Background Renal function declines progressively in patients who have diabetic nephropathy, and the decline may be slowed by antihypertensive drugs The purpose of this study was to determine whether captopril has kidney-protecting properties independent of its effect on blood pressure in diabetic nephropathy Methods We performed a randomized, controlled trial comparing captopril with placebo in patients with insulin-dependent diabetes mellitus in whom urinary protein excretion was > or = 500 mg per day and the serum creatinine concentration was Results Two hundred seven patients received captopril, and 202 placebo Serum creatinine concentrations doubled in 25 patients in the captopril group, as compared with 43 patients in the placebo group (P = 0007) The associated reductions in risk of a doubling of the serum creatinine concentration were 48 percent in the captopril group as a whole, 76 percent in the subgroup with a baseline serum creatinine concentration of 20 mg per deciliter (177 mumol per liter), 55 percent in the subgroup with a concentration of 15 mg per deciliter (133 mumol per liter), and 17 percent in the subgroup with a concentration of 10 mg per deciliter (884 mumol per liter) The mean (+/- SD) rate of decline in creatinine clearance was 11 +/- 21 percent per year in the captopril group and 17 +/- 20 percent per year in the placebo group (P = 003) Among the patients whose base-line serum creatinine concentration was > or = 15 mg per deciliter, creatinine clearance declined at a rate of 23 +/- 25 percent per year in the captopril group and at a rate of 37 +/- 25 percent per year in the placebo group (P = 001) Captopril treatment was associated with a 50 percent reduction in the risk of the combined end points of death, dialysis, and transplantation that was independent of the small disparity in blood pressure between the groups Conclusions Captopril protects against deterioration in renal function in insulin-dependent diabetic nephropathy and is significantly more effective than blood-pressure control alone

The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The collaborative study group

Background Renal function declines progressively in patients who have diabetic nephropathy, and the decline may be slowed by antihypertensive drugs. The purpose of this study was to determine whether captopril has kidney-protecting properties independent of its effect on blood pressure in diabetic nephropathy. Methods We performed a randomized, controlled trial comparing captopril with placebo in patients with insulin-dependent diabetes mellitus in whom urinary protein excretion was ≥ 500 mg per day and the serum creatinine concentration was ≤ 2.5 mg per deciliter (221 μmol per liter). Blood-pressure goals were defined to achieve control during a median follow-up of three years. The primary end point was a doubling of the base-line serum creatinine concentration. Results Two hundred seven patients received captopril, and 202 placebo. Serum creatinine concentrations doubled in 25 patients in the captopril group, as compared with 43 patients in the placebo group (P =0.007). The associated reductions in risk...

https://www.nejm.org/doi/pdf/10.1056/NEJM199311113292004

The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy.

Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy

The serum creatinine concentration is widely interpreted as a measure of the glomerular filtration rate (GFR) and is used as an index of renal function in clinical practice. Glomerular filtration of creatinine, however, is only one of the variables that determines its concentration in serum. Alterations in renal handling and metabolism of creatinine and methodological interferences in its measurement may have a profound impact on the serum concentration of creatinine. We review the fundamental principles of physiology, metabolism, and analytical chemistry that are necessary to correctly interpret the serum creatinine concentration. These principles are then applied to important clinical circumstances, including aging, pregnancy, diabetes mellitus, drug administration, and acute and chronic renal failure. Despite numerous limitations, serum creatinine remains a useful clinical tool, but more accurate measures of renal function are frequently necessary.

Serum creatinine as an index of renal function: new insights into old concepts.

In patients with renal diseases characterized by proteinuria, the initial insult to the kidney is usually followed by a progressive decline in the glomerular filtration rate. This decline has been thought to be due to changes in renal hemodynamics initiated by the loss of nephrons.1 When renal mass is reduced in rats, the remaining nephrons undergo sudden hypertrophy, with a concomitant lowering of arteriolar resistance and an increase in glomerular plasma flow.2,3 Afferent arteriolar tone decreases more than efferent arteriolar tone, and therefore, the hydraulic pressure in glomerular capillaries rises4 and the amount of filtrate formed by each nephron . . .

Pathophysiology of Progressive Nephropathies

OBJECTIVE--To determine whether inhibition of angiotensin converting enzyme can reduce the rate of decline in kidney function more than reducing blood pressure with other antihypertensive treatment. DESIGN--Prospective, open randomised study lasting a mean of 2.2 years in patients with diabetic nephropathy. SETTING--Three outpatient nephrology clinics. PATIENTS--40 patients with insulin dependent diabetes and diabetic nephropathy with reduced renal function. INTERVENTION--Antihypertensive treatment with enalapril or metoprolol, usually combined with frusemide. MAIN OUTCOME MEASURE--Rate of decline in glomerular filtration rate measured as chromium-51 edetic acid clearance. RESULTS--Glomerular filtration rate declined a mean of 2.0 (SD 3.2) ml/min/year in the group given enalapril and 5.6 (5.9) ml/min/year in the control group. The mean arterial blood pressure during the study was 102 (5) mm Hg in the patients given enalapril and 103 (5) mm Hg in the patients given metoprolol. Urinary albumin excretion during treatment with enalapril was 60% lower than during treatment with metoprolol. CONCLUSIONS--Enalapril has an antiproteinuric effect independent of the effect on systemic blood pressure. Treatment with enalapril can reduce the rate of decline in kidney function in patients with diabetic nephropathy more than equally effective antihypertensive treatment with metoprolol. This points to a specific renal protective effect of angiotensin converting enzyme inhibitors in diabetic nephropathy.

https://www.bmj.com/content/bmj/304/6823/339.full.pdf

Renal protective effect of enalapril in diabetic nephropathy.

The effects of angiotensin converting enzyme inhibition with captopril were investigated in patients with diabetic nephropathy and hypertension. After nine days9 treatment with captopril glomerular filtration rate was unchanged in 13 patients, whereas renal plasma flow had increased from 265 to 302 ml/min/1.73 m2 body surface area (p less than 0.05) and the filtration fraction had decreased from 14.3 to 12.8% (p less than 0.025). During two years9 treatment with captopril in 14 patients the mean arterial blood pressure had fallen by 5 mm Hg (p less than 0.005) and the deterioration in glomerular filtration rate had decreased from 10.3 to 2.4 ml/min/year (p less than 0.005). There was no correlation between the fall in blood pressure and the reduction in the deterioration of glomerular filtration rate. These findings suggest that the effects of angiotensin converting enzyme inhibition on renal haemodynamics protect renal function. Inhibitors of angiotensin converting enzyme should be considered for lowering blood pressure in patients with diabetic nephropathy.

https://www.bmj.com/content/bmj/293/6545/471.full.pdf

Beneficial effects of angiotensin converting enzyme inhibition on renal function in patients with diabetic nephropathy.

OBJECTIVE--To assess whether angiotensin converting enzyme inhibition reduces proteinuria in diabetic nephropathy more than blood pressure reduction with other antihypertensive treatment DESIGN--Prospective, open randomised study lasting eight weeks in patients with diabetic nephropathy SETTING--Outpatient nephrology clinics PATIENTS--40 Patients with type I diabetes and diabetic nephropathy with reduced renal function INTERVENTION--Antihypertensive treatment with enalapril or metoprolol, usually combined with frusemide MAIN OUTCOME MEASURES--Arterial blood pressure and urinary excretion of albumin and protein RESULTS--Arterial blood pressure after eight weeks was 135/82 (SD 13/7) mm Hg in the group given enalapril and 136/86 (16/12) mm Hg in the group given metoprolol Proteinuria and albuminuria were similar in both groups before randomisation After eight weeks' treatment, the geometric mean albumin excretion was 07 (95% confidence interval 05 to 12) g/24 h in the patients given enalapril and 16 (11 to 25) g/24 h in the patients given metoprolol (p less than 002) The proteinuria was 11 (07 to 17) and 24 (16 to 36) g/24 h respectively (p less than 002) CONCLUSIONS--Antihypertensive treatment with enalapril reduced proteinuria in patients with diabetic nephropathy more than an equally effective antihypertensive treatment with metoprolol This points to a specific antiproteinuric effect of the angiotensin converting enzyme inhibitor independent of the effect on systemic blood pressure

https://www.bmj.com/content/bmj/300/6729/904.full.pdf

Contrasting effects of enalapril and metoprolol on proteinuria in diabetic nephropathy.

With the aim of studying the diurnal variation in blood pressure in relation to degree of fluid retention, 24-h ambulatory blood pressure monitoring was performed in 31 insulin-dependent diabetic patients with nephropathy. The extracellular volume was calculated from the distribution volume of 51Cr-EDTA after a single injection. The study population was arbitrarily divided into two groups, depending on their extracellular volume. Group 1 included 15 patients with a lower extracellular volume and group 2, 16 patients with a higher extracellular volume. Ambulatory blood pressure was measured with a portable monitor using an oscillometric technique. In all patients, the mean ±SD 24-h ambulatory blood pressure was 135/79±14/7 mm Hg. Day and night-time blood pressures were 136/81±14/7 and 133/75±17/8, respectively (p<0.02). The ambulatory blood pressure was 135/80±14/7 in group 1 and 136/78±15/6 mm Hg in group 2. The nocturnal change in blood pressure was significantly greater in group 1 than in group 2, −9/−9±10/5 mm Hg and 1/−3±10/6 mm Hg, respectively (p=0.005/0.01). There were no other significant differences between the groups than the diurnal blood pressure pattern. There were significant correlations between day ambulatory blood pressure and night ambulatory blood pressure and 24-h ambulatory blood pressure and urinary albumin excretion. There was no correlation between auscultatory clinic blood pressure on the one hand and albuminuria on the other. Latent fluid retention therefore may contribute to nocturnal hypertension in diabetic nephropathy.

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Latent overhydration and nocturnal hypertension in diabetic nephropathy.

The new calcium antagonist felodipine with a pronounced arteriolar dilating capacity was used to treat 11 patients with severe hypertension resistant to treatment (4 with essential hypertension, 5 with renoparechymatous hypertension, 2 with renovascular hypertension). Mean glomerular filtration rate for 10 patients was 34 +/- 27 ml/min/1.73 m2 body surface area (51Cr-EDTA clearance) before felodipine. One patient was on haemodialysis treatment. Mean arterial blood pressure in the outpatient clinic was 206 +/- 39/119 +/- 18 mm Hg in spite of treatment with 3 or more antihypertensive drugs. All but 2 patients had been given an angiotensin converting-enzyme inhibitor without success. All vasodilating agents were discontinued and the following morning 5 to 10 mg felodipine was given orally. This resulted in a reduction of average supine blood pressure from 190/110 mm Hg to 150/90 mm Hg during the first hour. The antihypertensive effect was unchanged during 6 hours and the drug was subsequently administered twice or three times a day. Mean systolic and diastolic blood pressure after 1 month was 155 +/- 19/91 +/- 12 mm Hg. Eight patients showed a favourable long term response with a mean systolic and diastolic blood pressure of 154 +/- 17/89 +/- 6mm Hg after 6 months. One patient died from his underlying disease after 2 months and 1 patient discontinued treatment because of ankle oedema after 6 weeks. In the long term treated patients with glomerular filtration rates greater than 15 ml/min/1.73m2 all but 1 showed an improved renal function by 26 +/- 19% (n = 5) after initiation of felodipine therapy. In 2 cases with very low glomerular filtration rate (6 to 7 ml/min/1.73m2) the deterioration of renal function continued after felodipine, but at a slower rate. It is concluded that felodipine decreased blood pressure dramatically in patients with severe hypertension where a majority of the cases had been resistant to a previous therapy. The drug appeared safe also in advanced renal insufficiency.

S. Björck

Papers

Renal protective effect of enalapril in diabetic nephropathy.

Beneficial effects of angiotensin converting enzyme inhibition on renal function in patients with diabetic nephropathy.

Contrasting effects of enalapril and metoprolol on proteinuria in diabetic nephropathy.

Latent overhydration and nocturnal hypertension in diabetic nephropathy.

Renal Effects of Felodipine in Hypertensive Patients with Reduced Renal Function