John A. Opsahl

A comparison of coronary angioplasty and coronary artery bypass grafting outcomes in chronic dialysis patients

The objective of this study was to compare the outcomes of angina, myocardial infarction (MI), cardiac death, and all-cause death following percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass grafting (CABG). The study design was based on retrospective, nonrandomized analysis and was set in referral teaching hospitals and community hospitals. Eighty-four chronic dialysis patients with symptomatic coronary artery disease without prior revascularization were included in the study. Twenty-four patients underwent PTCA of one or more vessels, and 60 patients underwent CABG. Recurrence of angina, MI, cardiac death, and all-cause death following revascularization as well as the number of inpatient days preprocedure and postprocedure were recorded. The two patient groups were comparable in terms of age, sex, history of MI, left ventricular mass and function, and angina severity. Diabetes mellitus was more prevalent in the PTCA group. The CABG group had more severe coronary artery disease. The 2-year survival rate of the CABG patients (66%; 95% confidence interval = 53.79) did not differ from that of the PTCA patients (51%; 95% confidence interval = 27.65). Thirteen PTCA patients were restudied 106 +/- 108 days after recurrence of angina; nine (69%) of these patients were found to have angiographic restenosis. The postprocedure risk of angina and the combined endpoints of angina, MI, and cardiovascular death were significantly greater following PTCA than CABG. Percutaneous transluminal coronary angioplasty was the only consistent predictor of outcomes; the adjusted relative risks (compared with CABG) of postprocedure angina and combined endpoints were 16.4 and 10.2, respectively, and were several-fold higher than the unadjusted risks. We conclude that in chronic dialysis patients with symptomatic coronary disease, patients undergoing PTCA have a higher risk of subsequent angina and combined angina, MI, and cardiovascular death than those undergoing CABG. The optimal approach to coronary revascularization in this patient population remains to be determined.

Validity of creatinine clearance estimates in the assessment of renal function

In clinical practice, estimations of renal function are commonly used to calculate the appropriate dose for drugs that are renally cleared. Continuous‐infusion inulin clearance (CLIN), 4‐hour creatinine clearance (CLCR,m), and 24‐hour creatinine clearance (CLCR,a) were measured in 109 subjects (86 men and 23 women) with varying degrees of stable renal function (CLIN, 6 to 209 ml/min) and compared with CLCR values as predicted by five equations on the basis of plasma creatinine concentrations, age, weight, and/ or height. The CLCR,m was positively correlated with CLIN (r = 0.92; p < 0.0001) but exceeded CLIN by 15% between the range of 30 and 209 ml/min (CLIN). Similarly, CLCR,a correlated well with both CLCR,m (r = 0.84; p < 0.0005) and CLIN (r = 0.84; p < 0.0001). The relative role of tubular secretion in the overall clearance of creatinine increased with declining CLIN and exceeded 40% when CLIN was below 30 ml/min. CLCR estimated by the Cockcroft‐Gault and Mawer methods did not significantly differ from either CLCR,m or CLCR,a, whereas the other equations generally underestimated CLCR. Among the numerous mathematical equations, CLCR as estimated by the method proposed either by Mawer or Cockcroft and Gault was the best predictor of CLIN (CLIN = 1.05CLCR −18.38 or CLIN = 1.12CLCR −20.60, respectively; r = 0.81; p < 0.0001). The present data support the use of estimator equations proposed by Cockcroft and Gault or Mawer for rapid estimation of renal function in the clinical setting.

Effect of Bilateral Nephrectomy on Active Renin, Angiotensinogen, and Renin Glycoforms in Plasma and Myocardium

In an attempt to clarify the relationship of the circulating and myocardial renin-angiotensin systems, active renin concentration, its constituent major glycoforms (active renin glycoforms I through V), and angiotensinogen were measured in plasma and left ventricular homogenates from sodium-depleted rats under control conditions or 2 minutes, 3 hours, 6 hours, and 48 hours after bilateral nephrectomy (BNX). Control myocardial renin concentration was 1.4+/-0.1 ng angiotensin I (Ang I) per gram myocardium per hour and plasma renin concentration was 6.7+/-1.1 ng Ang I per milliliter plasma per hour. Control myocardial angiotensinogen was 0.042+/-0.004 micromol/kg myocardium and plasma angiotensinogen was 1.5 micromol/L plasma. Two minutes after BNX and corresponding stimulation of renin secretion by anesthesia and surgery, plasma renin concentration was increased disproportionately compared with myocardial renin. Three, 6, and 48 hours after BNX, renin decay occurred significantly faster from the plasma than from the myocardium. Forty-eight hours after BNX, myocardial renin concentrations had fallen to 15% of control values, while myocardial angiotensinogen concentrations had increased 12-fold and plasma angiotensinogen concentrations had increased by only 3.5-fold. Myocardial renin glycoform proportions were identical in myocardial homogenates and plasma in control animals. At 6 hours BNX, the proportions of plasma active renin glycoforms I+II fell, while those in the myocardium significantly increased. We conclude that in control rats, active renin and active renin glycoforms are distributed as if in diffusion equilibrium between plasma and the myocardial interstitial space. After BNX, myocardial renin concentration falls dramatically, suggesting that most cardiac renin is derived from plasma renin of renal origin. After BNX, renin glycoforms I+II are preferentially cleared from the plasma but preferentially retained by the myocardium. Control myocardial angiotensinogen concentrations are too low to result from simple diffusion equilibrium between plasma and the myocardial interstitium.

Coronary Artery Bypass Surgery in Patients on Maintenance Dialysis: Long-Term Survival

Coronary artery bypass grafting (CABG) can be performed with acceptable risk and results in symptomatic improvement in patients with end-stage renal disease (ESRD). However, the effect of CABG on long-term survival in these patients is unknown. We retrospectively identified 39 patients (group 1) with ESRD who underwent CABG for intractable angina between January 1975 and February 1987 while on maintenance dialysis. Thirty-nine dialysis patients (group 2) were also retrospectively selected for comparison and matched for age, sex, year of initiation, length of time on dialysis, and presence of diabetes mellitus and atherosclerotic heart disease at initiation of dialysis. Using life-table analysis, survival probability (with 95% confidence limits) was determined from the time of CABG for group 1 or after an equivalent period of time on dialysis for group 2. Two life-table analyses were performed; one with study end-points of death, withdrawal (renal transplantation, transfer to other dialysis facilities, and reoperation), and alive on dialysis; and a second with identical end points except that noncardiac deaths were treated as withdrawals. Coronary arteriography revealed severe three vessel disease, left ventricular dysfunction, and segmental wall motion abnormalities in most patients. A mean (+/- SD) of 2.56 +/- 0.75 vessels were bypassed with an operative mortality (30 days) of 2.6%. Mean follow-up after CABG in group 1 was 34.9 +/- 30.1 months, and in most patients functional classification improved. Mean follow-up for group 2 was 17.2 +/- 15.2 months. Two-year survival was 91.7% in group 1 and 51.4% in group 2 (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

A Review of Disorders of Water Homeostasis in Psychiatric Patients

Disorders of water homeostasis are common in psychiatric patients and include compulsive water drinking, the syndrome of inappropriate antidiuretic hormone secretion (SIADH), and the syndrome of self-induced water intoxication (SIWI). Although water intoxication was recognized nearly 70 years ago, the physiological basis of these disorders of water metabolism still remains elusive. This review will provide a historical overview, critique current studies on compulsive water drinking and SIWI, discuss possible etiologies, and present current approaches to treatment of these disorders. Because of the complexity of the subject, a review of normal water homeostasis and the SIADH will be included.

Pharmacokinetics and pharmacodynamics of codeine in end‐stage renal disease

The pharmacokinetics and pharmacodynamics of codeine and its metabolites codeine glucuronide, morphine, and morphine glucuronide were assessed after the administration of a single 60 mg oral dose of codeine sulfate and a single 60 mg intravenous dose of codeine phosphate in six healthy volunteers and six patients on chronic hemodialysis. Plasma and urine drug and metabolite concentrations were determined by sensitive and specific RIA procedures. Pharmacodynamics were assessed by pupillometry and vital sign determinations. Codeine elimination half‐life and mean residence time were increased significantly in the hemodialysis group (18.69 ± 9.03 hours and 12.77 ± 7.09 hours, mean ± SD, respectively) compared with the healthy volunteer group (4.04 ± 0.60 hours and 3.90 ± 0.52 hours, respectively). The total body clearance and volume of distribution of codeine were not significantly different between groups. Peak concentrations, times to peak concentrations, and AUCs for the three metabolites were also not significantly different between the groups, in part as a result of significant interpatient variability in the hemodialysis group. Examination of pupillometry and vital sign data did not reveal clinically significant differences in pharmacodynamics between the groups. Adjustment of dosage regimen may be required in some patients with uremia receiving multiple‐dose codeine therapy.

Effects of magnesium-aluminum hydroxide and calcium carbonate antacids on bioavailability of ofloxacin.

The effects of 15- and 5-ml doses of magnesium-aluminum hydroxide (MAH) and calcium carbonate (CC) antacids, respectively, on the bioavailability of ofloxacin after single oral 400-mg doses of ofloxacin were investigated in a 32-subject, randomized, crossover, open-label study. On four separate occasions, subjects received ofloxacin alone or antacid 24 h before, 2 h before, or 2 h after ofloxacin administration (n = 16 for each antacid). CC administration had no significant effect on the rate and extent of ofloxacin absorption regardless of the timing of antacid administration. A small but significant negative effect of MAH administration 2 h before ofloxacin administration was noted as evidenced by area under the curve and peak concentration in plasma data. Simultaneous administration of ofloxacin with either antacid was not investigated in this study. It appears that MAH and CC antacids in the doses used in this study generally do not interfere in a clinically significant manner with the bioavailability of ofloxacin, provided that an interval of at least 2 h separates the administration of these products.

Myocardial and plasma renin-angiotensinogen dynamics during pressure-induced cardiac hypertrophy

Plasma and left ventricular (LV) renin and angiotensinogen concentrations were assessed in a rat model of pressure-overload cardiac hypertrophy to determine if myocardial levels remained proportional to plasma levels over time. Three days after subdiaphragmatic aortic constriction (AC), LV hypertrophy was evident and renin concentrations in both plasma and LV, although not significantly elevated, were positively correlated with relative cardiac mass. After 42 days AC, LV hypertrophy remained, plasma and LV renin and angiotensinogen levels were not different from shams, and there was no correlation between renin and relative cardiac mass. Furthermore, LV renin and angiotensinogen concentrations remained at ∼25 and 4%, respectively, of those in plasma throughout the experiment. Myocytes from 3-day AC and sham-treated rats contained little renin as did LV from 48-h anephric rats. Incubations using calculated concentrations of myocardial interstitial renin and angiotensinogen revealed significant angiotensin I generation. These data suggest that LV renin in this model varies directly with plasma renin, is confined to the interstitial space, and can generate significant intramyocardial angiotensin I.Plasma and left ventricular (LV) renin and angiotensinogen concentrations were assessed in a rat model of pressure-overload cardiac hypertrophy to determine if myocardial levels remained proportional to plasma levels over time. Three days after subdiaphragmatic aortic constriction (AC), LV hypertrophy was evident and renin concentrations in both plasma and LV, although not significantly elevated, were positively correlated with relative cardiac mass. After 42 days AC, LV hypertrophy remained, plasma and LV renin and angiotensinogen levels were not different from shams, and there was no correlation between renin and relative cardiac mass. Furthermore, LV renin and angiotensinogen concentrations remained at approximately 25 and 4%, respectively, of those in plasma throughout the experiment. Myocytes from 3-day AC and sham-treated rats contained little renin as did LV from 48-h anephric rats. Incubations using calculated concentrations of myocardial interstitial renin and angiotensinogen revealed significant angiotensin I generation. These data suggest that LV renin in this model varies directly with plasma renin, is confined to the interstitial space, and can generate significant intramyocardial angiotensin I.

Body Fluid Spaces and Blood Pressure in Hemodialysis Patients During Amelioration of Anemia With Erythropoietin

Blood pressure (BP) may increase in hemodialysis patients during treatment of anemia with recombinant human erythropoietin (r-HuEPO). Since fluid volume is a determinant of BP in dialysis patients, changes in body fluid spaces during r-HuEPO therapy could affect BP. Thus, 51Cr-labeled red blood cell (RBC) volume, inulin extracellular fluid (ECF) volume, and urea total body water (TBW), as well as cardiac output, plasma renin activity (PRA), and plasma aldosterone concentration were determined postdialysis before and after r-HuEPO therapy in patients in whom changes in BP could be managed by ultrafiltration alone. Eleven patients entered the study: one had a renal transplant and two required addition of antihypertensive drug therapy and were excluded; eight, of whom two required antihypertensive drug therapy following the study, were included in the analyses. Results revealed an increase in predialysis hemoglobin from 67 to 113 g/L (6.7 to 11.3 g/dL) (P = 0.001) during 18 +/- 6 weeks of therapy. Predialysis diastolic BP increased from 80 to 85 mm Hg (P = 0.07), while postdialysis diastolic BP was unchanged at 73 mm Hg. 51Cr-RBC volume increased, from 0.7 to 1.3 L (P = 0.004). ECF tended to decrease, from 13.7 to 10.8 L (P = 0.064), while TBW decreased to a similar extent, but not significantly, 34.3 to 31.2 L (P = 0.16). Postdialysis ECF volume was positively correlated with mean arterial BP at baseline (r = 0.89, P = 0.007) and after therapy (r = 0.74, P = 0.035). However, the regression lines for this relationship were different (P = 0.022) before and after therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Active renin and angiotensinogen in cardiac interstitial fluid after myocardial infarction

The renin-angiotensin system promotes cardiac hypertrophy after myocardial infarction. The purpose of this study was to measure renin and angiotensinogen in plasma and myocardium 10 days after myocardial infarction. Infarction involving 45 +/- 4% of left ventricular circumference with accompanying hypertrophy was induced in rats (n = 14). Plasma and myocardial renin were increased after infarction compared with sham controls (n = 8) (27.4 +/- 3.2 vs. 7.5 +/- 1.8 ng ANG I. ml plasma. h-1, P < 0.0002; and 8.8 +/- 1.6 vs. 2. 5 +/- 0.1 ng ANG I. g myocardium-1. h-1, P < 0.008, respectively). After infarction, myocardial renin was correlated with infarct size (r = 0.62, P < 0.02) and plasma renin (r = 0.55, P < 0.04). Plasma angiotensinogen decreased in infarct animals, but myocardial angiotensinogen was not different from shams (1.1 +/- 0.08 vs. 2.03 +/- 0.06 nM/ml plasma, P < 0.002; and 0.081 +/- 0.008 vs. 0.070 +/- 0.004 nM/g myocardium, respectively). In conclusion, myocardial renin increased after infarction in proportion to plasma renin and infarct size, and myocardial angiotensinogen was maintained after infarction despite decreased plasma angiotensinogen and increased levels of myocardial renin.The renin-angiotensin system promotes cardiac hypertrophy after myocardial infarction. The purpose of this study was to measure renin and angiotensinogen in plasma and myocardium 10 days after myocardial infarction. Infarction involving 45 ± 4% of left ventricular circumference with accompanying hypertrophy was induced in rats ( n = 14). Plasma and myocardial renin were increased after infarction compared with sham controls ( n = 8) (27.4 ± 3.2 vs. 7.5 ± 1.8 ng ANG I ⋅ ml plasma ⋅ h-1, P < 0.0002; and 8.8 ± 1.6 vs. 2.5 ± 0.1 ng ANG I ⋅ g myocardium-1 ⋅ h-1, P < 0.008, respectively). After infarction, myocardial renin was correlated with infarct size ( r = 0.62, P < 0.02) and plasma renin ( r = 0.55, P < 0.04). Plasma angiotensinogen decreased in infarct animals, but myocardial angiotensinogen was not different from shams (1.1 ± 0.08 vs. 2.03 ± 0.06 nM/ml plasma, P < 0.002; and 0.081 ± 0.008 vs. 0.070 ± 0.004 nM/g myocardium, respectively). In conclusion, myocardial renin increased after infarction in proportion to plasma renin and infarct size, and myocardial angiotensinogen was maintained after infarction despite decreased plasma angiotensinogen and increased levels of myocardial renin.