Medline ® Abstracts for References 7,58,64,68,101

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors reduce blood pressure and urine protein excretion and slow the progression of chronic kidney disease.

PURPOSE: To determine the levels of blood pressure and urine protein excretion associated with the lowest risk for progression of chronic kidney disease during antihypertensive therapy with and without ACE inhibitors.

DATA SOURCES: 11 randomized, controlled trials comparing the efficacy of antihypertensive regimens with or without ACE inhibitors for patients with predominantly nondiabetic kidney disease.

STUDY SELECTION: MEDLINE database search for English-language studies published between 1977 and 1999.

DATA EXTRACTION: Data on 1860 nondiabetic patients were pooled in a patient-level meta-analysis. Progression of kidney disease was defined as a doubling of baseline serum creatinine level or onset of kidney failure. Multivariable regression analysis was performed to assess the association of systolic and diastolic blood pressure and urine protein excretion with kidney disease progression at 22 610 patient visits.

DATA SYNTHESIS: Mean duration of follow-up was 2.2 years. Kidney disease progression was documented in 311 patients. Systolic blood pressure of 110 to 129 mm Hg and urine protein excretion less than 2.0 g/d were associated with the lowest risk for kidney disease progression. Angiotensin-converting enzyme inhibitors remained beneficial after adjustment for blood pressure and urine protein excretion (relative risk, 0.67 [95% CI, 0.53 to 0.84]). The increased risk for kidney progression at higher systolic blood pressure levels was greater in patients with urine protein excretion greater than 1.0 g/d (P<0.006).

CONCLUSION: Although reverse causation cannot be excluded with certainty, a systolic blood pressure goal between 110 and 129 mm Hg may be beneficial in patients with urine protein excretion greater than 1.0 g/d. Systolic blood pressure less than 110 mm Hg may be associated with a higher risk for kidney disease progression.

It is unclear whether patients with nondiabetic kidney disease benefit from angiotensin-converting enzyme inhibitor (ACEI) therapy when they are at low risk for disease progression or when they have low urinary protein excretion. With the use of a combined database from 11 randomized, clinical trials (n = 1860), a Cox proportional hazards model, based on known predictors of risk and the composite outcome kidney failure or creatinine doubling, was developed and used to stratify patients into equal-sized quartiles of risk. Outcome risk and treatment effect were examined across various risk strata. Use of this risk model for targeting ACEI therapy was also compared with a strategy based on urinary protein excretion alone. Control patients in the highest quartile of predicted risk had an annualized outcome rate of 28.7%, whereas control patients in the lowest quartile of predicted risk had an annualized outcome rate of 0.4%. Despite the extreme variation in risk, there was no variation in the degree of benefit of ACEI therapy (P = 0.93 for the treatment x risk interaction). Significant interaction was detected between baseline urine protein and ACEI therapy (P = 0.003). When patients were stratified according to their baselineurinary protein excretion, among the subgroup of patients with proteinuria>or =500 mg/d, significant treatment effect was seen across all patients with a measurable outcome risk, including those at relatively low risk (1.7% annualized risk for progression). However, there was no benefit of ACEI therapy among patients with proteinuria<500 mg/d, even among higher risk patients (control outcome rate 19.7%). Patients with nondiabetic kidney disease vary considerably in their risk for disease progression, but the treatment effect of ACEI does not vary across risk strata. Patients with proteinuria<500 mg/d do not seem to benefit, even when at relatively high risk for progression.

BACKGROUND: Drugs that inhibit angiotensin-converting enzyme slow the progression of renal insufficiency in patients with diabetic neuropathy. Whether these drugs have a similar action in patients with other renal diseases is not known. We conducted a study to determine the effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of renal insufficiency in patients with various underlying renal diseases.

METHODS: In a three-year trial involving 583 patients with renal insufficiency caused by various disorders, 300 patients received benazepril and 283 received placebo. The underlying diseases included glomerulopathies (in 192 patients), interstitial nephritis (in 105), nephrosclerosis (in 97), polycystic kidney disease (in 64), diabetic nephropathy (in 21), and miscellaneous or unknown disorders (in 104). The severity of renal insufficiency was classified according to the base-line creatinine clearance: 227 patients had mild insufficiency (creatinine clearance, 46 TO 60 ml per minute), and 356 had moderate insufficiency (creatinine clearance, 30 to 45 ml per minute). The primary end point was a doubling of the base-lineserum creatine concentration or the need for dialysis.

RESULTS: At three years. 31 patients in the benazepril group and 57 in the placebo group had reached the primary end point (P<0.001). In the benazepril group, the reduction in the risk of reaching the end point was 53 percent overall (95 percent confidence interval, 27 to 70 percent), 71 percent (95 percent confidence interval, 21 to 90 percent) among the patients with mild renal insufficiency, and 46 percent (95 percent confidence interval, 12 to 67 percent) among those with moderate renal insufficiency. The reduction in risk was greatest among the male patients; those with glomerular diseases, diabetic nephropathy, or miscellaneous or unknown causes of renal disease; and those with base-line urinary protein excretion above 1 g per 24 hours. Benazepril was not effective in patients with polycystic disease. Diastolic pressure decreased by 3.5 to 5.0 mm Hg in the benazepril group and increased by 0.2 to 1.5 mm Hg in the placebo group.

CONCLUSIONS: Benazepril provides protection against the progression of renal insufficiency in patients with various renal diseases.

BACKGROUND: Stratum 2 of the Ramipril Efficacy in Nephropathy (REIN) study has already shown that in patients with chronic nephropathies and proteinuria of 3 g or more per 24 h, angiotensin-converting enzyme (ACE) inhibition reduced the rate of decline in glomerular filtration and halved the combined risk of doubling of serum creatinine or end-stage renal failure (ESRF) found in controls on placebo plus conventional antihypertensives. In REIN stratum 1, reported here, 24 h proteinuria was 1 g or more but less than 3 g per 24 h.

METHODS: In stratum 1 of this double-blind trial 186 patients were randomised to a ramipril or a control (placebo plus conventional antihypertensive therapy) group targeted at achieving a diastolic blood pressure of less than 90 mm Hg. The primary endpoints were change in glomerular filtration rate (GFR) and time to ESRF or overt proteinuria (>or =53 g/24 h). Median follow-up was 31 months.

FINDINGS: The decline in GFR per month was not significantly different (ramipril 0.26 [SE 0.05]mL per min per 1.73m2, control 0.29 [0.06]). Progression to ESRF was significantly less common in the ramipril group (9/99 vs 18/87) for a relative risk (RR) of 2.72 (95% CI 1.22-6.08); so was progression to overt proteinuria (15/99 vs 27/87, RR 2.40 [1.27-4.52]). Patients with a baseline GFR of 45 mL/min/1.73 m2 or less and proteinuria of 1.5 g/24 h or more had more rapid progression and gained the most from ramipril treatment. Proteinuria decreased by 13% in the ramipril group and increased by 15% in the controls. Cardiovascular events were similar. As expected, the rate of decline in GFR and the frequency of ESRF were much lower in stratum 1 than they had been in stratum 2.

INTERPRETATION: In non-diabetic nephropathies, ACE inhibition confers renoprotection even to patients with non-nephrotic proteinuria.

BACKGROUND: Restricting protein intake and controlling hypertension delay the progression of renal disease in animals. We tested these interventions in 840 patients with various chronic renal diseases.

METHODS: In study 1, 585 patients with glomerular filtration rates of 25 to 55 ml per minute per 1.73 m2 of body-surface area were randomly assigned to a usual-protein diet or a low-protein diet (1.3 or 0.58 g of protein per kilogram of body weight per day) and to a usual- or a low-blood-pressure group (mean arterial pressure, 107 or 92 mm Hg). In study 2, 255 patients with glomerular filtration rates of 13 to 24 ml per minute per 1.73 m2 were randomly assigned to the low-protein diet (0.58 g per kilogram per day) or a very-low-protein diet (0.28 g per kilogram per day) with a keto acid-amino acid supplement, and a usual- or a low-blood-pressure group (same values as those in study 1). An 18-to-45-month follow-up was planned, with monthly evaluations of the patients.

RESULTS: The mean follow-up was 2.2 years. In study 1, the projected mean decline in the glomerular filtration rate at three years did not differ significantly between the diet groups or between the blood-pressure groups. As compared with the usual-protein group and the usual-blood-pressure group, the low-protein group and the low-blood-pressure group had a more rapid decline in the glomerular filtration rate during the first four months after randomization and a slower decline thereafter. In study 2, the very-low-protein group had a marginally slower decline in the glomerular filtration rate than did the low-protein group (P = 0.07). There was no delay in the time to the occurrence of end-stage renal disease or death. In both studies, patients in the low-blood-pressure group who had more pronounced proteinuria at base line had a significantly slower rate of decline in the glomerular filtration rate.

CONCLUSIONS: Among patients with moderate renal insufficiency, the slower decline in renal function that started four months after the introduction of a low-protein diet suggests a small benefit of this dietary intervention. Among patients with more severe renal insufficiency, a very-low-protein diet, as compared with a low-protein diet, did not significantly slow the progression of renal disease.