| Part 1 Coronary stenting does not improve the long-term cardiovascular outcome of patients with mild to moderate renal insufficiencyIntroductionCardiovascular disease has been recognized as a major cause of morbidity and mortality in patients with end-stage renal disease (ESRD), as well as in those with chronic renal dysfunction not requiring dialysis. Percutaneous coronary angioplasty is effective therapy for symptomatic coronary atherosclerosis, but it is associated with poor clinical outcomes and high angiographic restenosis rates, not only in patients with ESRD, but also in those with mild to moderate renal insufficiency compared with patients with normal renal function.Placement of stents reduces the frequency of restenosis and adverse events compared to angioplasty alone in several randomized controlled trials of the general population. However, the benefits of stent use in patients with chronic renal insufficiency, normally excluded from these studies, has not been well studied. In patients with ESRD, high rate of target lesion revascularization after percutaneous coronary intervention (PCI) with stenting has been reported, but whether less-severe renal impairment is associated with increased adverse events and restenosis after stenting is controversial. Although several studies report similar rates of clinical and angiographic restenosis in patients with mild to moderate renal dysfunction and those with normal renal function at 9 to 12 months after stent implantation, higher mortality and adverse cardiac events rates following PCI with or without stenting have been found in patients with mild to moderate renal insufficiency. Furthermore, less is known about the impact of stenting on long-term cardiovascular outcomes of this population.Chronic kidney disease is characterized by progressive decline of glomerular filtration rate (GFR). GFR less than 60ml/min/1.73m2 is the cutoff value for definition of chronic kidney disease because it represents more than 50% reduction of the normal GFR and is associated with the onset of abnormalities of kidney failure, including increased prevalence and severity of risk factors for cardiovascular disease. The aim of this study is to determine the impact of coronary stent implantation on extended long-term (5 years) cardiovascular outcomes of patients with chronic renal insufficiency (defined as GFR<60 ml/min/1.73m2) in whom PCI with stenting was successful.MethodsPatientsTotal of 770 patients who successfully received selective PCI with stenting at Nanfang Hospital between January 1,1996 and December 31,2004 were eligible for inclusion. Patients excluded if they had undergone dialysis or renal transplantation (n=12), had acute renal failure before the PCI procedure (as defined by a rise in serum creatinine of 1 mg/dl above the baseline value) (n=6), did not have their serum creatinine values measured within 30 days before angiography (n=35), were not followed by this institution or lost during follow-up (n=45), or were undergoing PCI with stenting within 24h after myocardial infarction (MI) or had pre-procedural shock (n=65). The patients with valvular heart disease, congenital heart disease, obstructive or restrictive cardiomyopathy, and poorly visualized coronary anatomy on catheterization were also excluded. Thus, this study finally included 602 patients.Renal evaluationUsing the serum creatinine level obtained closest to the time, but before the PCI, Renal function was evaluated by estimated glomerular filtration rate (eGFR), using four-component Modification of Diet in Renal Disease (MDRD) equation:eGFR (ml/min/1.73m2)=186×(serum creatinine level [in milligrams per deciliter])-1.154×(age[in years])-0203×(0.742 if female). The evidence has shown that this equation gives a more accurate assessment of renal function than serum creatinine alone. Patients were then stratified by level of eGFR (eGFR≥60 ml/min/1.73m2 or eGFR 30 to 59 ml/min/1.73m2).PCI and angiographic evaluationPCI were performed using arterial access from the femoral or brachial arteries. During the intervention, patients were administered heparin and aspirin intravenously. Abciximab was administered as bolus dose followed by a 12-hour intravenous infusion at the discretion of the physician in charge. After the procedure, patients were administered either 250 mg of ticlopidine twice daily or 75 mg of clopidogrel daily for at least 4 weeks in combination with aspirin,100 mg twice daily, as indefinite therapy. Among included patients (n=602),540 (149 in renal insufficiency group,391 in non-renal insufficiency group) received bare metal stents and 62 (11 in renal insufficiency group,51 in non-renal insufficiency group) were treated with drug-eluting stents.If patients underwent more than one PCI with stenting, the index PCI is defined as the patient's first procedure during the study period. The coronary artery lesions at index PCI were classified according to the modified American College of Cardiology/American Heart Association grading system. Angiographic success was defined as PCI with>20% gain in luminal diameter stenosis of at least one treatment site, with residual stenosis<50%. Procedure success was defined as angiographic success without death, acute MI and emergency coronary bypass grafting (CABG) during the initial hospitalization. Left ventricular function was evaluated by measuring left ventricular ejection fraction (LVEF).Follow-up dataData were collected from a registry data base. This registry includes baseline demographic, clinical and angiographic data. Follow-up data were collected during the clinic visit or by telephone, using a standardized questionnaire at six months, one year and then annually after procedure. Demographic information, cardiovascular risk factors, comorbidity, and revascularization-related information (prior PCI and stent use) were collected at the time of the index PCI. The outcome of interest was the major adverse cardiac event rate (MACE), a composite of subsequent revascularization (defined as repeated PCI or CABG), non-fatal MI, and all-cause mortality after the index PCI. MI was diagnosed when typical prolonged chest pain was associated with either an increase of 2 times or more in levels of creatine kinase or its MB isoenzyme or the development of new pathological Q waves on a surface electrocardiogram. All adverse events were confirmed by reviewing the medical records of the patients followed at our institution.Repeat angiographic assessment was performed if the patients presented clinical recurrence of coronary ischemic during follow-up. Revascularization was considered indicated if there was>70% diameter stenosis on angiography or>50% stenosis together with a positive stress test or ischemic symptoms. Target lesion restenosis was defined as diameter of stenosis of≥50% at location of the index stented lesion. De novo stenosis was defined as a diameter of stenosis of≥50% at location other than the index lesion.Statistical analysesUnivariate analyses were made using the Student t test for continuous variables with normal distribution (presented as means±standard deviation [SD]), cross tables with the chisquare test for dichotomous variables, and non-parametric Mann-Whitmey rank sum test for categorical variables.Cumulative event rates were estimated using the Kaplan-Meier method and differences between groups assessed with the use of the log-rank test of significance. Cox regression was used to identify independent factors for MACE. Logistic regression analysis was also used to identify independent factors for or de novo stenosis. Any covariates that were significant in univariate analyses (P<0.25) were entered in a multivariate logistic or Cox model with a backward stepping algorithm. All tests were two-tailed and P<0.05 was considered significant. Statistical tests were performed with SPSS 13.0 for Windows.ResultsBaseline characteristicsOf the total study population (n=602),160 patients (26.6%) had a baseline estimated creatinine clearance (eGFR)<60 ml/min/1.73m2 and were considered to have renal insufficiency. Among these patients,92 (57.5%) were diagnosed hypertensive nephrosclerosis,29 (18.1%) had diabetic nephropathy,39 (24.4%) had chronic glomerulonephritis. The 442 patients (73.4%) with an eGFR≥60 ml/min/1.73m2 were considered to be without renal insufficiency. The median follow-up interval was 6.2 (interquartile range:4.5-9.2) years with follow-up of at least 5 years in 93.2%. In comparison to patients without renal insufficiency, patients with an eGFR<60 ml/min/1.73m2 were older and more likely to be women. The angiographic lesion characteristics at index PCI showed more complex coronary lesions (type C) and greater frequency of multi-vessel disease (≥3 vessels) in patients with baseline eGFR< 60 ml/min/1.73m2. The number of vessels treated and the procedure success rate at index PCI were comparable between the two groups.Clinical outcomes561 of patients (93.2%) were followed up by at least 5 years. There were no differences in rates of all-cause mortality, non-fatal MI, revascularization, or the composite of these major adverse cardiac events during the 1 year of follow-up between the groups with and without renal insufficiency. However, the 3-year cumulative event rates of non-fatal MI (17 patients [10.6%] versus 22 patients [5.0%]; P=0.013) and revascularization (27 patients [16.9%] versus 43 patients [9.7%]; P=0.016) was observed more frequently in patients with than without renal insufficiency. Cumulative rates of non-fatal MI, revascularization, as well as the MACE during 5 years of follow-up were significant greater in patients with renal insufficiency as compared with those without renal insufficiency. Unadjusted Kaplan-Meier plots of time to occurrence of the MACE for patients with and without renal insufficiency showed that the curves separated from the third year and continue to diverse during the subsequent follow-up.Angiographic outcomesDuring 5-year of follow-up,62 patients (38.8%) in patients with eGFR<60 ml/min/1.73m2 and 120 patients (27.1%) in patients with eGFR≥60 ml/min/1.73m2 developed clinical ischemic symptoms, such as angina and MI. Among these patients, repeated angiographic assessment was performed in 110 (91.7%) patients with eGFR≥60 ml/min/1.73m2 and in 52 (83.9%) patients with eGFR< 60 ml/min/1.73m2. The total repeated angiographic rates in groups with and without renal insufficiency were comparable (P=0.111). No significant difference in rate of target lesion revascularization was observed in patients with eGFR< 60 ml/min/1.73m2 compared with those with eGFR≥60 ml/min/1.73m2 (27 patients [51.9%] versus 48 patients [43.6%], P=0.323). However, patients with renal insufficiency showed significantly greater rate of de novo stenosis revascularization (30 patients [57.7%] versus 25 patients [22.7%], P<0.001). Most (38 patients [69.1%]) of de novo stenosis revascularization occurred after one year of follow-up.Medication treatment during follow-upMedications administered during follow-up were comparable between patients with and without renal insufficiency (aspirin:84.4% versus 86.7%, P=0.476; rein angiotensin system blockers:48.8% versus 49.8%, P=0.824;β-blockers:78.8% versus 79.9%, P=0.765; calcium channel antagonists:24.4% versus 23.1%, P=0.740; statins:62.5% versus 64.3%, P=0.693; GlycoproteinⅡb/Ⅲa:5.0% versus 6.3%, P=0.542).Multivariate analysisCox regression was used to identify independent factors for MACE. Univariate analysis demonstrated that baseline eGFR<60 ml/min/1.73m2 (adjusted odds ratio [OR]:1.745,95% confidence interval [CI]:1.248～2.440, P=0.001), increased age (for 10-year increase) (OR:1.366,95% CI:1.164～1.604, P<0.001), multi-vessel disease at index PCI (OR:1.663,95% CI:1.124～2.460, P=0.011) and aspirin treatment during follow-up (OR:0.641,95% CI:0.427～0.962, P=0.032) was significant associated with the risk of MACE. After adjustment for the covariates that were significant in univariate analyses (P<0.25), eGFR<60ml/min/1.73m2 remained an independent correlate for MACE (OR:1.488,95% CI:1.051～2.106, P=0.025).Logistic regression analysis was used to identify independent factors for de novo stenosis. Univariate analysis showed eGFR<60 ml/min/1.73m2 (OR:3.840,95% CI:1.753～8.413, P<0.001) was significant associated with the risk of de novo stenosis. Aspirin treatment (OR:0.640,95% CI:0.426～0.961, P=0.031) had borderline association with the risk of de novo stenosis. After adjustment for the covariates that were significant in univariate analyses (P<0.25), eGFR< 60ml/min/1.73m2 remained an independent risk factor for de novo stenosis (OR: 5.505,95% CI:2.151～14.090, P<0.001).ConclusionIn conclusion, we found that after successful coronary stenting, the late MACE is increased in patients with eGFR<60ml/min/1.73m2 over a 5-year follow-up period. There is significantly increased risk of de novo revascularization among patients with renal insufficiency, although the target lesion restenosis is not increased. Chronic renal insufficiency remains an independent correlate for MACE and de novo stenosis after adjustment for other conventional cardiovascular risk factors. These data suggest that successful coronary stenting may not improve the long-term outcomes of patients with coronary artery disease and chronic renal insufficiency. Other interventions that can improve the progression of coronary artery disease and kidney impairment should be strengthened, particularly in patients with GFR< 60ml/min. Part 2 Higher level of proteinuria during RAS inhibitors treatment is a strong predictor for renal outcome in non-diabetic kidney diseaseIntroductionProteinuria is an established risk factor for progressive renal function loss in both diabetic and non-diabetic chronic kidney disease (CKD). This risk appears to be independent of other recognized risk markers such as hypertension and hyperglycemia. Proteinuria can be effectively reduced with antihypertensive drugs that interrupt the renin-angiotensin-system (RAS). However, these drugs also reduce blood pressure, which has made it difficult to separate antihypertensive from antiproteinuric effects as the mediator of renal protection. Data from previous clinical trials have shown that blocking the RAS with either angiotensin-converting enzyme (ACE) inhibitors or angiotensinⅡtype 1 receptor blockers (ARB) is more renoprotective than other antihypertensive drugs and the benefit coincided with the reduction of proteinuria (or albuminuria). In the IDNT trial, renoprotection of blocking the RAS in diabetic nephropathy is associated with reduction in proteinuria. Results from the secondary analysis of RENAAL study reveal that the renoprotective property of an ARB losartan in patients with type 2 diabetic nephropathy can be attributed to its antiproteinuric effect.Non-diabetic CKD is the main cause of end-stage renal disease (ESRD) in China. The Renoprotection of Optimal Antiproteinuric Doses (ROAD) trial, the only study that evaluated the antiproteinuric effect of blocking the RAS using renal outcome as the hard endpoints, was performed in 339 Chinese non-diabetic CKD patients with overt proteinuria and renal insufficiency. In the ROAD trial, patients received individual uptitrated doses of an ACE inhibitor or an ARB against proteinuria and over 50% of the patients achieved maximal reduction in proteinuria during follow-up, which has made it possible to evaluate the contribution of antiproteinuric effect of RAS inhibitors on renoprotection in non-diabetic CKD with different levels of proteinuria during follow-up.The present study, through secondary analysis of data from ROAD trial, demonstrated that the level of initial reduction in proteinuria by RAS inhibitor therapy (residual proteinuria) and the degree of proteinuria during continued therapy (average reduction in proteinuria) are the better predictors for the risk of renal progression than the baseline proteinuria alone in patients with non-diabetic CKD. Minimization of proteinuria at least to the level<1.0g/d should be a therapeutic goal in the management of non-diabetic patients with heavy proteinuria and renal insufficiency.MethodsPatients and study designThe Renoprotection of Optimal Antiproteinuric Doses (ROAD) trial, a randomized, open-labeled, blinded end point study, was performed to exam the effect of antiproteinuric doses of an ACE inhibitor benazepril and an ARB losartan on renal protection in 360 Chinese non-diabetic CKD patients with overt proteinuria and renal insufficiency. A detailed design of the ROAD study, include inclusion/exclusion criteria, treatment protocols and results, has been published previously. Non-diabetic CKD patients aged 18-70 years with a serum creatinine level between 1.5-5.0 mg/dL (133-442μmol/L) and a urinary proteinuria>1.0 g/day, and had not received RAS inhibitors for at least 6 weeks was defined as an entry criterion. Important exclusion criteria were current treatment with corticosteroids, non-steroidal anti-inflammatory drugs or immunosuppressive drugs; hyper-or hypokalemia (serum potassium concentration≥5.6 mmol/L or≤3.5mmol/L); renovascular disease; and obstructive uropathy. Included patients were randomly assigned to four groups. All patients entered an 8-week pre-titration phase during which patients in Group 1 and 2 received 10 mg of benazepril and Group 3 and 4 treated with 50 mg of losartan. At end of the pre-titration phase,339 eligible patients (serum creatinine increase<30% of baseline; serum potassium level<5.6mmol/L; without other adverse events) entered the titration period. During this period, patients received open-label treatment with a conventional dosage of benazepril (10 mg/d), individual uptitration of benazepril (median 20 mg/d; range 10 to 40), a conventional dosage of losartan (50 mg/d), or individual uptitration of losartan (median 100 mg/d; range 50 to 200). Uptitration was performed to optimal antiproteinuric and tolerated dosages, and then these dosages were maintained. Median follow-up was 3.7 yr. Antihypertensive agents excluding RAS inhibitor (diuretics, calcium-channel antagonists, alpha-or beta-blockers, or combination of these medications) were added as necessary to achieve a systolic blood pressure of less than 130 mm Hg and a diastolic blood pressure of less than 80 mmHg.The primary endpoint was time to the composite of a doubling of the serum creatinine, ESRD, or death. Secondary end points included changes in the level of proteinuria and the rate of progression of renal disease.Data analysisThe target of current analysis focused on the secondary endpoint of proteinuria. Proteinuria was quantified by biuret method using 24-hour urine samples. Urinary protein excretion was measured during the baseline and every 2 weeks during titration period and monthly thereafter. Baseline proteinuria was determined by the average of the last two measurements prior to randomization.The level of proteinuria at month 6 after randomization was designated as residual proteinuria. The 6-month time point was chosen because this was the earliest time point that most variables of interest are available, the uptitration has finished, therapy effect had fully present, and no renal event occurred before month 6. Initial proteinuria reduction by RAS inhibitor therapy was calculated as 100%×(baseline proteinuria—residual proteinuria)/baseline proteinuria.Since proteinuria at 1 year or later may better indicate prognosis, we further analyzed proteinuria during continued RAS inhibitors treatment (time average proteinuria, TA-proteinuria). TA-proteinuria was determined as the average of the mean of all proteinuria measurements. The average proteinuria reduction during continued RAS inhibitor therapy was calculated as 100%×(baseline proteinuria—TA-proteinuria)/baseline proteinuria.In the current analysis, the renal endpoints are defined as the composite of a doubling of the serum creatinine, ESRD, or death. For patients who had multiple endpoints of different type, only the first occurrence of a renal event was considered as for the renal endpoint. Only four patients were lost during follow-up.Statistical analysisAll 339 participants who entered titration period in ROAD study were included in this analysis. The association between proteinuric and renal endpoint were estimated using the Kaplan-Meier procedure and significance was assessed by log-rank test. The proteinuric variables (baseline proteinuria, residual proteinuria, TA-proteinuria and proteinuria reduction) were stratified into several post hoc subgroups. The cut points were chosen to create reasonable sample sizes in each of the categories.To identify whether proteinuria at baseline and during treatment were independent predictors of the renal endpoint, multivariate Cox models were performed with the lowest category of proteinuric variables as a common reference to compute the hazard ratio (HR) and 95% confidence interval (CI) for the remainder of the categories. A backward selection method was used with the significance level <0.2 for removing a covariate from the model. Baseline risk factors were selected as follows:age, gender, body mass index (BMI), mean arterial pressure (MAP), serum creatinine, total cholesterol, serum potassium, haemoglobin and proteinuria. Covariates used for month 6 analysis included baseline variables described above, the therapy-induced changes in MAP, BMI, serum creatinine, haemoglobin, total cholesterol and serum potassium at month 6. Covariates used for analysis during follow-up included baseline variables described above, and time average variables (average of the mean of all variables measurements).To evaluate effect of proteinuria reduction on renal endpoint, analysis similar to month 6 and follow-up were conducted including Kaplan-Meier estimate and multivariate Cox regression model when patients were classified by three response groups in proteinuria reduction at month 6 or during follow-up. The baseline variables, the therapy-induced changes at month 6, and time average variables during follow-up were also included in the adjusted multivariate analyses.All P-values were two-tailed and values less than 0.05 were considered statistically significant. Analyses were performed with SPSS software (version 13.0; SPSS Inc., Chicago, IL, USA).ResultsHeavy proteinuria at baseline predicts risk of renal endpointAll these 339 non-diabetic patients eligible for this analysis had overt proteinuria (>1.0 g/d) and renal insufficiency. The mean proteinuria was 2.0 g/d and mean serum creatinine was 2.8 mg/dl.Kaplan-Meier curves for renal end point of three different baseline proteinuria categories showed that the levels of baseline proteinuria were roughly associated with the rate of renal endpoint. However, only the highest quartile proteinuria (≥3.0 g/d) group shows significant more renal events. Comparing the renal outcome of patients in the three groups, when adjusting for all the baseline risk factors, we found that the highest proteinuria group had a 2.4-fold (95%CI 1.41-4.21) increased risk of progression to renal endpoint compared to the low proteinuria group.Higher level of proteinuria during RAS inhibitors treatment predict risk of renal endpointProteinuria at month 6 after randomization is defined as residual proteinuria which reflects the level of proteinuria at "maximal antiproteinuric treatment". The levels of proteinuria at month 6 were closely related to the risk of renal endpoint. After adjusting for baseline risk factors and therapy-induced changes in these factors at month 6, we found that groups with residual proteinuria more than 1.0 g/d had a 3.4-fold (95%CI 1.25-9.17) increased risk of progression to renal endpoint, and those with residual proteinuria≥1.5 g/d had 5.9-fold (95%CI 2.30-15.09) increase in risk, as compare to the lower residual proteinuria (<0.5 g/d) group.To examine if RAS blockage-associated renal protection can be attributed to its antiproteinuric effect, we analyzed the hazard risk for renal endpoint over proteinuria at the sixth month treatment with RAS inhibitors. Patients with higher residual proteinuria had a higher risk for a renal endpoint regardless the dosage of RAS inhibitors or the type of RAS inhibitors.Since proteinuria at 1 year or later may better indicate prognosis, we further analyzed proteinuria during continued RAS inhibitors treatment (time average proteinuria, TA-proteinuria). A significant correlation has been found between TA-proteinuria and the renal endpoint rate. Similarly, Patients with higher TA-proteinuria had a higher risk for a renal endpoint regardless the dosage of RAS inhibitors or the type of RAS inhibitors. To better discern the adjusted risk associated with residual proteinuria and TA-proteinuria, we included baseline risk markers (such as baseline proteinuria and blood pressure), therapy-induced changes in these markers at month 6 and during follow-up (such as changes of MAP, BMI and serum creatinine) into the Cox regression model. After adjusted for these variables, higher residual proteinuria and TA-proteinuria, but not baseline proteinuria remained strong predictors for renal endpoint.To circumvent the problem that those with high baseline proteinuria levels have the greater reduction in proteinuria during RAS inhibitors treatment, we analyzed the hazard risk for renal endpoint in patients with same level of baseline proteinuria but different level of residual proteinuria or TA-proteinuria. Patients were subdivided according to above or below the median value of proteinuria at baseline and above or below median value at month 6 or during follow-up. Data show that risk increases stepwise in each group from the group with low baseline/low month 6 level to the group with high baseline/high month 6 level. The rates for the endpoint show the same stepwise increases. Similarly, TA-proteinuria follows the same pattern.Reduction in proteinuria predict risk of renal endpointTo validate the notion that the greater reduction in proteinuria results in lower proteinuria during follow-up and then reduces risk for renal progression, we further analyzed the effect of proteinuria reduction on renal outcome. Proteinuria was changed by-47%(95%CI-89%～4.6%) at month 6 in the total study groups, by-53% (95%CI-92%～-22%) in the group with titrated doses of RAS inhibitors, and by-37% (95%CI-82%～21%) in the group with conventional doses. The level of proteinuria remained relatively stable during follow-up in both groups. During treatment, every 0.5g reduction in residual proteinuria or TA-proteinuria was associated with a risk reduction of 50%. When we subdivided the total population into three subgroups according to their initial (month 6) antiproteinuric response (<25%,≥25<50% and≥50% response), renal endpoint occurred more frequently in the groups that had little to no suppression of proteinuria, but those had significant reduction in proteinuria showed fewer renal endpoint during follow-up. Even after correcting for the baseline risk markers and therapy-induced changes in these variables, the importance of reducing proteinuria remained strong (adjusted HR 0.29,95% 0.17-0.49). Similarly, the reduction of TA-proteinuria follows the same pattern.ConclusionOur analyses show that a higher level of urine protein excretion, particularly during treatment and follow-up, is associated with a higher risk of renal progression, and should be regarded as a modifiable risk factor in non-diabetic CKD. Sustained proteinuria over 1 gram per day was the independent predictor for progressive renal function loss in such patients. Thus, minimization of proteinuria at least to the level below 1 gram per day should be an important therapeutic goal in the management of non-diabetic CKD patients with proteinuria and renal dysfunction. |
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