John H. Bauer

Clinical Appraisal of Creatinine Clearance as a Measurement of Glomerular Filtration Rate

The plasma creatinine and the endogenous creatinine clearances are two of the most commonly used tests in clinical medicine to assess glomerular filtration rate. However, the contribution that tubular secretion of creatinine has on the total endogenous creatinine clearance (Ccr) is not generally known, nor are the effects renal insufficiency has on the tubular secretion of creatinine. To assess the above, 123 human subjects, with a wide range of renal function, underwent simultaneous Ccr and inulin clearances (Cin). The results indicate that: (1) Ccr approximates Cin only when Cin is normal; (2) a normal plasma creatinine of Ccr is not measurable evidence of a normal Cin; and (3) with progressive decline in Cin, there is progressive increase in the tubular secretion of creatinine, leading to a progressive disparity between Ccr and Cin.

The long-term effect of propranolol therapy on renal function

Abstract It has been reported that the intravenous administration of beta blocking agents reduces renal plasma flow and glomerular filtration rate from 10 to 20 per cent. In contrast, little is known about the chronic effects of these agents on renal function when given orally. To assess this question, eight normal subjects underwent timed true and regular creatinine clearances (C cr ), inulin clearances (C in ) and para-amino hippurate clearances (C PAH ) after sequential weeks of therapy with 0, 80, 160, 240 and 320 mg of propranolol/day. Weight, blood pressure and heart rate were measured on each visit. Compliance was tested and confirmed by monitoring plasma propranolol concentrations. The results indicate that the use of propranolol in normal man significantly reduces C in (27 per cent) and C PAH (26 per cent). Such decreases are probably, in part, due to reductions in cardiac output, as suggested by reductions in systolic blood pressure and heart rate. Furthermore, there was a sustained reduction in C in following the withdrawal of propranolol therapy. C cr technics did not reflect the magnitude of the reduction in glomerular filtration rate. The fractional excretion of creatinine demonstrated a significant inverse relationship to C in , suggesting that creatinine secretion is increased with propranolol. We conclude that propranolol therapy results in prolonged changes in glomerular filtration rate, which may not revert to normal following its withdrawal.

Short- and long-term effects of calcium entry blockers on the kidney

The renal effects of the calcium entry-blocking drugs diltiazem, nifedipine, nitrendipine, nicardipine and verapamil are reviewed. Although nifedipine may acutely increase plasma renin activity, most of the calcium entry blockers have no sustained effect on any of the components of the renin-angiotensin-aldosterone system. Although all of the calcium entry blockers effectively lower blood pressure, none adversely affects renal function: Glomerular filtration rate and effective renal plasma flow are maintained. Diltiazem may increase glomerular filtration rate via attenuation of the intrarenal effects of angiotensin II or norepinephrine. Although all of the calcium entry blockers acutely increase salt and water excretion, most of the calcium entry blockers have no clinically sustained effect on salt and water excretion; serum electrolytes, urinary sodium and potassium excretion, body fluid composition and body weight are usually unchanged. Calcium entry blockers can be expected to assume a prominent role in the treatment of hypertension because of their ability to lower blood pressure while preserving renal perfusion and function.

Age-Related Changes in the Renin-Aldosterone System

SummaryAge-related changes in the renin-aldosterone system in normal humans are well documented. The most pronounced changes are observed at the extremes of life: plasma renin activity and plasma aldosterone levels are highest in the newborn, and lowest in the elderly population. There is a close temporal and directional relationship between the age-related decrease in plasma renin activity and the age-related decrease in plasma aldosterone. The renin-aldosterone system is also influenced by sex and race.The activation of the renin-aldosterone system in newborns and infants probably represents an important physiological mechanism designed to maintain positive sodium balance. The decreases in plasma renin activity and plasma aldosterone levels observed in elderly persons are usually only modest, and are not associated with clinical alterations in fluid or electrolyte metabolism. The superimposition of a disease process, or the injudicious prescription of a drug, inhibiting renin release or angiotensin II production, could theoretically facilitate sodium wasting in newborns or infants, or precipitate hyporeninaemic hypoaldosteronism in older adults.The primary clinical importance of age-related changes in the renin-aldosterone system relates to its impact on the proper classification of an individual’s renin-aldosterone profile when attempting to diagnose a clinical condition (e.g. low, normal or high renin hypertension). This is particularly true for newborns, infants and children to age 4, and for adults entering the sixth decade of life.

Effects of calcium entry blockers on renin-angiotensin-aldosterone system, renal function and hemodynamics, salt and water excretion and body fluid composition

The renal effects of the calcium entry-blocking drugs diltiazem, nifedipine, verapamil and nitrendipine are reviewed. Although nifedipine stimulates plasma renin activity on a short-term basis, none of the calcium entry blockers produces a clinically significant sustained effect on any of the components of the renin-angiotensin-aldosterone system. Although all of the calcium entry blockers effectively lower blood pressure, none adversely affects renal function; glomerular filtration rate and effective renal plasma flow are maintained. Diltiazem may increase glomerular filtration rate via attenuation of the intrarenal effects of angiotensin II or norepinephrine. Although diltiazem and nifedipine increase salt and water excretion on a short-term basis, none of the calcium entry blockers produces a clinically significant sustained effect on salt and water excretion; serum electrolytes, urinary sodium and potassium excretion, body fluid composition and body weight are unchanged. Thus, calcium entry blockers can be expected to assume a prominent role in the treatment of hypertension because of their ability to lower blood pressure while preserving renal perfusion and function.

Propranolol in human plasma and breast milk

To assess the problem of continuing propranolol therapy in a breast-feeding mother, studies were performed to determine simultaneously plasma and breast milk concentrations of propranolol after single dose (40 mg) and continuous dose (40 mg 4 times daily) treatment with this drug. Breast milk and plasma concentrations of propranolol peaked between 2 and 3 hours after dosing. Propranolol concentrations in breast milk were less than 40 and 64 percent, respectively, of peak plasma propranolol concentrations after single dose and continuous dose administration. It was estimated that the maximal cumulative propranolol load to this breast-feeding infant, consuming 500 ml of whole milk, when the mother received 40 mg of propranolol 4 times daily would be 21 microgram/24 hours. This dose is considerably less than the usual therapeutic dose of propranolol for infants.

A Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Effect of Enalapril in Patients With Clinical Diabetic Nephropathy

It is unknown if the antiproteinuric effect of angiotensin-converting enzyme (ACE) inhibitors reflects attenuation in the rate of progression of diabetic nephropathy. We report the results of a randomized, double-blind clinical trial designed to evaluate the longitudinal (18-month) effect of the ACE inhibitor, enalapril (5 to 40 mg/d), versus a placebo on 24-hour urinary protein excretion and on the rate of progression of renal disease in 33 patients with clinical diabetic nephropathy. Systemic blood pressure was controlled throughout the trial with conventional antihypertensive drugs. Glomerular filtration rate (GFR), determined by Tc99mDTPA renal clearance, and urinary protein excretion were monitored at 3-month intervals. Enalapril, in contrast to placebo therapy, was associated with an initial (40%) and sustained (33%) decrease in urinary protein excretion. Patients randomized to both enalapril or placebo experienced mean decreases in GFR, from 1.01 mL/s/1.73 m2 (61 mL/min/1.73 m2) to 0.85 mL/s/1.73 m2 (51 mL/min/1.73 m2), and from 1.06 mL/s/1.73 m2 (64 mL/min/1.73 m2) to 0.97 mL/s/1.73 m2 (58 mL/min/1.73 m2), respectively. Eleven of 18 patients (61%) randomized to enalapril, and 10 of 15 (66%) patients randomized to placebo, had a decrease in GFR; their rates of progression were -1.18 mL/min/1.73 m2/mo and -1.00 mL/min/1.73 m2/mo, respectively. In the absence of changes in blood pressure, the addition of an ACE inhibitor to patients with clinical diabetic nephropathy could not be shown to confer a unique renal protective effect. A prolonged decrease in 24-hour protein excretion could not be shown to predict attenuation in the progression of established clinical diabetic nephropathy.

Role of Angiotensin Converting Enzyme Inhibitors in Essential and Renal Hypertension: Effects of Captopril and Enalapril on Renin-Angiotensin-Aldosterone, Renal Function and Hemodynamics, Salt and Water Excretion, and Body Fluid Composition

Among the many generic classes of drugs currently being used for the treatment of hypertension, few, following long-term therapy, improve or correct the underlying renal function and hemodynamic abnormalities encountered in patients with sustained hypertension. This review focuses on the renal effects of the angiotensin converting enzyme inhibitors captopril and enalapril. Each drug is discussed in terms of its short- and long-term effects on the renin-angiotensin-aldosterone system, renal function and hemodynamics, salt and water excretion, and body fluid composition. Data are presented that demonstrate that enalapril, used alone or in combination with diuretic therapy, has the unique ability to control hypertension, to improve glomerular filtration rate and effective renal plasma/renal blood flow, and to decrease renal vascular resistance, without producing adverse effects on salt and water excretion or body fluid composition. If the safety of enalapril is confirmed in long-term studies, the drug will clearly assume a prominent role as either first- or second-step (in combination with a diuretic) therapy in the treatment of hypertension.

Renal effects of diltiazem in primary hypertension.

Although the calcium channel blocker diltiazem has been shown to be an effective antihypertensive agent, its effect on renal function, salt and water excretion, and body fluid composition has not been well characterized in patients with primary hypertension. Therefore, these parameters were prospectively studied in 18 subjects with primary hypertension after placebo and 8 weeks of diltiazem monotherapy. Diltiazem monotherapy was confirmed to be an effective antihypertensive agent. Although mean arterial pressure was reduced from 121 to 108 mm Hg, diltiazem had no overall effect on glomerular filtration rate, renal plasma blood flow, salt and water excretion, or body fluid composition. Renal vascular resistance, however, was decreased. In subjects with pretreatment glomerular filtration rates of 80 ml/min/1.73 m2 or less, diltiazem therapy was associated with marked improvement in glomerular filtration rate (48%) and effective renal plasma flow (36%). Since the filtration fraction was unchanged, changes in glomerular filtration rate may have been related to the attenuated intrarenal effects of angiotensin II or norepinephrine, or both.

Amlodipine Therapy Corrects Renal Abnormalities Encountered in the Hypertensive State

Calcium antagonists may increase glomerular filtration rate and renal plasma flow by antagonizing the intrarenal effects of angiotensin II and/or norepinephrine. We prospectively studied the effects of amlodipine, a once-a-day dihydropyridine calcium channel antagonist, in 19 patients with essential hypertension. Studies were performed after 4 weeks of placebo and 6 weeks of amlodipine therapy, and included the assessment of systolic and diastolic BP, renal clearances of inulin and p-aminohippurate, and determination of body fluid composition. Systolic and diastolic BPs were reduced following 6 weeks of amlodipine monotherapy. In spite of significant decreases in mean arterial pressure, there were increases in inulin clearance (+ 13%), and p-aminohippurate clearance (+ 19%). Filtration fraction was not changed. Renal vascular resistance was decreased (-25%). Total blood volume, extracellular fluid volume, and total body water and body weight were not changed. We conclude that amlodipine therapy has the potential to reverse renal abnormalities encountered in the hypertensive state.