 patients, and the control group had 105 patients. The 2 groups were matched for variables such as age, sex, weight, baseline serum creatinine, diabetes, dye load, use of diuretics, statins and preprocedure prophylactic measures for CIN. Results: The incidence of CIN was found to be 4.55%. The CIN group had 96 patients out of which 56 patients (58.3%) were on chronic ACEI or ARB, while the control group had 105 patients, but only 36 of patients (34.3%) were on ACEI or ARB (p<0.001).The odds ratio for development of CIN with respect to ACEI or ARB use was 2.68 (95% confidence interval, 1.51-4.76). Conclusion: Use of ACEI or ARB is an independent risk factor for developing CIN. It is reasonable to discontinue their use 48 hours prior to exposure to radiocontrast agents, especially in patients with multiple risk factors.     

No Association of Angiotensin-Converting Enzyme Inhibitor or Angiotensin 2 Receptor Blocker Intake with Acute Kidney Injury in Patients Undergoing Kidney Biopsy

Background: Treatment with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin 2 receptor blockers (ARBs) is associated with an increased risk for acute kidney injury after cardiovascular interventions. However, for patients undergoing kidney biopsy, no data is available. Methods: Four hundred and sixty-six patients undergoing kidney biopsy were retrospectively analyzed of whether or not concomitant intake of ACEIs or ARBs impairs kidney function. Results: Three hundred and twenty-three patients received ACEIs or ARBs or both before kidney biopsy. ACEI/ARB intake had no effect on kidney function compared to patients without this medication (all p > 0.05). Conclusion: Treatment with ACEIs or ARBs is not associated with risk of acute kidney injury in subjects undergoing kidney biopsy.     

Risks for end-stage renal disease, cardiovascular events, and death in Hispanic versus non-Hispanic white adults with chronic kidney disease

Rates of ESRD are rising faster in Hispanic than non-Hispanic white individuals, but reasons for this are unclear. Whether rates of cardiovascular events and mortality differ among Hispanic and non-Hispanic white patients with chronic kidney disease (CKD) also is not well understood. Therefore, this study examined the associations between Hispanic ethnicity and risks for ESRD, cardiovascular events, and death in patients with CKD. A total of 39,550 patients with stages 3 to 4 CKD from Kaiser Permanente of Northern California were included. Hispanic ethnicity was obtained from self-report supplemented by surname matching. GFR was estimated from the abbreviated Modification of Diet in Renal Disease equation, and clinical outcomes, patient characteristics, and longitudinal medication use were ascertained from health plan databases and state mortality files. After adjustment for sociodemographic characteristics, Hispanic ethnicity was associated with an increased risk for ESRD (hazard ratio [HR] 1.93; 95% confidence interval [CI] 1.72 to 2.17) when compared with non-Hispanic white patients, which was attenuated after controlling for diabetes and insulin use (HR 1.50; 95% CI 1.33 to 1.69). After further adjustment for potential confounders, Hispanic ethnicity remained independently associated with an increased risk for ESRD (HR 1.33; 95% CI 1.17 to 1.52) as well as a lower risk for cardiovascular events (HR 0.82; 95% CI 0.76 to 0.88) and death (HR 0.72; 95% CI 0.66 to 0.79). Among a large cohort of patients with CKD, Hispanic ethnicity was associated with lower rates of death and cardiovascular events and a higher rate of progression to ESRD. The higher prevalence of diabetes among Hispanic patients only partially explained the increased risk for ESRD. Further studies are required to elucidate the cause(s) of ethnic disparities in CKD-associated outcomes.     

Influence of hypertension on cardiovascular outcomes in hemodialysis patients

Cardiovascular disease is a leading cause of morbidity and mortality in chronic hemodialysis patients. Most patients with chronic kidney disease have hypertension and its prevalence remains high following renal replacement therapy. Early studies suggested that hypertension was a risk factor for total and cardiovascular mortality in chronic hemodialysis patients, but the results of more recent studies have caused experts to question these assertions. Systolic hypertension, widened pulse pressure, and nondipping may be better predictors of mortality compared to diastolic hypertension or increased mean arterial pressure. Hypertension in hemodialysis patients is a risk factor for left ventricular hypertrophy (LVH), diastolic dysfunction, and congestive heart failure; good blood pressure control may promote its regression. Atherosclerosis and ventricular arrhythmias may also be linked to hypertension. Thus blood pressure control with a focus on systolic pressure appears to be a prudent strategy to improve cardiovascular outcomes in hemodialysis patients.     

Impact of malnutrition-inflammation on the association between homocysteine and mortality

Whether high total serum homocysteine levels (tHcy) contribute to increase mortality or offer a survival advantage in chronic hemodialysis patients remains controversial. We conducted a prospective study to determine the impact of tHcy on survival in this population with special respect to chronic inflammation-malnutrition state (CIMS). In this prospective study, 459 hemodialysis patients from 10 dialysis centers located in two regions of France were included. A number of baseline parameters were measured including tHcy and markers of CIMS. Over a mean follow-up period of 54 months, 219 deaths (47.7%) occurred, of which 114 (52%) were of cardiovascular (CV) origin. tHcy of equal to or greater than 30 micromol/l was associated with a higher risk of all-cause mortality in patients without CIMS (hazard ratio (HR): 1.55 (confidence interval (CI): 1.12-4.72)), but not in overall dialysis population or those with CIMS. When only CV mortality was considered, tHcy of equal to or greater than 30 micromol/l was associated with a higher risk in patients without (CIMS HR: 1.91 (CI: 1.23-3.23)), but not in those with CIMS. Hyperhomocysteinemia is a strong risk factor for all-cause and CV mortality in hemodialysis patients who do not present CIMS. This association might be masked in patients with CIMS.     

Naturally occurring higher hemoglobin concentration does not increase mortality among hemodialysis patients

A small percentage of hemodialysis patients maintain higher hemoglobin concentrations without transfusion or erythropoietic therapy. Because uncertainty exists regarding the effects of higher hemoglobin concentration on mortality and quality of life among hemodialysis patients, studying this group of patients with sufficient endogenous erythropoietin may provide additional insights. The prospective, observational Dialysis Outcomes and Practice Patterns Study provides an opportunity to investigate this group. Among 29,796 patients in 12 nations, 545 (1.8%) maintained hemoglobin concentrations >12 g/dl for 4 months without erythropoietic support. This subset tended to be male, to have a longer duration of end-stage renal disease, and to not dialyze via a catheter. Cystic disease as the underlying cause of renal failure was over-represented in this group but was present in only 25%. Lung disease, smoking, and cardiovascular disease were associated with increased likelihood of naturally higher hemoglobin concentration. Quality-of-life scores were not higher among this subset compared with the other patients. Unadjusted mortality risk for patients with hemoglobin >12 g/dl and no erythropoietic therapy was lower than for the other patients, but after thorough adjustment for case mix, there was no difference between groups (relative risk, 0.98; 95% CI 0.80 to 1.19). These data show that naturally occurring hemoglobin concentration >12 g/dl does not associate with increased mortality among hemodialysis patients.     

Arteriovenous fistula use is associated with lower cardiovascular mortality compared with catheter use among ESRD patients

The arteriovenous fistula (AVF) is the recommended form of dialysis vascular access, however, limited studies suggest that AVF creation may result in increased cardiovascular stress and remodeling. To explore the contribution of vascular access type to cardiovascular-related (CV) mortality, we analyzed USRDS Clinical Performance Measures data comprising 4854 patients that initiated dialysis between October 1, 1999-December 31, 2004. CV mortality included death from acute myocardial infarction, atherosclerotic heart disease, cardiomyopathy, arrhythmia, cardiac arrest or stroke. Risk of cardiovascular mortality during a 4-year observation was analyzed by Cox-regression methods with adjustments for demographic and co-morbid conditions. AVF use was strongly associated with lower all-cause and CV mortality. After adjustment for covariates, AVF use 90 days after dialysis initiation remained significantly associated with lower cardiovascular mortality [hazard ratio (HR) 0.69, p = 0.0004] compared with catheter use. These findings suggest that vascular access type influences cause-specific mortality beyond that of infection, and support existing guidelines recommending the use of an AVF early in the course of chronic end-stage renal disease therapy.     

Bedtime dosing of antihypertensive medications reduces cardiovascular risk in CKD

Time of ingestion of hypertension medications can affect circadian patterns of BP, but whether this translates into an effect on clinical outcomes is unknown. Here, in an open-label trial, we randomly assigned 661 patients with CKD either to take all prescribed hypertension medications upon awakening or to take at least one of them at bedtime. We measured 48-hour ambulatory BP at baseline and 3 months after any adjustment in treatment or, at the least, annually. After a median follow-up of 5.4 years, patients who took at least one BP-lowering medication at bedtime had an adjusted risk for total cardiovascular events (a composite of death, myocardial infarction, angina pectoris, revascularization, heart failure, arterial occlusion of lower extremities, occlusion of the retinal artery, and stroke) that was approximately one-third that of patients who took all medications upon awakening (adjusted HR 0.31; 95% CI 0.21 to 0.46; P < 0.001). Bedtime dosing demonstrated a similar significant reduction in risk for a composite outcome of cardiovascular death, myocardial infarction, and stroke (adjusted HR 0.28; 95% CI 0.13 to 0.61; P < 0.001). Furthermore, patients on bedtime treatment had a significantly lower mean sleep-time BP and a greater proportion demonstrated control of their ambulatory BP (56% versus 45%, P = 0.003). Each 5-mmHg decrease in mean sleep-time systolic BP was associated with a 14% reduction in the risk for cardiovascular events during follow-up (P < 0.001). In conclusion, among patients with CKD and hypertension, taking at least one antihypertensive medication at bedtime improves control of BP and reduces the risk for cardiovascular events.