Renin-secreting clear cell carcinoma of the kidney.

A young woman with mild to moderate hypertension and normal PRA, serum potassium levels, and urinary aldosterone excretion rate was found to have a renal tumor by selective renal arteriogram. Renal vein renin activity indicated an increased production of renin from the kidney containing the tumor. At surgery, a clear cell carcinoma of the kidney was found that contained renin activity in excess of the surrounding kidney tissue. The renin activity appeared identical to human kidney renin. Previous renin-producing tumors have been associated with severe hypertension, elevated plasma renin activity, hypokalemia, and elevated urinary aldosterone excretion. This case should call attention to the renin-secreting tumor as a cause of even mild hypertension.

Papilledema in two patients with acromegaly and intrasellar pituitary tumors.

Two patients had bilateral papilledema complicating acromegaly. Both patients had enlarged blind spots, but otherwise visual fields were normal. Suprasellar extension of the pituitary tumors was diligently sought with the use of visual field examination, pneumoencephalography, internal carotid arteriography, and computed axial tomography, and tumor extension did not exist. Transphenoidal and transethmoidal routes were used to perform partial hypophysectomies in these patients. The procedure was completely successful in one patient and partially successful in the other patient. After hypophysectomy, papilledema resolved in both patients. This beneficial effect may be the result of anatomical changes, the reduction in growth hormone levels, or both. These observations suggest that the acromegaly may be different from papilledema that occurs secondary to suprasellar expansion of pituitary tumors.

The prediction of anatomical morphology of primary aldosteronism using serum 18-hydroxycorticosterone levels.

Serum 18-hydroxycorticosterone, aldosterone, and potassium were measured under basal conditions in 34 patients with documented primary aldosteronism, 10 patients with essential hypertension, and 9 normal subjects. The results revealed that 22 of 23 patients with aldosterone-producing adenomas had 18-hydroxycorticosterone levels greater than 100 ng/dl, and all 9 patients with idiopathic adrenal hyperplasia had plasma levels less than 100 ng/dl. Two patients with unusual macromicronodular hyperplasia of the adrenal glands had levels greater than 100 ng/dl. We found a significant relationship between serum potassium and the ratio of 18-hydroxycorticosterone to aldosterone in patients with idiopathic adrenal hyperplasia, but not in those with an aldosterone-producing adenoma. We conclude that measurement of serum 18-hydroxycorticosterone is a useful predictor of the etiology of primary aldosteronism.

Alterations in the responses of the sympathetic nervous system and renin in borderline hypertension.

We investigated the effect of stimuli activate the sympathetic nervous system on plasma catecholamines, renin activity, urinary metanephrine and normetanephrine, and various hemodynamic parameters in normal subjects (NIs) and borderline hypertensive (BH) subjects. No differences were observed in sympathetic nervous system activity or renin activity when the subjects were in the resting state on a 150 mEq sodium diet. However, the BH group exhibited greater responses in terms of plasma catecholamines and plasma renin activity in response to sodium deprivation and treadmill exercise. Although hemodynamic differences in the cold pressor test and handgrip exercise did not emerge, the radio of atrial size decrement to venous tone increment during the Valsalva maneuver was significantly reduced in the BH group. The investigations suggest that in the basal state, BH subjects have appropriate levels of activation of the sympathetic and renin systems for a normal level of pressure but that perturbations of pressure and volume factors lead to unmasking of abnormalities in regulation of both systems. The data are also consistent with the suggestion that venous compliance is reduced in these patients.

Plasma binding and the affinity of propranolol for a beta receptor in man.

The effects of plasma drug binding on the relationship between propranolol concentration and the antagonism of isoproterenol tachycardia have been investigated in 8 normal subjects and 8 hypertensive patients. During chronic intravenous infusion of propranolol giving a narrow range of total plasma concentrations (22.5 to 50 ng/ml), there was, at best, a poor correlation with effects. On the other hand, there was excellent correlation between efficacy and free drug concentration, which fitted the predictions of the receptor theory of competitive antagonism. The true affinity constant for the binding of propranolol to its receptor can be calculated in terms of free drug concentration (KAfree) and was found to vary 2-fold compared to the affinity constant in terms of total plasma concentration (KAtotal) which varied 4-fold, the greater variation being due to plasma binding differences. Compared to normal subjects, KAfree and KAtotal were smaller in hypertensive subjects, implying lesser sensitivity to the drug, and plasma propranolol binding was greater. There was no difference in KAfree between high- and low-renin essential hypertensives, but KAtotal was smaller in the high-renin group due to increased plasma binding which did not reach statistical significance. It is concluded that the effect of propranolol on heart rate is a predictable function of free drug concentration in man and that the contribution of individual variation in receptor sensitivity to differences in oral dosage requirement is minor compared to that of variations in bioavailability.

The effects of benazepril, a new angiotensin-converting enzyme inhibitor, in mild to moderate essential hypertension: a multicenter study.

Benazepril hydrochloride is a new angiotensin-converting enzyme inhibitor. In a multicenter study, 206 patients with mild to moderate hypertension were randomized to receive benazepril at a dose of 2, 5, 10, or 20 mg, hydrochlorothiazide, 25 mg, or placebo once daily for 4 weeks. The 20 mg dosage of benazepril lowered blood pressure to a degree equal to that of 25 mg hydrochlorothiazide: -12.2/7.7 mm Hg and -13.4/-7.5 mm Hg, respectively. Hydrochlorothiazide proved to be more effective in black subjects. At lower dosage levels of benazepril (2, 5, and 10 mg), blood pressure reduction was not significantly different from that with placebo. In those patients who failed to achieve goal diastolic blood pressure of less than 90 mm Hg with monotherapy after 4 weeks, the addition of open-label hydrochlorothiazide (25 mg/day) to benazepril, hydrochlorothiazide, or placebo produced a substantial additional decrease in blood pressure over a 2-week period. No definite adverse effects on hematologic measurements, serum biochemistry test results, or urinalyses were noted. Subjective adverse experiences were common in all groups but except in three or possibly four instances were not considered causally related to the study drug.

Thiazide treatment of hypertension. Effects of thiazide diuretics on serum potassium, magnesium, and ventricular ectopy.

Thiazide diuretics are considered to be the cornerstone of contemporary antihypertensive therapy and are generally recommended as the initial treatment for patients with mild to moderate, uncomplicated hypertension. Hypokalemia and hypomagnesemia are two metabolic alterations that are associated with long-term thiazide therapy. Thirty-five patients (20 with low renin status and 15 with normal renin status) with mild to moderate essential hypertension were treated with hydrochlorothiazide in a dose-titration experiment after a four-week lead-in period. The initial daily dose was 12.5 mg; this was increased at four-week intervals to 25 mg, 37.5 mg, and 50 mg daily. The endpoint dose of this titration was that dose at which the patient's blood pressure normalized, or the dose of 50 mg, if that dose was reached. Patients were maintained on their endpoint dose of hydrochlorothiazide for 24 weeks of continuous thiazide monotherapy beyond the dose titration. The serum potassium and serum magnesium levels during the control period were 4.4 +/- 0.2 mmol/liter and 2.30 +/- 0.08 mg/dl, respectively. During dose titration, each incremental increase of hydrochlorothiazide produced a decrease in blood pressure and a stepwise decrease in serum potassium and magnesium levels. A previously reported study involving 38 patients with mild to moderate hypertension (22 with low renin status and 16 with normal renin status) used similar methods to study higher-dose thiazide therapy. An initial dose of 50 mg daily of hydrochlorothiazide was administered; this was increased at four-week intervals to 100 mg, 150 mg, and 200 mg. The serum potassium and serum magnesium levels during the control period were 4.5 +/- 0.2 mmol/liter and 2.1 +/- 0.18 mg/dl, respectively. In the hypertensive patients with normal renin status, doses of hydrochlorothiazide greater than 50 mg did not result in further blood pressure lowering effects; however, the undesirable effects of hypokalemia and hypomagnesemia continued to be manifested and increased at higher doses of hydrochlorothiazide. Thirty-eight patients who had previously experienced hypokalemia, palpitations, or cardiac arrhythmia were placed on hydroclorothiazide therapy for one to three months and were monitored for arrhythmias after treadmill exercise. The occurrence of premature ventricular contractions correlated significantly with the decrease in serum potassium (r = 0.73, p less than 0.001) and serum magnesium (r = 0.68, p less than 0.001) levels during hydrochlorothiazide therapy and with the product of the change of the two cations (r = 0.81, p less than 0.001).

Magnesium depletion, diuretics, and arrhythmias.

Increasing information on the potentially serious risks of potassium and magnesium depletion associated with diuretic therapy demands a clinical focus on understanding the factors involved and on methods for preventing these electrolyte deficiencies. Data suggest that serum potassium and magnesium levels may be normal in the presence of tissue depletion, but decreases in serum levels are almost always associated with tissue and whole-body depletion of these electrolytes in patients in whom such depletion cannot be risked. Ventricular ectopy has also been associated with depletion of potassium and magnesium, which may explain the increased risk of sudden unexpected death in hypertensive patients. Any clinician who treats hypertension or congestive heart failure must consider whether to replete potassium and magnesium in patients already receiving diuretic therapy, or, better still, consider how to prevent depletion of these electrolytes in patients in whom such depletion cannot be risked. If prevention is selected, the clinician must then evaluate the data on available diuretic combinations for efficacy in electrolyte conservation, bioavailability, and dosage convenience. The combination of triamterene and hydrochlorothiazide (Maxzide, 75 mg triamterene/50 mg hydrochlorothiazide) has demonstrated electrolyte conservation, with bioavailability and dosage convenience.

Potassium and magnesium abnormalities: diuretics and arrhythmias in hypertension.

Thiazide diuretics are widely accepted as the cornerstone of antihypertensive treatment programs. Hypokalemia is a commonly encountered metabolic consequence of long-term thiazide therapy but the effect of thiazide on serum magnesium is less well known. Thirty-eight patients (22 low renin, 16 normal renin) with moderate diastolic hypertension were treated with hydrochlorothiazide administered twice a day. The initial daily dose was 50 mg; this was increased at four week intervals to 50 mg, 100 mg, 150 mg, and 200 mg. Dose escalation was discontinued when either normalization blood pressure was attained or the 200 mg dose level was reached. Patients were then maintained with their hydrochlorothiazide dose for 24 weeks of continuous thiazide monotherapy. The serum potassium during the control period was 4.5 +/- 0.2 mmol/liter. During dose escalation and long-term maintenance therapy, the serum potassium and magnesium levels fell in a step wise, dose-dependent fashion. In another 38-patient study, the effects of hydrochlorothiazide therapy (100 mg daily) on the occurrence of premature ventricular contractions were observed during rest as well as during static and dynamic exercise. During rest 0.6 +/- 0.08 premature ventricular contractions per minute (mean +/- SEM) were observed, and during dynamic exercise 0.8 +/- 0.15 premature ventricular contractions per minute. During hydrochlorothiazide therapy (50 or 100 mg per day) premature ventricular contractions per minute were 1.4 and 5.7, respectively. The occurrence of premature ventricular contractions correlated significantly with the decrease observed in serum potassium (r = 0.71, p less than 0.001) and in serum magnesium (r = 0.68, p less than 0.001). Thiazide therapy appears to cause both potassium and magnesium depletion, and decreases in both correlate well with the appearance of ventricular ectopic depolarizations.

Serum magnesium and potassium levels in hypertensive patients after a therapeutic switch from hydrochlorothiazide plus a potassium supplement to maxzide.

Determinations of serum magnesium and potassium levels and blood pressure were made in 40 hypertensive patients in whom daily therapy with 50 mg of hydrochlorothiazide plus potassium supplements was switched to a once-daily regimen of 50 mg of hydrochlorothiazide plus 75 mg of triamterene (Maxzide). Patients showed no clinically significant changes in blood pressure or in serum magnesium or serum potassium values following the switch. It is concluded that therapy in patients receiving hydrochlorothiazide and up to 60 meq of potassium can be safely switched to Maxzide without adversely affecting serum magnesium levels, serum potassium levels, or blood pressure control.

Sustained hypertension after section of the glossopharyngeal nerve.

A case of sustained hypertension produced by unilateral section of the glossopharyngeal nerve is reported. Special tests revealed baroreceptor dysfunction. The hypertension was responsive to propranolol therapy. Review of the literature revealed no other documented cases of sustained hypertension although transient hypertension is common.

Differentiation between malignant and benign solitary thyroid nodules by fluorescent scanning.

A quantitative fluorescent technique has been developed for making in vivo iodine content determinations of the total thyroid gland or of selected parts. In solitary thyroid nodules "cold" to radionuclide studies, the ratio of iodine content in the nodule to that in a corresponding area of the contralateral lobe has proven to be a good indicator of malignancy. In a preliminary study of 42 surgical patients, an iodine content ratio (ICR) below 0.60 (chosen a posteriori) proved to be an excellent indication of malignancy with a sensitivity of 100%, a specificity (predictive value) of 79%, and an overall accuracy of 90%. Further definitive studies are needed to verify these preliminary observations.

Thiazide treatment of systemic hypertension: effects on serum magnesium and ventricular ectopic activity.

Clinical and investigational evidence has proved an association between thiazide-induced electrolyte imbalances and ventricular arrhythmias. It is hypothesized that this increases the potential for sudden unexplained death. Elderly hypertensive patients are at particular risk because of their tendency to have significantly depressed serum magnesium levels, which decrease even further when treated with thiazide diuretics. Potassium supplementation does not effectively restore electrolyte balance unless accompanied by magnesium. Therefore, concomitant administration of potassium and magnesium supplementation appears to be an approach to reducing the risk of arrhythmias and death in thiazide-treated hypertensive patients.

Electrolyte disarray and cardiovascular disease.

Thiazide diuretics have frequently been recommended as initial therapy in patients with mild to moderate hypertension. However, their undesirable metabolic consequences have been suspected of contributing to increases in cardiovascular morbidity and mortality. Even at low doses, there is a definite decrease in both potassium and magnesium levels. The degree of decrease in potassium and magnesium levels has been shown to be directly related to the hydrochlorothiazide dosage. Many investigators have now reported an increase in ventricular ectopy associated with diuretic-induced hypokalemia. Whereas there is no single study that conclusively proves that thiazide therapy results in malignant arrhythmias and an increased risk of sudden death, the circumstantial evidence is strong. Although sodium restriction is critical to potassium restoration, it rarely works alone. Potassium chloride supplementation can be effective in restoring potassium but not magnesium. Potassium-sparing diuretic combinations can both prevent and treat hypokalemia and hypomagnesemia, possibly reducing the risk of potentially lethal arrhythmias and sudden death.

Are there unknown mineralocorticoids in low-renin essential hypertension?

The blood pressure elevation of primary aldosteronism is caused by excessive production of the known mineralocorticoid, aldosterone. The blood pressure elevation of low-renin essential hypertension may also be caused by mineralocorticoid excess, but which which mineralocorticoid is responsible is uncertain. Normal levels of aldosterone, found in this disorder despite suppressed plasma renin, and the presence of an unknown mineralocorticoid have been hypothesized to explain low-renin essential hypertension. We contrasted the blood pressure responses and changes in aldosterone seen in patients with low-renin essential hypertension and primary aldosteronism during treatment with two adrenal enzyme inhibitors. The results demonstrate the similarity between decrease in blood pressure and in aldosterone during early adrenal inhibition in both primary aldosteronism and in low-renin essential hypertension. During treatment with a distal adrenal blocker, patients with primary aldosteronism demonstrated decreases in both aldosterone and blood pressure, whereas patients with low-renin essential hypertension showed a decrease in aldosterone without significant change in blood pressure. This suggested that aldosterone was not the major mineralocorticoid responsible for low-renin essential hypertension. Unknown mineralocorticoid excretion decreased (along with blood pressure) during early inhibition but failed to decrease (along with blood pressure) during late inhibition at a time when aldosterone excretion decreased. This suggests that unknown mineralocorticoids play significant roles in the blood pressure elevation of low-renin essential hypertension.

Prognostic factors in adrenal cortical tumors. A mathematical analysis of clinical and morphologic data.

Forty-one patients with adrenal cortical tumors were evaluated retrospectively for the presence of histologic and non-histologic features associated with malignant behavior. The patients who survived operation were followed at least five years. The association of these features with subsequent metastasis was examined by both parametric and nonparametric statistical methods. Twelve criteria were statistically significant in predicting subsequent metastasis. The most significant of these were: clinical evidence of weight loss, broad fibrous bands traversing the tumor, a diffuse growth pattern, vascular invasion, tumor cell necrosis, and tumor mass. The tendency toward metastasis for each tumor was expressed in indices that correlated well with diagnoses made by conventional histologic means, but were more accurate in predicting subsequent clinical behavior than nonquantitative methods of evaluation.

Bilateral renal artery stenosis and renovascular hypertension.

Experience with the diagnostic evaluation and operative management of 38 hypertensive patients having bilateral renal revascularization is presented. Twenty-four patients had atherosclerotic occlusions and 14 had fibromuscular dysplasia. Renal vein renin assays (RVRA) and/or split renal function studies (SRFS) were performed in 37 of the 38 patients before operation. Although RVRA was negative in 29 percent and SRFS negative in 31 percent, 24 of 26 patients (92 percent) having both tests done had at least one positive study. Twenty-one patients had simultaneous bilateral repairs and 12 had staged bilateral reconstructions. The incidence of technical failures in these two groups was 21 and 9 percent, respectively. Excluding three uncorrected technical failures and two patients with recurrent branch renal artery lesions, 90 percent of patients with atherosclerosis and all patients with fibromuscular dysplasia had a favorable blood pressure response to operation. This study supports the use of both RVRA and SRFS in the diagnostic evaluation of hypertensive patients with renal artery stenosis. If these functional tests lateralize to one side, repair of that side only is recommended. If the functional studies do not lateralize, operation is suggested only when hypertension is severe and is not controlled readily with medications. In this circumstance reconstruction of the side that appears to be diseased most severely is recommended. Contralateral repair is undertaken only when hypertension persists and when repeat functional studies lateralize to the unoperated side.

Revascularization of the poorly functioning kidney.

The effect of renal vascularization on renal function in kidneys with poor preoperative excretory function is summarized in this report. Twenty-five patients with kidneys having preoperative creatinine clearance of less than 30 ml/min, as determined during split renal function studies (SRFS), which were revascularized for treatment of secondary renovascular hypertension and then were reevaluated by repeat SRFS form the basis of this report. There were 13 male and 12 female patients. The type of renal artery lesion was atherosclerotic in 21 patients and fibromuscular dysplastic in four patients. Eight individuals had total renal artery occlusion. Significant contralateral renal artery disease was present in 15 patients (60%). Preoperative creatinine clearances in the affected kidneys ranged from 0.27 ml/min (mean, 16 +/- 9 ml/min). after operation, creatinine clearances ranged from 0 to 72 ml/min (mean, 32 +/- 16 ml/mn). Fifteen of the 16 kidneys with preoperative creatinine clearances less than 20 ml/min had improvement in renal function following revascularization (P less than 0.01). Improvement (60%) or cure (36%) in hypertension followed revascularization in 24 of the 25 patients. The most dependable predictor of successful management of both hypertension and retrieval of renal function in these patients was the arteriographic demonstration of a patent distal vessel without evidence of severe intrarenal stenoses. These results support an aggressive attitude toward the use of revascularization in the operative treatment of such patients with renovascular hypertension, even when the residual excretory function is minimal or absent.

Renovascular hypertension: anatomic and renal function changes during drug therapy.

Serial renal function studies were performed on 41 patients wtih renovascular hypertension (RVH) secondary to atherosclerotic renal artery disease who had been randomly selected for nonoperative management. In 19 patients, serum creatinine levels increased between 25% and 120%. The glomerular filtration rates dropped between 25% and 50% in 12 patients. Fourteen patients (37%) lost more than 10% of renal length. In four patients (12%), a significant stenosis progressed to total occlusion. Seventeen patients (41%) had deterioration of renal function or loss of renal size that led to operation. One patient required removal of a previously reconstructible kidney. Of the 17 patients with deterioration, 15 had acceptable blood pressure (BP) control during the period of nonoperative observation. Progressive deterioration of renal function in nonoperatively treated patients with atherosclerotic renal artery stenosis and RVH is common, and occurs even in the presence of BP control with drugs.

Effect of some organic acids in the incubation step on plasma renin activity.

The organic acids potassium hydrogen phthalate (KHphthalate), maleic, critic, acetic, formic, and oxalic were used to adjust the pH of plasma to 5.6 +/- 0.2 in the incubation step of the procedure for the determination of plasma renin activity (PRA). When compared to the PRA determined after pH adjustment with hydrochloric acid (HCl), it was found that KHphthalate and maleic acid produced a statistically significant increase in PRA. In comparison to HCl, KHphthalate and maleic acid showed a mean percent difference of 61% and 27% respectively for a one hour incubation; and, 57% and 34% respectively for a three hour incubation.