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Background: Intravenous sodium bicarbonate has been proposed to reduce the risk for contrast-induced nephropathy (CIN)., Purpose: To determine the effect of sodium bicarbonate on the risk for CIN., Data Sources: MEDLINE, PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials from 1950 to December 2008; conference proceedings; and ClinicalTrials.gov, without language restriction., Study Selection: Randomized, controlled trials of intravenous sodium bicarbonate that prespecified the outcome of CIN as a 25% increase in baseline serum creatinine level or an absolute increase of 44 micromol/L (0.5 mg/dL) after radiocontrast administration., Data Extraction: Using standardized protocols, 2 reviewers serially abstracted data for each study., Data Synthesis: 23 published and unpublished trials with information on 3563 patients and 396 CIN events were included. The pooled relative risk was 0.62 (95% CI, 0.45 to 0.86), with evidence of significant heterogeneity across studies (I(2) = 49.1%; P = 0.004). Some heterogeneity was due to the difference in the estimates between published and unpublished studies: relative risk, 0.43 (CI, 0.25 to 0.75) versus 0.78 (CI, 0.52 to 1.17), respectively. Meta-regression showed that small, poor-quality studies that assessed outcomes soon after radiocontrast administration were more likely to suggest benefit (P < 0.05 for all). No clear effects of treatment on the risk for dialysis, heart failure, and total mortality were identified., Limitation: Power to assess clinical end points was limited., Conclusion: The effectiveness of sodium bicarbonate treatment to prevent CIN in high-risk patients remains uncertain. Earlier reports probably overestimated the magnitude of any benefit, whereas larger, more recent trials have had neutral results. Large multicenter trials are required to clarify whether sodium bicarbonate has value for prevention of CIN before routine use can be recommended., Primary Funding Source: None.

Objective: To assess the magnitude and independence of the effects of routine blood pressure lowering and intensive glucose control on clinical outcomes in patients with long-standing type 2 diabetes., Research Design and Methods: This was a multicenter, factorial randomized trial of perindopril-indapamide versus placebo (double-blind comparison) and intensive glucose control with a gliclazide MR-based regimen (target A1C 0.1): the separate effects of the two interventions for the renal outcomes and death appeared to be additive on the log scale. Compared with neither intervention, combination treatment reduced the risk of new or worsening nephropathy by 33% (95% CI 12-50%, P = 0.005), new onset of macroalbuminuria by 54% (35-68%, P < 0.0001), and new onset of microalbuminuria by 26% (17-34%). Combination treatment was associated with an 18% reduction in the risk of all-cause death (1-32%, P = 0.04)., Conclusions: The effects of routine blood pressure lowering and intensive glucose control were independent of one another. When combined, they produced additional reductions in clinically relevant outcomes.

Chronic kidney disease is a major worldwide public health problem that causes substantial morbidity and mortality. Studies from the Asia-Pacific region have reported some of the highest chronic kidney disease prevalence rates in the world, but access to dialysis is limited in many countries, making it imperative to identify high-risk individuals. We performed a participant-level data overview of prospective studies conducted in the Asia-Pacific region to quantify the magnitude and direction of the associations between putative risk factors and renal death. Age- and sex-adjusted Cox proportional hazards models were applied to pooled data from 35 studies to calculate hazard ratios (95% CIs) for renal death associated with a standardized change in risk factors. Among 560 352 participants followed for a median of 6.8 years, a total of 420 renal deaths were observed. Continuous and positive associations among systolic blood pressure, diastolic blood pressure, fasting blood glucose, and total cholesterol levels with renal death were observed, as well as a continuous but inverse association with high-density lipoprotein cholesterol. Systolic blood pressure was the strongest risk factor for renal death with each SD increase in systolic blood pressure (19 mm Hg) associated with >80% higher risk (hazard ratio: 1.84; 95% CI: 1.60 to 2.12). Neither cigarette smoking nor excess weight was related to the risk of renal death (P>0.10). The results were similar for cohorts in Asia and Australia. These results suggest that primary prevention strategies for renal disease should focus on individuals with elevated blood pressure, diabetes mellitus, and dyslipidemia.

There are limited data regarding whether albuminuria and reduced estimated GFR (eGFR) are separate and independent risk factors for cardiovascular and renal events among individuals with type 2 diabetes. The Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE) study examined the effects of routine BP lowering on adverse outcomes in type 2 diabetes. We investigated the effects of urinary albumin-to-creatinine ratio (UACR) and eGFR on the risk for cardiovascular and renal events in 10,640 patients with available data. During an average 4.3-yr follow-up, 938 (8.8%) patients experienced a cardiovascular event and 107 (1.0%) experienced a renal event. The multivariable-adjusted hazard ratio for cardiovascular events was 2.48 (95% confidence interval 1.74 to 3.52) for every 10-fold increase in baseline UACR and 2.20 (95% confidence interval 1.09 to 4.43) for every halving of baseline eGFR, after adjustment for regression dilution. There was no evidence of interaction between the effects of higher UACR and lower eGFR. Patients with both UACR >300 mg/g and eGFR <60 ml/min per 1.73 m(2) at baseline had a 3.2-fold higher risk for cardiovascular events and a 22.2-fold higher risk for renal events, compared with patients with neither of these risk factors. In conclusion, high albuminuria and low eGFR are independent risk factors for cardiovascular and renal events among patients with type 2 diabetes.

Background: There has been considerable interest in the hypothesis that low birth weight may be a marker of impaired nephrogenesis and that this is causally related to chronic kidney disease (CKD)., Study Design: Systematic review and meta-analysis of observational studies., Setting & Population: Studies of the relationship between birth weight and CKD published before February 1, 2008, were identified by using electronic searches., Selection Criteria: All studies that had collected data for birth weight and kidney function at greater than 12 months of age were eligible for inclusion, except for studies of extremely low-birth-weight infants, very premature infants, or toxic exposure in utero. STUDY FACTOR: Birth weight., Outcomes: CKD defined as albuminuria, low estimated glomerular filtration rate (<60 mL/min/1.73 m(2) or < 10th centile for age/sex), or end-stage renal disease., Results: We analyzed 31 relevant cohort or case-control studies with data for 49,376 individuals and data for 2,183,317 individuals from a single record-linkage study. Overall, 16 studies reported a significant association between low birth weight and risk of CKD and 16 observed a null result. The combination of weighted estimates from the 18 studies for which risk estimates were available (n = 46,249 plus 2,183,317 from the record linkage study) gave an overall odds ratio (OR) of 1.73 (95% confidence interval [CI], 1.44 to 2.08). Combined ORs were consistent in magnitude and direction for risks of albuminuria (OR, 1.81; 95% CI, 1.19 to 2.77), end-stage renal disease (OR, 1.58; 95% CI, 1.33 to 1.88), or low estimated glomerular filtration rate (OR, 1.79; 95% CI, 1.31 to 2.45)., Limitations: A reliance on published estimates and estimates provided on request rather than individual patient data and the possibility of reporting bias., Conclusions: Existing data indicate that low birth weight is associated with subsequent risk of CKD, although there is scope for additional well-designed population-based studies with accurate assessment of birth weight and kidney function and consideration of important confounders, including maternal and socioeconomic factors.

Background: Cardiovascular disease accounts for more than half the number of deaths among dialysis patients. The role of HMG CoA reductase inhibitors (statins) in the treatment of dyslipidaemia in dialysis patients is unclear and their safety has not been established., Objectives: To assess the benefits and harms of statins in peritoneal dialysis (PD) and haemodialysis patients (HD)., Search Strategy: We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled trials (CENTRAL, in The Cochrane Library), the Cochrane Renal Group's specialised register and handsearched reference lists of textbooks, articles and scientific proceedings., Selection Criteria: Randomised controlled trials (RCTs) and quasi-RCTs comparing statins with placebo, no treatment or other hypolipidaemic agents in dialysis patients., Data Collection and Analysis: Two authors independently assessed study quality and extracted data. Statistical analyses were performed using the random effects model after testing for heterogeneity. The results were expressed as mean difference (MD) for continuous outcomes and risk ratios (RR) for dichotomous outcomes with 95% confidence intervals (CI)., Main Results: Fourteen studies (2086 patients) compared statins versus placebo or other lipid lowering agents. Compared to placebo, statins did not decrease all-cause mortality (10 studies, 1884 patients; RR 0.95, 95% CI 0.86 to 1.06) or cardiovascular mortality (9 studies, 1839 patients: RR 0.96, 95% CI 0.65 to 1.40). There was a lower incidence of nonfatal cardiovascular events with statins compared to placebo in haemodialysis patients (1 study, 1255 patients; RR 0.86, 95% CI 0.74 to 0.99). Compared with placebo, statin use was associated with a significantly lower end of treatment average total cholesterol (14 studies, 1823 patients; MD -42.61 mg/dL, 95% CI -53.38 to -31.84), LDL cholesterol (13 studies, 1801 patients; MD -43.06 mg/dL, 95% CI -53.78 to -32.35) and triglycerides (14 studies, 1823 patients: MD -24.01 mg/dL, 95% CI -47.29 to -0.72). There was similar occurrence of rhabdomyolysis and elevated liver function tests with statins in comparison to placebo., Authors' Conclusions: Statins decreased cholesterol levels in dialysis patients similar to that of the general population. With the exception of one study, studies were of short duration and therefore the efficacy of statins in decreasing the mortality rate is still unclear. Statins appear to be safe in this high-risk population. Ongoing studies should provide more insight about the efficacy of statins in reducing mortality rates in dialysis patients.

Background: The reduction in renal transplant rejection rates achieved over the last 20 years have not translated into a commensurate improvement in long-term graft survival. Cyclosporine has been central to immunosuppressive regimens throughout this period but its effect on long-term transplant outcomes remains unclear., Methods: This randomized controlled trial allocated first cadaveric renal transplant recipients in seven centers around Australia to three immunosuppressive regimens: azathioprine and prednisolone (AP), long-term cyclosporine alone (Cy), or cyclosporine initiation followed by withdrawal at 3 months and azathioprine and prednisolone replacement (WDL)., Results: Between 1983 and 1986, 489 patients were randomized with 98% follow-up to a median of 20.6 years. Mean graft survival (censoring deaths) was superior in the WDL group (14.8 years) when compared with both AP (12.4 years, P=0.01 log-rank test) and Cy (12.5 years, P=0.01 log-rank test) groups by intention-to-treat. Without death censoring, graft survival with WDL was superior to AP (9.5 years vs. 6.7 years, P=0.04) and of borderline superiority to Cy (9.5 years vs. 8.5 years, P=0.06). Patient survival was not different between the three groups. Renal function was superior in AP (at 1, 10, and 15 years posttransplant) and WDL (at 1, 5, 10, 15, and 20 years) groups when compared with Cy., Conclusion: This study illustrates superior long-term renal transplant survival and preservation of renal function with a protocol using cyclosporine withdrawal. If long-term renal transplant outcomes are to improve, we should reconsider guidelines recommending universal maintenance use of cyclosporine.

Background: Cardiovascular disease accounts for more than half the number of deaths among dialysis patients. The role of HMG CoA reductase inhibitors (statins) in the treatment of dyslipidaemia in dialysis patients is unclear and their safety has not been established., Objectives: To assess the benefits and harms of statins in peritoneal dialysis (PD) and haemodialysis patients (HD)., Search Strategy: We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled trials (CENTRAL, in The Cochrane Library), the Cochrane Renal Group's specialised register and handsearched reference lists of textbooks, articles and scientific proceedings., Selection Criteria: Randomised controlled trials (RCTs) and quasi-RCTs comparing statins with placebo, no treatment or other hypolipidaemic agents in dialysis patients., Data Collection and Analysis: Two authors independently assessed study quality and extracted data. Statistical analyses were performed using the random effects model after testing for heterogeneity. The results were expressed as mean difference (MD) for continuous outcomes and risk ratios (RR) for dichotomous outcomes with 95% confidence intervals (CI)., Main Results: Fourteen studies (2086 patients) compared statins versus placebo or other lipid lowering agents. Compared to placebo, statins did not decrease all-cause mortality (10 studies, 1884 patients; RR 0.95, 95% CI 0.86 to 1.06) or cardiovascular mortality (9 studies, 1839 patients: RR 0.96, 95% CI 0.65 to 1.40). There was a lower incidence of nonfatal cardiovascular events with statins compared to placebo in haemodialysis patients (1 study, 1255 patients; RR 0.86, 95% CI 0.74 to 0.99). Compared with placebo, statin use was associated with a significantly lower end of treatment average total cholesterol (14 studies, 1823 patients; MD -42.61 mg/dL, 95% CI -53.38 to -31.84), LDL cholesterol (13 studies, 1801 patients; MD -43.06 mg/dL, 95% CI -53.78 to -32.35) and triglycerides (14 studies, 1823 patients: MD -24.01 mg/dL, 95% CI -47.29 to -0.72). There was similar occurrence of rhabdomyolysis and elevated liver function tests with statins in comparison to placebo., Authors' Conclusions: Statins decreased cholesterol levels in dialysis patients similar to that of the general population. With the exception of one study, studies were of short duration and therefore the efficacy of statins in decreasing the mortality rate is still unclear. Statins appear to be safe in this high-risk population. Ongoing studies should provide more insight about the efficacy of statins in reducing mortality rates in dialysis patients.

Background: Dyslipidaemia occurs frequently in chronic kidney disease (CKD) patients and contributes both to cardiovascular disease and worsening renal function. Statins are widely used in non-dialysis dependent CKD patients (pre-dialysis) even though evidence favouring their use is lacking., Objectives: To evaluate the benefits and harms of statins in CKD patients who were not receiving renal replacement therapy., Search Strategy: We searched MEDLINE, EMBASE, CENTRAL (in The Cochrane Library), and hand-searched reference lists of textbooks, articles and scientific proceedings., Selection Criteria: Randomised controlled trials (RCTs) and quasi-RCTs comparing statins with placebo, no treatment or other statins in adult pre-dialysis CKD patients., Data Collection and Analysis: Two authors independently assessed study quality and extracted data. Results were expressed as mean difference (MD) for continuous outcomes (lipids, creatinine clearance and proteinuria) and risk ratio (RR) for dichotomous outcomes (all-cause mortality, cardiovascular mortality, fatal and non-fatal cardiovascular events, elevated liver enzymes, rhabdomyolysis and withdrawal rates) with 95% confidence intervals (CI)., Main Results: Twenty six studies (25,017 participants) comparing statins with placebo were identified. Total cholesterol decreased significantly with statins (18 studies, 1677 patients: MD -41.48 mg/dL, 95% CI -49.97 to -33.99). Similarly, LDL cholesterol decreased significantly with statins (16 studies, 1605 patients: MD -42.38 mg/dL, 95% CI -50.71 to -34.05). Statins decreased both the risk of all-cause (21 RCTs, 18,781 patients, RR 0.81, 95% CI 0.74, 0.89) and cardiovascular deaths (20 studies, 18,746 patients: RR 0.80, 95% CI 0.70 to 0.90). Statins decreased 24-hour urinary protein excretion (6 studies, 311 patients: MD -0.73 g/24 h, 95% CI -0.95 to -0.52), but there was no significant improvement in creatinine clearance - a surrogate marker of renal function (11 studies, 548 patients: MD 1.48 mL/min, 95% CI -2.32 to 5.28).The incidence of rhabdomyolysis, elevated liver enzymes and withdrawal rates due to adverse events (well known complications of statins use), were not significantly different between patients receiving statins and placebo., Authors' Conclusions: Statins significantly reduced the risk of all-cause and cardiovascular mortality in CKD patients who are not receiving renal replacement therapy. They do not impact on the decline in renal function as measured by creatinine clearance, but may reduce protein excretion in urine. Statins appear to be safe in this population. Guidelines recommendations on hyperlipidaemia management in CKD patients could therefore be followed targeting higher proportions of patients receiving a statin, with appropriate monitoring of adverse events.

Background: Cardiovascular deaths account for the majority of deaths in kidney transplant recipients and dyslipidaemia contributes significantly to their cardiovascular disease. Statins are widely used in kidney transplant patients given their established benefits in the general population, however evidence favouring their use is lacking., Objectives: To assess the benefits and harms of statin therapy on mortality and renal outcomes in kidney transplant recipients., Search Strategy: We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), and hand searched reference lists of articles and scientific proceedings., Selection Criteria: Randomised controlled trials (RCTs) and quasi-RCTs comparing statins with placebo, no treatment or other statins in kidney transplant recipients., Data Collection and Analysis: Two authors independently assessed study quality and extracted data. Statistical analyses were performed using the random effects model after testing for heterogeneity. Results were expressed as mean difference (MD) for continuous outcomes (lipid parameters) and risk ratio (RR) for dichotomous outcomes (mortality, allograft rejection, liver enzymes, occurrence of rhabdomyolysis and study withdrawal) with 95% confidence intervals (CI)., Main Results: Sixteen studies (3229 patients) comparing statins versus placebo (15) or another statin (1) were included. Compared to placebo, statins did not decrease all-cause mortality (14 studies: RR 1.30, 95% CI 0.54 to 3.12). Point estimates favoured statins in terms of cardiovascular mortality (13 studies: RR 0.68, 95% CI 0.46 to 1.03) and non-fatal cardiovascular events (1 study: RR 0.70, 95% CI 0.48 to 1.01), however the results were not statistically significant. Compared to placebo, the use of statins was associated with a significantly lower end of treatment average total cholesterol (10 studies: MD -42.33 mg/dL (1.26 mmol/L), 95% CI -53.02 to -31.64), LDL cholesterol (10 studies: MD -46.15 mg/dL (1.19 mmol/L), 95% CI -55.97 to -36.33) and triglycerides (10 studies: MD -25.46 mg/dL (0.26 mmol/L), 95% CI -33.95 to 16.9). There was no significant difference in the risk of acute rejection (5 studies: RR 0.61; 95% C.I.0.32 to 1.16.) No data on chronic rejection was available and no major toxicity was noted., Authors' Conclusions: Statins significantly reduced hyperlipidaemia and tended to reduce cardiovascular events in kidney transplant recipients, but no effect has yet been demonstrated for mortality outcomes. Most of the data was derived from one large long-term study. Considering the significant impact of statins on all-cause and cardiovascular mortality in the general and predialysis populations, more studies are needed in kidney transplant patients.

Reduced-sodium, increased-potassium salt substitutes lower blood pressure but may also have direct effects on vascular structure and arterial function. This study aimed to test the effects of long-term salt substitution on indices of these outcomes. The China Salt Substitute Study was a randomized, controlled trial designed to establish the effects of salt substitute (65% sodium chloride, 25% potassium chloride, 10% magnesium sulfate) compared with regular salt (100% sodium chloride) on blood pressure among 600 high-risk individuals living in six rural areas in northern China over a 12-month intervention period. Data on central aortic blood pressure, aortic pressure augmentation (AUG), augmentation index (AIx), the differences of the peak of first and baseline waves (P(1)-P(0)) and pulse wave reflection time (RT) were collected at randomization and at the completion of follow-up in 187 participants using the Sphygmocor pulse wave analysis system. Mean baseline blood pressure was 150.1/91.4 mm Hg, mean age was 58.4 years, 41% were male and three quarters had a history of vascular disease. After 12 months of intervention, there were significant net reductions in peripheral (7.4 mm Hg, P=0.009) and central (6.9 mm Hg, P=0.011) systolic blood pressure levels and central pulse pressure (4.5 mm Hg, P=0.012) and correspondingly there was a significant net reduction in P(1)-P(0) (3.0 mm Hg, P=0.007), borderline significant net reduction in AUG (1.5 mm Hg, P=0.074) and significant net increase in RT (2.59 ms, P=0.001). There were no detectable reductions in peripheral (2.8 mm Hg, P=0.14) or central (2.4 mm Hg, P=0.13) diastolic blood pressure levels or AIx (0.06%, P=0.96). In conclusion, over the 12-month study period the salt substitute significantly reduced not only peripheral and central systolic blood pressure but also reduced arterial stiffness.

BP is an important determinant of kidney disease among patients with diabetes. The recommended thresholds to initiate treatment to lower BP are 130/80 and 125/75 mmHg for people with diabetes and nephropathy, respectively. We sought to determine the effects of lowering BP below these currently recommended thresholds on renal outcomes among 11,140 patients who had type 2 diabetes and participated in the Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE) study. Patients were randomly assigned to fixed combination perindopril-indapamide or placebo, regardless of their BP at entry. During a mean follow-up of 4.3 yr, active treatment reduced the risk for renal events by 21% (P < 0.0001), which was driven by reduced risks for developing microalbuminuria and macroalbuminuria (both P < 0.003). Effects of active treatment were consistent across subgroups defined by baseline systolic or diastolic BP. Lower systolic BP levels during follow-up, even to <110 mmHg, was associated with progressively lower rates of renal events. In conclusion, BP-lowering treatment with perindopril-indapamide administered routinely to individuals with type 2 diabetes provides important renoprotection, even among those with initial BP <120/70 mmHg. We could not identify a BP threshold below which renal benefit is lost.

Background: Patients undergoing dialysis have a substantially increased risk of cardiovascular mortality and morbidity. Although several trials have shown the cardiovascular benefits of lowering blood pressure in the general population, there is uncertainty about the efficacy and tolerability of reducing blood pressure in patients on dialysis. We did a systematic review and meta-analysis to assess the effect of blood pressure lowering in patients on dialysis., Methods: We systematically searched Medline, Embase, and the Cochrane Library database for trials reported between 1950 and November, 2008, without language restriction. We extracted a standardised dataset from randomised controlled trials of blood pressure lowering in patients on dialysis that reported cardiovascular outcomes. Meta-analysis was done with a random effects model., Findings: We identified eight relevant trials, which provided data for 1679 patients and 495 cardiovascular events. Weighted mean systolic blood pressure was 4.5 mm Hg lower and diastolic blood pressure 2.3 mm Hg lower in actively treated patients than in controls. Blood pressure lowering treatment was associated with lower risks of cardiovascular events (RR 0.71, 95% CI 0.55-0.92; p=0.009), all-cause mortality (RR 0.80, 0.66-0.96; p=0.014), and cardiovascular mortality (RR 0.71, 0.50-0.99; p=0.044) than control regimens. The effects seem to be consistent across a range of patient groups included in the studies., Interpretation: Treatment with agents that lower blood pressure should routinely be considered for individuals undergoing dialysis to reduce the very high cardiovascular morbidity and mortality rate in this population.

The Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial investigated the effects of routine blood pressure lowering and intensive blood glucose control on major vascular events in people with Type 2 diabetes. In this factorial randomized study, 11,140 individuals with Type 2 diabetes were randomly assigned to a fixed combination of perindopril and indapamide or matching placebo, and to intensive glucose control with the use of modified-release gliclazide plus other drugs required to achieve a hemoglobin A1c of 6.5% of less, or standard guideline-based glucose control. The primary outcomes were composites of major macrovascular and major microvascular events (major vascular events), analyzed jointly and separately. Active treatment in the blood pressure-lowering arm reduced blood pressure by 5.6/2.2 mmHg compared with placebo, and the relative risks of major vascular events, all deaths and cardiovascular deaths by 9% (p = 0.043), 14% (p = 0.025) and 18% (p = 0.027), respectively. These effects appeared independent of the initial blood pressure level or the use of concomitant treatments. Intensive glucose control lowered glycated hemoglobin levels to a mean of 6.5% and reduced the relative risk of major vascular events by 10% (p = 0.01), primarily through a 21% (p = 0.006) reduction in nephropathy. Intensive glucose control was not associated with a significant reduction in macrovascular events; however, unlike reports from the recently reported Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, there was no evidence of any increase in all-cause mortality or cardiovascular death with more intensive glucose control. This trial has provided important new evidence with direct implications for clinical management of blood pressure and blood glucose in patients with Type 2 diabetes.

Background: The associations between decreased kidney function and cardiovascular disease recently have been established. However, there is uncertainty about the consistency between the independent associations of proteinuria as a risk factor across all cardiovascular end points. We undertook a meta-analysis of published cohort studies to provide a reliable estimate of the strength of association between proteinuria and risk of stroke., Study Design: Meta-analysis of observational cohort studies., Setting & Population: General population of participants with diabetes. Studies were excluded if participants had known glomerular disease or had undergone dialysis or transplantation., Selection Criteria for Studies: MEDLINE, EMBASE, and CINAHL databases were searched for studies that reported age- or multivariate-adjusted risk ratio with some estimate of the variance of the association between proteinuria and risk of stroke, without language restriction., Factor: Proteinuria or albuminuria., Outcomes: Fatal or nonfatal stroke., Results: Data from 10 published studies involving 140,231 participants and 3,266 strokes were eligible for inclusion. Participants with proteinuria had a 71% greater risk of stroke compared with those without proteinuria (95% confidence interval, 1.39 to 2.10). There was evidence of significant quantitative heterogeneity in the magnitude of the association across studies (I(2) = 60%; P for heterogeneity = 0.008), which was partially explained by differences in methods for measuring proteinuria. The risk of stroke remained significant after adjustment for other vascular risk factors., Limitations: Because individual patient data were unavailable, we were unable to fully examine the impact of adjustment for known cardiovascular risk factors on the strength of the association between proteinuria and stroke risk. It is possible that the pooled estimate was affected by regression dilution bias., Conclusions: These findings support the independent relationship between proteinuria and stroke. Additional studies are warranted to determine whether interventions to reduce proteinuria are effective at reducing rates of stroke.

Aims: Large-scale observational studies show that lower blood pressure is associated with lower cardiovascular risk in both men and women although some studies have suggested that different outcomes between the sexes may reflect different responses to blood pressure-lowering treatment. The aims of these overview analyses were to quantify the effects of blood pressure-lowering treatment in each sex and to determine if there are important differences in the proportional benefits of treatment between men and women., Methods and Results: Thirty-one randomized trials that included 103,268 men and 87,349 women contributed to these analyses. For each outcome and each comparison summary estimates of effect and 95% confidence intervals were calculated for men and women using a random-effects model. The consistency of the effects of each treatment regimen across the sexes was examined using chi(2) tests of homogeneity. Achieved blood pressure reductions were comparable for men and women in every comparison made. For the primary outcome of total major cardiovascular events there was no evidence that men and women obtained different levels of protection from blood pressure lowering or that regimens based on angiotensin-converting-enzyme inhibitors, calcium antagonists, angiotensin receptor blockers, or diuretics/beta-blockers were more effective in one sex than the other (all P-homogeneity > 0.08)., Conclusion: All of the blood pressure-lowering regimens studied here provided broadly similar protection against major cardiovascular events in men and women. Differences in cardiovascular risks between sexes are unlikely to reflect differences in response to blood pressure-lowering treatments.

Background: Markers of kidney dysfunction such as proteinuria or albuminuria have been reported to be associated with coronary heart disease, but the consistency and strength of any such relationship has not been clearly defined. This lack of clarity has led to great uncertainty as to how proteinuria should be treated in the assessment and management of cardiovascular risk. We therefore undertook a systematic review of published cohort studies aiming to provide a reliable estimate of the strength of association between proteinuria and coronary heart disease., Methods and Findings: A meta-analysis of cohort studies was conducted to obtain a summary estimate of the association between measures of proteinuria and coronary risk. MEDLINE and EMBASE were searched for studies reporting an age- or multivariate-adjusted estimate and standard error of the association between proteinuria and coronary heart disease. Studies were excluded if the majority of the study population had known glomerular disease or were the recipients of renal transplants. Two independent researchers extracted the estimates of association between proteinuria (total urinary protein >300 mg/d), microalbuminuria (urinary albumin 30-300 mg/d), macroalbuminuria (urinary albumin >300 mg/d), and risk of coronary disease from individual studies. These estimates were combined using a random-effects model. Sensitivity analyses were conducted to examine possible sources of heterogeneity in effect size. A total of 26 cohort studies were identified involving 169,949 individuals and 7,117 coronary events (27% fatal). The presence of proteinuria was associated with an approximate 50% increase in coronary risk (risk ratio 1.47, 95% confidence interval [CI] 1.23-1.74) after adjustment for known risk factors. For albuminuria, there was evidence of a dose-response relationship: individuals with microalbuminuria were at 50% greater risk of coronary heart disease (risk ratio 1.47, 95% CI 1.30-1.66) than those without; in those with macroalbuminuria the risk was more than doubled (risk ratio 2.17, 1.87-2.52). Sensitivity analysis indicated no important differences in prespecified subgroups., Conclusion: These data confirm a strong and continuous association between proteinuria and subsequent risk of coronary heart disease, and suggest that proteinuria should be incorporated into the assessment of an individual's cardiovascular risk.

Objectives: We sought to determine whether an elevated burden of chronic kidney disease is found among disadvantaged groups living in the United States, Australia, and Thailand., Methods: We used data on participants 35 years or older for whom a valid serum creatinine measurement was available from studies in the United States, Thailand, and Australia. We used logistic regression to analyze the association of income, education, and employment with the prevalence of chronic kidney disease (estimated glomerular filtration rate<60 mL/min/1.73 m(2))., Results: Age- and gender-adjusted odds of having chronic kidney disease were increased 86% for US Whites in the lowest income quartile versus the highest quartile (odds ratio [OR] = 1.86; 95% confidence interval [CI] = 1.27, 2.72). Odds were increased 2 times and 6 times, respectively, among unemployed (not retired) versus employed non-Hispanic Black and Mexican American participants (OR=2.89; 95% CI=1.53, 5.46; OR=6.62; 95% CI=1.94, 22.64. respectively). Similar associations were not evident for the Australian or Thai populations., Conclusions: Higher kidney disease prevalence among financially disadvantaged groups in the United States should be considered when chronic kidney disease prevention and management strategies are created. This approach is less likely to be of benefit to the Australian and Thai populations.

Objective: To quantify the relative risk reductions achieved with different regimens to lower blood pressure in younger and older adults., Design: Meta-analyses and meta-regression analyses used to compare the effects on the primary outcome between two age groups (<65 v > or =65 years). Evidence for an interaction between age and the effects of treatment sought by fitting age as a continuous variable and estimating overall effects across trials., Primary Outcome: total major cardiovascular events., Results: 31 trials, with 190 606 participants, were included. The meta-analyses showed no clear difference between age groups in the effects of lowering blood pressure or any difference between the effects of the drug classes on major cardiovascular events (all P> or =0.24). Neither was there any significant interaction between age and treatment when age was fitted as a continuous variable (all P>0.09). The meta-regressions also showed no difference in effects between the two age groups for the outcome of major cardiovascular events (<65 v > or =65; P=0.38)., Conclusions: Reduction of blood pressure produces benefits in younger (<65 years) and older (> or =65 years) adults, with no strong evidence that protection against major vascular events afforded by different drug classes varies substantially with age.

Recent epidemiological studies have shown a J-shaped association between the risk of stroke and systolic blood pressure (SBP) levels in people with chronic kidney disease (CKD). The Perindopril Protection Against Recurrent Stroke Study (PROGRESS) was a randomized, placebo-controlled trial demonstrating that perindopril-based blood pressure (BP) lowering reduced the risk of stroke in 6105 participants with prior cerebrovascular disease. We estimated the effects of therapy on the risk of recurrent stroke in 1757 of these participants with stage 3 or greater CKD according to baseline BP and the relationship between achieved follow-up BP and the risk of stroke. Active therapy produced comparable and significant reductions in the risk of stroke across all baseline SBP levels. The age- and gender-adjusted incidence of stroke increased significantly in a log-linear relationship for achieved SBP levels and strokes per 1000 person-years. This association persisted after adjusting for potential confounding factors. We found that perindopril-based BP lowering effectively prevented recurrent stroke in people with CKD, across a wide range of BP levels, without evidence of an increased risk of stroke in people with low BP levels.

Objective: To analyse the benefits and harms of statins in patients with chronic kidney disease (pre-dialysis, dialysis, and transplant populations)., Design: Meta-analysis., Data Sources: Cochrane Central Register of Controlled Trials, Medline, Embase, and Renal Health Library (July 2006)., Study Selection: Randomised and quasi-randomised controlled trials of statins compared with placebo or other statins in chronic kidney disease., Data Extraction and Analysis: Two reviewers independently assessed trials for inclusion, extracted data, and assessed trial quality. Differences were resolved by consensus. Treatment effects were summarised as relative risks or weighted mean differences with 95% confidence intervals by using a random effects model., Results: Fifty trials (30 144 patients) were included. Compared with placebo, statins significantly reduced total cholesterol (42 studies, 6390 patients; weighted mean difference -42.28 mg/dl (1.10 mmol/l), 95% confidence interval -47.25 to -37.32), low density lipoprotein cholesterol (39 studies, 6216 patients; -43.12 mg/dl (1.12 mmol/l), -47.85 to -38.40), and proteinuria (g/24 hours) (6 trials, 311 patients; -0.73 g/24 hour, -0.95 to -0.52) but did not improve glomerular filtration rate (11 studies, 548 patients; 1.48 ml/min (0.02 ml/s), -2.32 to 5.28). Fatal cardiovascular events (43 studies, 23 266 patients; relative risk 0.81, 0.73 to 0.90) and non-fatal cardiovascular events (8 studies, 22 863 patients; 0.78, 0.73 to 0.84) were reduced with statins, but statins had no significant effect on all cause mortality (44 studies, 23 665 patients; 0.92, 0.82 to 1.03). Meta-regression analysis showed that treatment effects did not vary significantly with stage of chronic kidney disease. The side effect profile of statins was similar to that of placebo. Most of the available studies were small and of suboptimal quality; mortality data were provided by a few large trials only., Conclusion: Statins significantly reduce lipid concentrations and cardiovascular end points in patients with chronic kidney disease, irrespective of stage of disease, but no benefit on all cause mortality or the role of statins in primary prevention has been established. Reno-protective effects of statins are uncertain because of relatively sparse data and possible outcomes reporting bias.

We describe the prevalence of stage III and IV chronic kidney disease in Thailand from a representative sample of individuals aged 35 years and above using a stratified, multistage, cluster-sampling method. Population estimates were calculated by applying sampling weights from the 2000 Thai census. Glomerular filtration rates were estimated from serum creatinine using the Cockroft-Gault and the simplified Modification of Diet in Renal Disease (MDRD) formulae. The prevalence of stage III disease among individuals aged 35 years and above was estimated to be about 20% using the Cockroft-Gault formula and about 13% from the MDRD formula. Stage IV disease was present in about 0.9 and 0.6% of this population using the respective formulae. The highest prevalence rates were observed in less well-developed rural areas and the lowest in developed urban areas. The prevalence of chronic kidney disease was significantly higher than that reported in individuals over 40 years old from the United States for both stage III and IV disease and higher than the reported incidence in Taiwan and Australia. This high prevalence of chronic kidney disease in Thailand has obvious implications for the health of its citizens and for the allocation of health-care resources.

Chronic kidney disease (CKD) is associated with a high risk of cardiovascular disease, but evidence regarding the effectiveness of interventions to reduce that risk is lacking. The Perindopril Protection against Recurrent Stroke Study (PROGRESS) study enrolled 6105 participants with cerebrovascular disease and randomly allocated them to perindopril-based blood pressure-lowering therapy or placebo. Individuals with CKD were at approximately 1.5-fold greater risk of major vascular events, stroke, and coronary heart disease, and were more than twice as likely to die (all P< or =0.002). Perindopril-based treatment reduced the risk of major vascular events by 30% and stroke by 35% among subjects with CKD, and the absolute effects of treatment were 1.7-fold greater for those with CKD than for those without. Considering patients with CKD and a history of cerebrovascular disease, perindopril prevented one stroke or other cardiovascular event among every 11 patients treated over five years. In conclusion, kidney function should be considered when determining the need for blood pressure lowering therapy in patients with cerebrovascular disease.

Objectives: ADVANCE (Action in Diabetes and Vascular Disease - PreterAx and DiamicroN MR Controlled Evaluation) is a large-scale clinical trial designed to investigate the benefits of blood pressure lowering and intensive glucose control in patients with type 2 diabetes mellitus., Methods and Participants: ADVANCE is a 2 x 2 factorial randomized trial evaluating the benefits of the low-dose fixed combination of perindopril and indapamide versus placebo to lower blood pressure and of an intensive gliclazide-MR-based regimen, targeting glycosylated haemoglobin (HbA1c) levels of 6.5% or less versus standard therapy to lower blood glucose. The two primary outcomes, taken separately and jointly, are a composite macrovascular endpoint and a composite microvascular endpoint., Results: A total of 11 140 participants were randomized between July 2001 and March 2003 from among 12 878 individuals with type 2 diabetes recruited from 215 centres in 20 countries, who entered a 6-week run-in phase. The average (SD) baseline blood pressure of 145(22)/81 (11) mmHg fell by 8/3 mmHg during the run-in phase during which participants received one tablet of open-labelled perindopril 2 mg-indapamide 0.625 mg. Only 3.6% of the 12 878 patients who entered the run-in phase withdrew because of suspected intolerance to perindopril-indapamide. With over 4 years of follow-up on average so far, over 80% of participants are still adhering to randomized therapy. Follow-up of the blood pressure arm will be completed during 2007., Conclusion: The safety and efficacy of perindopril-indapamide in lowering blood pressure and of a gliclazide-MR-based regimen in lowering blood glucose have been established with the completion of a 6-week run-in phase and of more than 4 years of post-randomization follow-up. It is anticipated that ADVANCE will provide many new insights including: whether blood pressure lowering with perindopril-indapamide reduces the risk of both macrovascular and microvascular events irrespective of baseline blood pressure; whether more intensive blood pressure lowering with a gliclazide-MR-based regimen targeting on HbA1c levels of 6.5% or less reduces these two outcomes compared with standard guidelines therapy; and finally whether the separate benefits of these two treatment regimens are additive.

The choice of drugs to initiate therapy for the management of hypertension remains contentious and diuretics are central to this controversy. Because most of the major trials involve complex treatment algorithms and allow diverse background treatments, one of the greatest challenges lies in separating out true class-specific effects - for example, separating true class-specific effects of diuretics from those of beta blockers. Despite these difficulties, the evidence confirms that diuretics are at least as effective as the newer first line groups in preventing cardiovascular events. The main area of doubt lies in relation to the risk of renal outcomes and of metabolic outcomes, such as new onset diabetes - where the evidence suggests that drugs that inhibit the renin-angiotensin system may be more protective than all other drug classes. These issues are reflected in the most recent international guidelines, all of which include diuretics among the first-line drugs for the treatment of hypertension, although they do differ on the role of diuretics in the initiation of therapy. Diuretics remain important for treating hypertension, especially in combination with other drug classes. The particular place of diuretics in the rank order of drugs must be tailored to suit the clinical situation in the individual patient. This will vary from a preferred option, as in black patients or elderly patients with systolic hypertension, to a second-line option in patients at high risk of developing new onset diabetes.

Objective and Rationale: ADVANCE (Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation) is a large-scale trial designed to investigate the benefits of blood pressure lowering and intensive glucose control in patients with type 2 diabetes, and to address a number of unresolved issues: whether blood pressure-lowering therapy and intensive glucose control therapy will reduce the risk of major vascular disease regardless of initial blood pressure or glucose concentration; whether more intensive glucose control targeting a haemoglobin A1c (HbA1c) level of 6.5% or less will confer greater protection against microvascular disease; and whether the benefits of the two interventions are additive., Design and Methods: ADVANCE is a 2 x 2 factorial randomized clinical trial evaluating the risks and benefits of the low-dose fixed combination of perindopril and indapamide versus placebo to lower blood pressure and of an intensive gliclazide-MR-based glucose control regimen, targeting an HbA1c of 6.5% or less versus standard guidelines based therapy for glucose control. There are two primary outcomes: a composite macrovascular endpoint and a composite microvascular endpoint., Results: A total of 12 878 participants from 215 centres in 20 countries entered a 6-week run-in phase between June 2001 and January 2003, and 11 140 patients were randomly assigned by March 2003. The average (SD) systolic and diastolic blood pressure fell from 145 (22)/81 (11) to 137 (20)/78 (10) mmHg during the 6-week run-in phase, during which participants received one tablet of open-labelled perindopril 2 mg/indapamide 0.625 mg. Of the 12 878 patients who entered the run-in, only 3.6% withdrew because of suspected intolerance to perindopril/indapamide. The study is half way through follow-up and both the study medications (perindopril 2 mg/indapamide 0.625 mg and gliclazide-MR) continue to be well tolerated. Completion is expected in 2007., Conclusion: Safe and effective blood pressure lowering with the fixed low-dose combination of perindopril and indapamide was confirmed during the run-in phase in 11 140 patients with type 2 diabetes, who were subsequently randomly assigned. Post-randomization study treatments have been well tolerated, and the completion of follow-up is scheduled in 2007.

Background: ADVANCE is a major international trial assessing the effects of routine compared with more intensive blood pressure lowering and intensive glucose control on macrovascular and microvascular outcomes, among high-risk individuals with type 2 diabetes. We describe the experience of participants receiving active blood pressure lowering therapy during the run-in phase of the study, and the characteristics of participants who withdrew during this phase., Methods: All participants potentially eligible for inclusion in ADVANCE underwent 6 weeks of therapy with fixed low-dose perindopril 2 mg and indapamide 0.625 mg combination daily, as part of an active run-in phase of the study. This treatment was provided in addition to the participants' existing therapeutic regimen, including other blood pressure lowering drugs., Results: Of the 12 878 registered participants who entered the run-in phase, 11140 participants were randomized. Only 459 participants (3.6%) withdrew due to suspected intolerance of perindopril-indapamide. The mean blood pressure fell by an average of 8/3 mmHg from 145/81 mmHg (standard deviation 22/11 mmHg) to 137/78 (20/10). Participants who proceeded to randomization were broadly similar to those who withdrew during the run-in phase; however, some features suggest that those randomized were a higher risk group overall., Conclusions: A substantial fall in blood pressure was observed following 6 weeks of treatment with a fixed low-dose combination of perindopril-indapamide in a broad range of high-risk individuals with type 2 diabetes. Good tolerability and safety of the study drug was confirmed during the active run-in phase of the ADVANCE study.

Thin basement membrane nephropathy (TBMN) often is diagnosed clinically when there is persistent dysmorphic or glomerular hematuria, but minimal proteinuria, normal kidney function, and no other obvious cause. This study investigated hematuria in patients with TBMN. A total of 112 patients with biopsy examination-proven TBMN were studied. All had hematuria at the time of presentation, with a mean urinary red blood cell (RBC) count of 256 +/- 250 x 10 3 /mL. Seventy-five (67%) patients attended for review over a median of 48 months (range, 3-120 mo) and provided a total of 485 urine specimens. Twenty-one patients (28%) had no hematuria by phase-contrast microscopy on at least 1 occasion. These corresponded to 32 urine specimens (7% of total). Of the 21 patients, the most recent urinary RBC counts were within the normal range in 11 (52%), but hematuria had recurred in the other 10 (48%). Hematuria is persistent in most patients with TBMN, but occasionally it resolves or is intermittent.

A retrospective survey was performed to establish patient and graft outcome for all 41 patients at our centre receiving sirolimus (SRL) in combination with calcineurin inhibition (CNI) as primary therapy for the 6 years prior to March 2002. Patient mortality [12%; n = 5 (TTP, lymphoma, mucormycosis, and small bowel perforation] was significantly higher at 3 months compared with those not receiving SRL, but not thereafter. 12.8% had delayed graft function and 33% had one or more episodes of rejection in the first 6 months. Mean GFR at 12 months was significantly lower (47.3 mL/min) in the SRL group compared with those not receiving SRL (51.3 mL/min). Twenty-two patients had a 12-month protocol biopsy; CNI toxicity was present in 36%. SRL was associated with significant hyperlipidaemia (serum cholesterol, 5.2 +/- 1.4 at baseline vs 7.3 +/- 1.7 mmol/L at 3 months, P <.001; triglycerides, 2.3 +/- 1.4 at baseline vs 2.7 +/- 1.1 mmol/L at 3 months, P <.05). Mild thrombocytopenia occurred in 23% but was not associated with haemorrhagic events. LDH increased by 62%, remaining elevated out to 2 years post engraftment. Seven patients developed insulin requiring diabetes mellitus, similar to the rate observed in our general transplant population.Thus, in this early experience, SRL in combination with CNI was associated with significant mortality and morbidity including CNI toxicity, presumably a reflection of a heavy burden of immunosuppression. However, 1-year graft survival on SRL was similar to the mean Australia-wide graft survival regardless of immunosuppression. The future use of SRL may center around CNI sparing and avoidance type protocols.

Although accelerated atherosclerosis and arteriosclerosis are common in patients with renal failure, the pathogenesis of these changes is poorly understood. Parathyroid hormone (PTH) levels are elevated in renal failure, and have been linked to uraemic vascular changes in some studies. We examined the in vitro effects of increasing doses of the 1-34 fragment of PTH on human aortic vascular smooth muscle cells (VSMCs). Factors examined were: (1) collagen production using tritiated hydroxyproline incorporation and transcription of procollagen alpha(1)(I) mRNA; (2) change in the surface area of collagen I lattices; (3) mRNA transcription of the collagen binding protein beta1 integrin; (4) proliferation using tritiated thymidine incorporation, and (5) methyl tetrazolium salt conversion to estimate live cell number after 5 days' exposure to PTH. PTH at a concentration of 200 pmol/l increased total collagen synthesis (188 +/- 25% of control, p < 0.01) as well as transcription of procollagen alpha(1)(I) mRNA (136 +/- 11% of control, p < 0.005). PTH also increased reorganisation of collagen I lattices (surface area 47 +/- 8% of well for control vs. 35.7 +/- 2.5 and 34.3 +/- 3.0% for PTH 100 and 200 pmol/l, respectively, p = 0.02) and upregulated beta1 integrin mRNA expression (160 +/- 20% of control at PTH concentration of 200 pmol/l, p < 0.05). PTH had no effect on VSMC proliferation or number at doses up to 200 pmol/l. In conclusion, PTH increases production and reorganisation of collagen by VSMCs in vitro. It is possible that more aggressive control of hyperparathyroidism in patients with renal failure may help to reduce the burden of cardiovascular disease in this patient population., (Copyright 2003 S. Karger AG, Basel)

Background: Abnormalities of the aortic valve occur with increased frequency in patients with renal failure and may contribute to the observed excess cardiovascular mortality. Little data exist on the rate at which aortic stenosis progresses in this patient group., Methods: A retrospective case-control study was designed to compare the rate of progression of aortic stenosis in dialysis patients with that in sex-matched controls. Dialysis patients with aortic stenosis were identified by a search of the echocardiography database. Twenty-eight dialysis patients were compared to 56 sex-matched controls, all of whom had aortic stenosis on at least two echocardiograms 6 months apart. Changes in mean and peak transvalvular gradient as well as valve area were calculated from echocardiographic data and compared., Results: Aortic stenosis progressed more rapidly in the dialysis patients than in the controls when measured by change in valve area (-0.19 vs. -0.07 cm2/year; p < 0.001) and change in peak transvalvular gradient (6.5 vs. 3.9 mm Hg/ year; p = 0.04). There was also a trend towards more rapid progression of mean transvalvular gradient (4.9 vs. 2.5 mm Hg/year; p = 0.052). On multivariate linear regression analysis, only end-stage renal failure (p = 0.02) and baseline valve area (p = 0.04) predicted accelerated progression of aortic stenosis., Conclusions: Aortic stenosis progressed more rapidly in the presence of renal failure. The time frames for review and operation in dialysis patients should be shorter than for the general population., (Copyright 2003 S. Karger AG, Basel)

Renal artery stenosis is a common, progressive cause of hypertension and renal impairment, and is frequently treated with percutaneous transluminal dilatation and stenting. The outcome of this procedure is still being evaluated. The records of 198 consecutive patients who had stents inserted at the Royal Melbourne Hospital were analysed retrospectively, and adequate follow-up information on 148 (75%), in whom a total of 182 renal arteries had been treated was obtained. Technical success was achieved in 144 patients (97%). Complications occurred in 19 patients (13.3%), with major complications occurring in 10 (7.0%) and one death occurring in relation to the procedure. A fall in average systolic blood pressure of 13.2 mmHg (12.1-14.3 mmHg) was seen and a fall in diastolic blood pressure of 10.1 mmHg (9.3-10.9 mmHg), without an increase in the number of antihypertensive drugs used. Renal function remained stable in the majority of patients, particularly those who had minimal baseline renal impairment. Restenosis was common after 6 months, occurring eventually in 29% of screened patients, but was not shown to affect clinical outcomes. Insertion of renal artery stents is a safe and effective treatment for renal artery stenosis.

Progressive renal disease is associated with the development of fibrosing lesions not only in the glomerulus, but also in the interstitial and vascular compartments of the kidney. A growing body of work suggests that the mechanisms involved in this process are to a large extent shared by the glomerular mesangial cell, tubulointerstitial fibroblast and vascular smooth muscle cell. In this review we consider evidence that treatment strategies focused on any one of these cells are likely to be of universal benefit in the abrogation of the ongoing scarring that accompanies progressive renal disease, while at the same time reducing the progressive vascular sclerosis so often ultimately responsible for the excessive mortality seen in patients with renal failure.