Gavin J. Becker

Angiotensin-Converting Enzyme Inhibitors and Progression of Nondiabetic Renal Disease: A Meta-Analysis of Patient-Level Data

Chronic renal disease is a major public health problem in the United States. According to the 1999 Annual Data Report of the U.S. Renal Data System, more than 357 000 people have end-stage renal disease (ESRD), and the annual cost of treatment with dialysis and renal transplantation exceeds

The Effect of Protein Restriction on the Progression of Renal Insufficiency

15.6 billion (1). Patients undergoing dialysis have reduced quality of life, a high morbidity rate, and an annual mortality rate of 20% to 25% (1). Identification of therapies to prevent ESRD is an important public health goal. Angiotensin-converting enzyme (ACE) inhibitors are highly effective in slowing the progression of renal disease due to type 1 diabetes (26), and evidence of their efficacy in type 2 diabetes is growing (712). However, although 14 randomized, controlled trials have been completed (1325; Brenner BM; Toto R. Personal communications), no consensus exists on the use of ACE inhibitors in nondiabetic renal disease (2628). In a previous meta-analysis of 11 randomized, controlled trials, we found that therapy with ACE inhibitors slowed the progression of nondiabetic renal disease (29). Since our meta-analysis was performed on group data rather than individual-patient data, we could not fully assess the relationship between the effect of ACE inhibitors and blood pressure, urinary protein excretion, or other patient characteristics (30). Thus, we could not determine whether an equal reduction in blood pressure or urinary protein excretion by using other antihypertensive agents would be as effective in slowing the progression of renal disease. Nor could we determine whether the baseline blood pressure, urinary protein excretion, or other patient characteristics modified the response to treatment. In the current report, we used pooled analysis of individual-patient data to answer these questions. We reasoned that the large number of patients in the pooled analysis would provide sufficient statistical power to detect relationships between patient characteristics and risk for progression of renal disease and interactions of patient characteristics with treatment effect. In principle, strong and consistent results from analysis of this large database would clarify the effects of ACE inhibitors for treatment of nondiabetic renal disease. Methods Study Design We obtained individual-patient data from nine published (1322) and two unpublished (Brenner BM; Toto R. Personal communications) randomized, controlled trials assessing the effects of ACE inhibitors on renal disease progression in predominantly nondiabetic patients. Search strategies used to identify clinical trials have been described elsewhere and are reviewed in Appendix 2. We included 11 randomized trials on progression of renal disease that compared the effects of antihypertensive regimens including ACE inhibitors to the effects of regimens without ACE inhibitors, with a follow-up of at least 1 year. In these studies, the institutional review board at each participating center approved the study, and all patients gave informed consent. Patients underwent randomization between March 1986 and April 1996. Hypertension or decreased renal function was required for entry into all studies. Exclusion criteria common to all studies were acute renal failure, treatment with immunosuppressive medications, clinically significant congestive heart failure, obstructive uropathy, renal artery stenosis, active systemic disease, insulin-dependent diabetes mellitus, history of transplantation, history of allergy to ACE inhibitors, and pregnancy. Table 1 shows characteristics of the patients in each study. Table 1. Study and Patient Characteristics in the Randomized, Controlled Trials Included in the Pooled Analysis Before randomization, patients already taking an ACE inhibitor were switched to alternative medications for at least 3 weeks. After randomization, the ACE inhibitor groups received enalapril in seven studies (1419; Brenner BM; Toto R. Personal communications) and captopril (13), benazepril (20), cilazapril (18), and ramipril (21, 22) in one study each. The control groups received placebo in five studies (1922; Brenner BM; Toto R. Personal communications), a specified medication in five studies (nifedipine in two studies [13, 17] and atenolol or acebutolol in three studies [15, 16, 18]), and no specified medication in one study (14). Other antihypertensive medications were used in both groups to reach the target blood pressure, which was less than 140/90 mm Hg in all studies. All patients were followed at least once every 6 months for the first year and at least once yearly thereafter. Blood pressure and laboratory variables were measured at each visit. Table 1 shows outcomes of each study. We pooled the 11 clinical trials on the basis of similarity of study designs and patient characteristics. In addition, the presence of preexisting hypertension and use of antihypertensive agents in most patients in the control groups in each clinical trial justified pooling data from placebo-controlled and active-controlled trials. Thus, the pooled analysis addresses the clinically relevant question of whether antihypertensive regimens including ACE inhibitors are more effective than anti-hypertensive regimens not including ACE inhibitors in slowing the progression of nondiabetic renal disease. Outcomes Two primary outcomes were defined: ESRD, defined as the initiation of long-term dialysis therapy, and a combined outcome of a twofold increase in serum creatinine concentration from baseline values or ESRD. Because ESRD is a clinically important outcome, we believed that definitive results of analyses using this outcome would be clinically relevant. However, because most chronic renal diseases progress slowly, few patients might reach this outcome during the relatively brief follow-up of these clinical trials, resulting in relatively low statistical power for these analyses. Doubling of baseline serum creatinine is a well-accepted surrogate outcome for progression of renal disease in studies of antihypertensive agents (2, 20) and would be expected to occur more frequently than ESRD, providing higher statistical power for analyses using this outcome. Doubling of baseline serum creatinine concentration was confirmed by repeated evaluation in only one study, which used this variable as the primary outcome. Therefore, we did not require confirmation of doubling for our analysis. Other outcomes included death and a composite outcome of ESRD and death. Withdrawal was defined as discontinuation of follow-up before the occurrence of an outcome or study end. Reasons for withdrawal were 1) nonfatal side effects possibly due to ACE inhibitors, including hyperkalemia, cough, angioedema, acute renal failure, or hypotension; 2) nonfatal cardiovascular disease events, including myo-cardial infarction, congestive heart failure, stroke, transient ischemic attack, or claudication; 3) other nonfatal events, such as malignant disease, pneumonia, cellulitis, headache, or gastrointestinal disturbance; and 4) other reasons, including loss to follow-up, protocol violation, or unknown. Statistical Analysis Five investigators participated in data cleaning. Summary tables were compiled from the individual-patient data from each study and checked against tables in published and unpublished reports. Discrepancies were resolved by contacting investigators at the clinical or data coordinating centers whenever possible. Because the studies followed different protocols, we had to standardize the variable definitions, follow-up intervals, and run-in periods; details of our approach are provided in Appendix 2. S-Plus (MathSoft, Inc., Seattle, Washington) and SAS (SAS Institute, Inc., Cary, North Carolina) software programs were used for all statistical analyses (31, 32). Univariate analysis was performed to detect associations between the covariates and outcomes. Baseline patient characteristics were treatment assignment (ACE inhibitor vs. control), age (logarithmic transformation), sex, ethnicity, systolic blood pressure, diastolic blood pressure, mean arterial pressure, serum creatinine concentration (reciprocal transformation), and urinary protein excretion. Study characteristics were blinding, type of antihypertensive regimen in the control group, planned duration of follow-up, whether dietary protein or sodium was restricted, and year of publication. Baseline patient characteristics and study characteristics were introduced as fixed covariates. Since renal biopsy was not performed in most cases and since criteria for classification of cause of renal disease were not defined, the cause of renal disease was not included as a variable in the analysis. Follow-up patient characteristics (blood pressure and urinary protein excretion) were adjusted as time-dependent covariates; the value recorded at the beginning of each time segment was used for that segment. This convention was used so that each outcome would be determined only by previous exposure. The intention-to-treat principle was followed for comparison of randomized groups. Cox proportional-hazards regression models were used to determine the effect of assignment to ACE inhibitors (treatment effect) and other covariates on risk for ESRD and the combined outcome (33, 34). Multivariable models were built by using candidate predictors that were associated with the outcome (P<0.2) in the univariate analysis. Each model was adjusted for study, but since some studies had no events, we could not include a dummy variable for each study. Rather, we adjusted models for studies that differed significantly from the rest (studies 2 [14], 5 [15], 10 [20], and 11 [21, 22]). We also performed tests for interactions between all covariates and treatment effect. All P values were based on two-sided tests, and significance was set at a P value less than 0.05. Results are expressed as relative risks with 95% CIs. Residual diagnostics were performed on these final models (33, 34)

Spironolactone in Addition to ACE Inhibition to Reduce Proteinuria in Patients with Chronic Renal Disease

Dietary protein intake may be an important determinant of the rate of decline in renal function in patients with chronic renal insufficiency. We conducted a prospective, randomized study of the efficacy of protein restriction in slowing the rate of progression of renal impairment. The study lasted 18 months and included 64 patients with serum creatinine concentrations ranging from 350 to 1000 micromol per liter. The patients were randomly assigned to follow either a regular diet or an isocaloric protein-restricted diet (0.4 g of protein per kilogram of the body weight per day). Blood-pressure levels and the balance between calcium and phosphate were similar in the two groups. End-stage renal failure developed in 9 of the 33 patients (27 percent) who followed the regular diet during the study, as compared with 2 of the 31 patients (6 percent) who followed the protein-restricted diet (P less than 0.05). The mean (+/- SE) glomerular filtration rate, as measured by the clearance of 51Cr bound to EDTA, fell from 0.25 +/- 0.03 to 0.10 +/- 0.05 ml per second (P less than 0.01) in the group on the regular diet, whereas it fell from 0.23 +/- 0.04 to 0.20 +/- 0.05 ml per second (P not significant) in the group on the protein-restricted diet. We conclude that dietary protein restriction is effective in slowing the rate of progression of chronic renal failure.

Double-Blind, Placebo-Controlled Study on the Effect of the Aldosterone Receptor Antagonist Spironolactone in Patients Who Have Persistent Proteinuria and Are on Long-Term Angiotensin-Converting Enzyme Inhibitor Therapy, with or without an Angiotensin II Receptor Blocker

To the Editor: Angiotensin-converting–enzyme (ACE) inhibitors have been shown to reduce proteinuria and slow the progression of renal disease.1 Although to date angiotensin II has been the focus of...

The role of tubulointerstitial injury in chronic renal failure

Studies have shown that dual therapy with angiotensin-converting enzyme inhibitors (ACEI) and either angiotensin II receptor blockers or aldosterone receptor antagonists is more effective in reducing proteinuria than either agent used alone. The questions that remain are as follows: (1) Which of these agents should be used as dual therapy with the ACEI? (2) Does a higher level of blockade of the renin-angiotensin-aldosterone system with triple therapy offer an advantage over dual blockade? A 3-mo randomized, double-blind, placebo-controlled study was performed in 41 patients with proteinuria >1.5 g/d. Four treatment groups were compared: (1) Ramipril + spironolactone placebo + irbesartan placebo, (2) ramipril + irbesartan + spironolactone placebo, (3) ramipril + irbesartan placebo + spironolactone, and (4) ramipril + irbesartan + spironolactone. The percentage change in protein excretion differed according to treatment arm (ANOVA: F(3,35) = 8.6, P < 0.001). Pair-wise comparison showed that greater reduction in protein excretion occurred in treatment regimens that incorporated spironolactone. The reduction in proteinuria at 3 mo was as follows: Group 1, 1.4%; group 2, 15.7%; group 3, 42.0%; and group 4, 48.2%. The reduction in proteinuria among patients who were taking spironolactone-containing regimens was sustained at 6 and 12 mo. This study suggests that aldosterone receptor blockade offers a valuable adjuvant treatment when used with ACEI therapy for the reduction of proteinuria. Results suggest no advantage of triple blockade over dual blockade of the renin-angiotensin-aldosterone system to reduce proteinuria.

Prevalence and risk factors for osteopenia in dialysis patients

Progressive renal failure results from a triad of glomerulosclerosis, tubulointerstitial fibrosis and vascular sclerosis. The mechanisms by which tubules are injured, and by which the tubular epithelial cell then excites interstitial inflammation culminating in fibroblast activation and fibrosis have become increasingly understood. Most current methods to prevent progressive glomerulosclerosis would inherently prevent tubular injury and interstitial fibrosis. The behaviour and control of the renal fibroblast is being investigated, with the potential for direct interference with its functions.

Summary of KDIGO guideline. What do we really know about management of blood pressure in patients with chronic kidney disease

Dialysis patients are at risk for low bone mineral density (BMD) consequent of hyperparathyroidism, 1,25-dihydroxyvitamin D deficiency, previous immunosuppression, chronic acidosis, secondary amenorrhea, and chronic heparin and aluminum exposure. We wanted to determine the prevalence and distribution of osteopenia and the influence of risk factors for osteopenia in dialysis patients. Dual energy x-ray absorptiometry was used to record BMD at the lumbar spine (LS), hip, and nondominant forearm. Results were expressed as Z-scores (standard deviations from the mean of a healthy age- and gender-matched reference population). Osteopenia was defined as a Z-score worse than -2. In the 250 dialysis patients studied, the prevalence of osteopenia at the LS, femoral neck (FN) and ultradistal radius (UD) was 8%, 13% and 20%, respectively. The median Z-scores at these sites were all significantly different from the healthy reference population median of 0 and were 0.29 (P = 0.008), -0.67 (P < 0.001), and -1.01 (P < 0.001), respectively. Previous transplantation was associated with as much as a one Z-score lower BMD at the FN (P = 0.0069) and UD (P = 0.0011) and a marginally significant reduction at the LS (P = 0.0777). Previous parathyroidectomy was associated with a markedly higher LS BMD (P = 0.0001) and a higher BMD at the FN (P = 0.0017) but not the UD (P = 0.3691). A history of secondary amenorrhea was associated with a lower FN BMD (P = 0.0047) but not a significantly lower BMD at the LS (P = 0.0978) or UD (P = 0.2327). In hemodialysis patients without a history of transplantation, parathyroidectomy, or secondary amenorrhea, there was no correlation between Z-score at any site and duration of dialysis. Thus, osteopenia in dialysis patients occurs in both axial and appendicular sites and sites of compact and cancellous bone. It is more common with previous transplantation and secondary amenorrhea, whereas a history of parathyroidectomy is associated with increased BMD. No relationship was found between BMD and duration of hemodialysis, which suggests that important changes in BMD occur during the predialysis stage of chronic renal failure.

Parathyroid hormone has a prosclerotic effect on vascular smooth muscle cells

The Kidney Disease: Improving Global Outcomes Clinical Practice Guideline for management of blood pressure (BP) in chronic kidney disease (CKD) supersedes the 2004 Kidney Disease Quality Outcomes Initiative document on this topic. The new guideline has been designed to assist clinical decision making in patients with CKD who are not receiving dialysis. The recommendations in the guideline acknowledge that no single BP target is optimal for all CKD patients and encourage individualization of treatment depending on age, the severity of albuminuria, and comorbidities. In general, the available evidence indicates that in CKD patients without albuminuria the target BP should be ≤140 mm Hg systolic and ≤90 mm Hg diastolic. However, in most patients with an albumin excretion rate of ≥30 mg/24 h (i.e., those with both micro- and macroalbuminuria), a lower target of ≤130 mm Hg systolic and ≤80 mm Hg diastolic is suggested. In achieving BP control, the value of lifestyle changes and the need for multiple pharmacological agents is acknowledged. Use of agents that block the renin-angiotensin-aldosterone system is recommended or suggested in all patients with an albumin excretion rate of ≥30 mg/24 h. Recommendations are almost identical in CKD patients with and without diabetes. Special considerations relevant to children and those of older age and those who have received a kidney transplant are included. Ongoing controversies in BP management in the context of CKD are highlighted along with key areas for future research.

Interstitial myofibroblasts in IgA glomerulonephritis.

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 α1(I) mRNA; (2) change in the surface area of collagen I lattices; (3) mRNA transcription of the collagen binding protein β1 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 α1(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 β1 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.

IMPACT OF ACUTE REJECTION THERAPY ON INFECTIONS AND MALIGNANCIES IN RENAL TRANSPLANT RECIPIENTS

We examined renal biopsy specimens from patients with mesangial IgA glomerulonephritis (n = 25; plasma creatinine 0.05-0.30 mmol/l) to ascertain whether the myofibroblast has a role in progressive renal interstitial fibrosis. Myofibroblasts were identified by morphology and alpha smooth muscle actin (alpha-SMA) immunostaining at the light and electron microscope level. Results were related to staining for interstitial leukocytes and collagen III. A control group consisted of 6 normal renal transplant donors from whom biopsy specimens were taken at the time of vascular anastomosis. The fractional volume of interstitial alpha-SMA staining was greater in patients with mesangial IgA glomerulonephritis than in the control group (17.2 vs. 1.3%; p < 0.001). alpha-SMA staining was increased in areas of interstitial fibrosis with prominent periglomerular and peritubular distribution. Ultrastructural studies established that alpha-SMA staining in the renal interstitium was intracellular, cytoplasmic, and confined to myofibroblast-like cells and processes. The alpha-SMA expression correlated with fractional volume of tubular atrophy/dilation (r = 0.79, p < 0.001), interstitial connective tissue (r = 0.66, p < 0.001), leucocytes (r = 0.72, p < 0.005), and collagen III (r = 0.71, p < 0.001). Staining correlated with renal function at the time of biopsy (r = 0.64, p < 0.005) and after 2 years of follow-up (r = 0.77, p < 0.01). In conclusion, cells with a myofibroblast-like phenotype have a significant role in the progression of tubulointerstitial injury.