William Schlueter

Improvement of lipid abnormalities associated with proteinuria using fosinopril, an angiotensin-converting enzyme inhibitor

The nephrotic syndrome is associated with several complications including edema, hyperlipidemia, and protein malnutrition [1, 2]. These complications are largely related to the severity of the proteinuria. Elevation of the serum lipid concentrations is of major concern because it contributes to the high cardiovascular morbidity and mortality observed in patients with the nephrotic syndrome [3]. Patients with heavy proteinuria have recently been shown to have elevated levels of lipoprotein(a) (lp[a]) [4]. Lipoprotein(a) has both thrombogenic and atherogenic properties and is increasingly recognized as an independent risk factor for cardiovascular disease [5, 6]. For these reasons, reducing the hyperlipidemia associated with proteinuria could be viewed as a major therapeutic goal. In addition, recent data from animal studies suggest that hyperlipidemia may accelerate the progression of renal insufficiency, although the significance of these findings for renal disease in humans remains uncertain [7-10]. Angiotensin-converting enzyme (ACE) inhibitors slow the rate of progression of kidney disease in experimental models of renal insufficiency [11-13]. These agents have also been shown to reduce microalbuminuria in patients with incipient diabetic nephropathy [14, 15] and overt proteinuria in patients with diabetic and nondiabetic renal disease [16-18]. Taken together, these studies are suggestive of a special beneficial effect of ACE inhibitors in patients with renal disease. However, a benefit from reducing proteinuria in terms of improving the outcome of renal disease or in terms of other systemic (nonrenal) effects has not been shown in humans. One potential benefit of drug use aimed at reducing proteinuria might be the lessening of the lipid abnormalities associated with overt proteinuria. Studies in humans that have shown a reduction in proteinuria with ACE inhibitors did not focus on the effect of this intervention on the lipid profile [14-18]. We report that fosinopril, an ACE inhibitor with dual hepatic and renal elimination [19], had a prompt and sustained beneficial effect on both proteinuria and lipid profile abnormalities in patients with proteinuric renal disease enrolled in a placebo-controlled, double-blind trial of 12 weeks duration followed by an open-label trial of fosinopril of 6 months. Table. SI Units, Drug, and Abbreviations Methods Patients Twenty-eight patients with proteinuric renal disease who entered a double-blind study (fosinopril sodium compared with placebo) are reported. Two patients were withdrawn from the study during the double-blind phase; one was lost to follow-up, and the other had an increase in serum creatinine from 230 to 292 mol/L. Sixteen of the 26 patients who completed the double-blind phase were subsequently enrolled in an extended trial of fosinopril sodium. All patients except one were men; 17 were black, 8 were white, and 1 was Asian. Their ages ranged from 28 to 70 years. Diabetic nephropathy was diagnosed when overt proteinuria was documented in patients who had type 2 diabetes and clinical features consistent with diabetic nephropathy. Kidney biopsies were not done in diabetic patients. In nondiabetic patients, the diagnosis of glomerular disease was determined by kidney biopsy except in five patients who declined the procedure. The cause of their renal diseases were as follows: type 2 diabetic nephropathy in 15 patients, focal glomerular sclerosis in 3, membranous nephropathy in 2, and mesangio-capillary glomerulonephritis in 1. The cause of the renal disease in the remaining five nondiabetic patients was not determined. For a patient to be included in the study, his or her proteinuria had to exceed 2.0 g/d and serum creatinine concentration had to be 265 mol/L or less. Of the 26 patients, 21 had nephrotic-range proteinuria, defined as protein excretion exceeding 3.0 g/d [20]. Exclusion criteria were 1) treatment with converting enzyme inhibitors within 4 weeks of the baseline phase; 2) ongoing therapy with medications such as corticosteroids or immunosuppressives or with medications that could influence protein excretion such as nonsteroidal anti-inflammatory agents; 3) recent history of serum potassium concentrations exceeding 5.5 mmol/L; 4) poorly controlled diabetes mellitus; 5) uncontrolled hypertension defined as a diastolic blood pressure of 115 mm Hg or higher; 6) congestive heart failure; 7) noncompliance with medications; and 8) failure to collect 24-hour urine specimens or to keep clinic appointments. All participants gave informed written consent to participate in the study according to a protocol approved by the institutional review boards of both hospitals. Intervention Before patients entered the study, all antihypertensive medications were withdrawn. All patients received one placebo tablet daily for 3 weeks (baseline phase). After the baseline phase was completed, patients were randomly assigned to either fosinopril (10 mg once every morning orally, n = 17) or matching placebo (one tablet every morning orally, n = 9) in a double-blind manner with a 2-to-1 allocation ratio for randomization. In both groups, verapamil slow-release (SR), 240 mg per day, was added after week 2 of the double-blind phase if diastolic blood pressure exceeded 95 mm Hg (nine patients in the fosinopril group and four patients in the placebo group). After 8 weeks, the dose of the blinded medications was doubled if protein excretion had not decreased by at least 30% or if the patients diastolic blood pressure exceeded 95 mm Hg. Of the 26 patients, the dose was doubled in 19 patients (12 in the fosinopril group and 7 in the placebo group). During the baseline phase and throughout the study, oral furosemide, at a dose ranging from 20 to 160 mg daily (but constant for each patient), was allowed if edema was pronounced or to help control blood pressure (eight patients in the fosinopril group and six patients in the placebo group). Four patients were receiving medications known to affect serum lipid levels: lovastatin (two patients), colestipol, and an estrogen preparation. Except when indicated, the data from these patients were excluded from analysis of the effect of fosinopril on serum lipids to avoid confounding variables. When the double-blind phase was completed, all patients were given one placebo tablet daily for 6 weeks (washout phase). During this washout phase, oral verapamil SR, 240 mg per day, was permitted only for those patients who had received it during the double-blind phase. After completion of the 6-week washout period, verapamil SR was withdrawn from all patients. A 23-week open-label trial of oral fosinopril, 10 mg once a day, was then started. Beginning at week 7 of this phase, the dose of fosinopril was increased to 20 mg every morning in all patients. Oral furosemide was given at the same dose throughout the study in 7 of the 16 patients. Dietary and Analytical Evaluations A dietary history was obtained by a registered dietitian during the baseline phase, at week 8 of the double-blind phase, and at the end of the open-label phase. Total caloric intake and the percentage of the caloric intake composed of fat, protein, and carbohydrates were recorded. All patients were instructed not to change their usual diet during the study. Patients were asked to refrain from strenuous exercise (jogging, weight lifting, vigorous aerobics) on the days when they collected 24-hour urine specimens. At each visit, the patients blood pressure was measured with a standard sphygmomanometer. After the patient rested in a seated position for 10 minutes, the blood pressure and heart rate were measured three times at 5-minute intervals; the means of the three readings were recorded. Mean arterial pressure was calculated as the diastolic blood pressure plus one third of the difference between the systolic and diastolic blood pressure. Clinical and laboratory data were recorded at the entry visit and weeks 2 and 3 of the baseline phase; weeks 1, 2, 4, 6, 8, 10, and 12 of the double-blind phase; weeks 2 and 6 of the washout phase; and weeks 1, 3, 7, 11, 15, 19, and 23 of the open-label phase. Venous blood was drawn to determine a complete blood count, fasting blood glucose, electrolytes, creatinine, urea nitrogen, total serum protein and albumin, liver function enzymes, triglycerides, and serum total cholesterol. A 24-hour urine sample was collected to measure total protein, albumin, creatinine, urea nitrogen, and sodium excretion. Urinary creatinine was measured to assess both creatinine clearance and the adequacy of the collection. Urine urea nitrogen and sodium were used as markers of protein and sodium intake, respectively. Serum total cholesterol and high-density lipoprotein (HDL) cholesterol levels were measured as previously described [21]. Serum low-density lipoprotein (LDL) cholesterol was calculated as (total cholesterol [HDL cholesterol + triglycerides/5]). This formula can be used only when triglycerides are less than 400 mg/dL. Two patients whose serum triglycerides exceeded 400 mg/dL were excluded from analysis of the effect of fosinopril on serum LDL cholesterol. Plasma lp(a) protein was measured using an assay based on sandwich enzyme-linked immunosorbent assay (ELISA) that is insensitive to the presence of plasminogen [22]. Serum ACE activity was measured 24 hours after the previous dose of fosinopril by the spectrophotometric method described by Cushman and Cheung [23]. Statistical Analysis When paired analysis was used, data are reported as mean values followed by the mean change from baseline with the associated 95% confidence intervals (CI). Where appropriate, data are also reported as mean standard error of the mean. Two-way analysis of variance (ANOVA) was used to compare the change in protein excretion and total serum cholesterol from baseline over the course of the randomized trial between the two treatment groups. Results General Data When considered as a

Urinary sodium in the evaluation of hyperchloremic metabolic acidosis.

IT has long been held that systemic acidemia provides the proximate stimulus for the kidney to increase urinary acidification in response to metabolic acidosis.1 2 3 4 This view has been challenged...

A subdepressor low dose of ramipril lowers urinary protein excretion without increasing plasma potassium.

Angiotensin-converting enzyme (ACE) inhibitors are increasingly administered to patients with chronic renal disease. One issue of concern with the use of ACE inhibitors in patients with impaired renal function is the possible development of hyperkalemia. We reasoned that the impact of ACE inhibitors on plasma potassium could be minimized by administering these agents at very low doses. To examine this issue, we investigated the effect of a low dose of ramipril (1.25 mg orally once daily) and an eight-fold higher dose (10 mg orally once daily) on plasma potassium in 13 patients with proteinuria and mild chronic renal insufficiency. The study was divided into four phases: placebo (4 weeks), low-dose ramipril (8 weeks), high-dose ramipril (8 weeks), and washout phase (4 weeks). With the low dose of ramipril, urinary protein excretion decreased significantly as early as after 1 week of administration (from 4.4 +/- 0.5 to 3.7 +/- 0.4 g/24 h; P < 0.025) and did not decrease any further thereafter even when the dose was increased eight-fold. Mean arterial blood pressure and plasma potassium did not change significantly with the low dose of ramipril, whereas with the higher dose, mean arterial blood pressure decreased significantly (from 107 +/- 2.0 to 100 +/- 2.0 mm Hg, P < 0.005), and plasma potassium increased significantly (from 4.53 to 4.78 mEq/L, P < 0.05). We conclude that a low dose of ramipril can reduce proteinuria to the same extent as an eight-fold higher dose without significantly lowering blood pressure or increasing plasma potassium. This latter feature may be advantageous for the treatment of patients at risk for hyperkalemia who require ACE inhibitors.

Selected Aspects of ACE Inhibitor Therapy for Patients with Renal Disease: Impact on Proteinuria, Lipids and Potassium

Overt proteinuria is often accompanied by hypercholesterolemia and is associated with increased lipoprotein(a) levels. These lipid abnormalities are probably involved in the high incidence of macrovascular complications associated with diabetic nephropathy and possibly other kinds of non‐diabetic proteinuric renal disease. Over the last decade many studies have shown that ACE inhibitors can reduce urinary protein excretion but little attention was paid to the impact of this form of therapeutic intervention on the lipid profile. In this article we review our recent data showing that fosinopril administration was associated with significant decreases in both urinary protein excretion, serum total cholesterol levels, and plasma lp(a) levels. The use of ACE inhibitors in patients with renal impairment can result in the development of hyperkalemia as a result of suppression of angiotensin II‐driven aldosterone secretion by the adrenal gland. Inhibition of aldosterone secretion may depend on the degree of inhibition of angiotensin II formation in the circulation and also locally in the adrenal gland. Because the various ACE inhibitors exhibit different degrees of ACE inhibition at the tissue level, we have postulated that angiotensin II‐dependent aldosterone production will be inhibited to a lesser degree by agents that have low tissue affinity for the adrenal gland. The implication of this theoretical concept for the development of hyperkalemia in patients with impaired renal function treated with ACE inhibitors is discussed.

Renal Effects of Antihypertensive Drugs

SummaryAntihypertensive drugs have disparate effects on renal haemodynamics, tubular function, plasma electrolytes, and hormonal responses. Calcium entry blockers and angiotensin-converting enzyme (ACE) inhibitors are unique in that they may increase glomerular filtration rate (GFR) and renal blood flow in patients with hypertension. Both classes of drugs are distinctive in that they prevent salt retention because of their inhibitory effect on tubular sodium reabsorption. In addition to these attributes, which are desirable in terms of lowering systemic blood pressure, these 2 classes of drugs exert important intrarenal effects which may participate in limiting the progression of renal disease. ACE inhibitors have been shown to protect against the development of glomerulosclerosis in various experimental models of renal insufficiency. Importantly, there is emerging evidence from human studies supporting a distinctive beneficial effect of these agents on renal function in patients with hypertension, mild chronic renal insufficiency and diabetes mellitus.Calcium entry blockers have also been shown to exert some beneficial effect in limiting the progression of experimental kidney disease but neither an improvement in glomerular sclerosis nor a decrease in proteinuria have been clearly documented. At present ACE inhibitors appear the most attractive agents in terms of arresting the progression of renal disease.Acute deterioration in renal function may occur following the administration of ACE inhibitors, calcium entry blockers, and β-blockers. This complication should be considered in every patient on antihypertensive therapy who suffers an unexplained deterioration in renal function. In particular, the sudden deterioration in renal function following initiation of therapy with an ACE inhibitor is a clue to the possible presence of bilateral renal artery stenosis or stenosis of a solitary functioning kidney. Renal damage may also occur in patients with unilateral renal artery stenosis even though total (2-kidney) GFR may not be appreciably reduced. In this setting, a captopril renal scan with hippuran and diethylenetriamine pentaacetic acid (DTPA) provides physiological information regarding the renal blood flow and GFR of each kidney. In patients with unilateral renal artery stenosis the impact of ACE inhibitor therapy on GFR may be discerned by the use of the DTPA scan, which may demonstrate a reduction in GFR in the stenotic kidney that is not apparent by evaluation of total kidney GFR. This suggests that despite adequate control of systemic blood pressure and unchanged plasma creatinine progressive kidney damage in the stenotic kidney ensues.

Metabolic effects of converting enzyme inhibitors: Focus on the reduction of cholesterol and lipoprotein(a) by fosinopril

It is generally believed that the use of angiotensin-converting enzyme (ACE) inhibitors has no effect on the lipid profile. Our recent data show that in patients with proteinuric renal disease, serum levels of total cholesterol and lipoprotein(a) [Lp(a)] may be lowered during treatment with an ACE inhibitor, fosinopril sodium. During a 12-week randomized, placebo-controlled, double-blind study involving 26 patients with mild-to-moderate renal impairment, fosinopril administration was associated with significant decreases in both urinary protein excretion and serum total cholesterol levels, whereas placebo was not. During a 6-week washout phase, both parameters returned to baseline in fosinopril-treated patients and remained unchanged in placebo recipients. In addition, fosinopril-treated patients had a decrease in plasma levels of Lp(a), whereas this was not seen in placebo-treated patients. When data from a subset of 13 patients with proteinuric renal disease and hypertension were examined, a significant decrease in serum total cholesterol levels was observed; this decrease reversed after discontinuation of fosinopril. Analysis of the effect of fosinopril on plasma Lp(a) levels in a subset of patients who had type II diabetes mellitus and overt proteinuria revealed a significant decrease in plasma Lp(a) after administration of fosinopril. Moreover, fosinopril lowered plasma Lp(a) levels in blacks, whose pretreatment levels were higher than those of whites with comparable degrees of proteinuria and levels of serum total cholesterol. Thus, the reduction in serum Lp(a) levels may be related not only to amelioration of proteinuria, but also to another direct action of fosinopril on the metabolism of Lp(a).

Assessment of collecting tubule hydrogen ion secretion in acute respiratory alkalosis using the urinary pCO2

The use of the urine-blood (U-B) pCO2 difference as a marker of collecting tubule H+ secretion (CTH+S) faces serious interpretative pitfalls when applied to animals with respiratory acidosis. The present study was aimed to examine the use of this parameter in rats with acute respiratory alkalosis. During infusion of sodium bicarbonate, the U-B pCO2 was only slightly lower in hypocapnic than in eucapnic rats (30±2.2 and 39±3.3 mmHg,p<0.05) and this difference was no longer significant when this parameter was examined as a function of urine bicarbonate concentration. In contrast, the increment in urine pCO2 elicited by bicarbonate loading (i.e. the Δ pCO2) was markedly reduced in hypocapnic as compared to eucapnic rats (22±3.0 and 38±4.5 mmHg, respectively, p<0.01). The infusion of carbonic anhydrase while the urine was highly alkaline and the blood pCO2 kept constant resulted in a decrement in eurine pCO2 which was less in hypocapnic than in eucapnic rats (−23.9±1.9 vs −33±2.8 mmHg, p<0.02). These findings indicate that pCO2 generation from CTH+S and titration of bicarbonate is reduced in hypocapnic rats. The data are in accord with our proposal that the Δ pCO2 is a better index of CTH+S than the U-B pCO2 in the assessment of respiratory acid-base disorders.