The effect of altered sodium concentration in the distal nephron segments on renin release.

Ethacrynic acid, a potent inhibitor of sodium reabsorption in the ascending limb of Henle's loop, produces a sharp rise in renal venous renin activity within 5 min after intravenous administration in anesthetized dogs. This response persists when volume depletion is prevented by returning urinary outflow to the femoral vein. Comparable studies with chlorothiazide, a diuretic with little or no effect on the medullary portion of the ascending limb of the loop of Henle, failed to produce a significant increase in renal venous renin activity.When administered during ureteral occlusion, ethacrynic acid produced no change in renal venous renin activity until ureteral occlusion was released and flow restored. Following release of the ureters, a prompt rise in renal venous renin was again observed within 5 min of release. Control studies of ureteral occlusion yielded a fall in renal venous renin activity following release of the ureter without administration of ethacrynic acid. These studies identify a prompt stimulatory effect of ethacrynic acid on renin release that is unrelated to volume depletion but dependent upon the presence of tubular urine flow. Although further definition of the site and characteristics of the distal tubular mechanism for stimulation of renin release requires more direct study, the data presented here indicate that changes in sodium concentration in distal tubular fluid serve as a stimulus for renin release.

Modulation of plasma aldosterone concentration by plasma potassium in anephric man in the absence of a change in potassium balance.

In studies on seven anephric patients, glucose and insulin administration before hemodialysis produced a significant reduction in plasma potassium concentration (mean reduction = 1.3, 1.7, and 1.4 meq/liter at 60, 120, and 180 min, respectively) which was accompanied by a significant and sustained reduction in plasma aldosterone concentration. There was a significant correlation between plasma aldosterone and plasma potassium concentration (r = +0.74, P < 0.001) and between changes in the concentration of plasma aldosterone occurring in individual patients and the corresponding changes in plasma potassium concentration (r = +0.52, P < 0.01). There was no significant change in plasma sodium concentration, and plasma corticoid concentration, which was monitored as an index of ACTH elaboration, was reduced at 60 min but increased subsequently as symptoms attributable to hypoglycemia were observed. These studies demonstrate that plasma aldosterone concentration can be modulated acutely by transitory changes in plasma potassium concentration without a change in potassium balance. The effect of glucose and insulin administration on intracellular potassium in the adrenal cortex is uncertain, and although increased net movement of potassium into cells is the presumptive mechanism of the reduction in plasma potassium concentration, whether the potassium content of the adrenal cortex may have increased or decreased or remained essentially unchanged, cannot be inferred from our data.

The effect of carbohydrates on ammonium and ketoacid excretion during starvation.

The metabolic effects of oral ingestion of minute quantities of carbohydrate during prolonged starvation were studied in nine obese subjects. Measurements were made during a control period of total starvation, during the ingestion of 7.5 g carbohydrate daily, and finally during the ingestion of 15.0 g carbohydrate daily. Daily ketoacid excretion fell after carbohydrate ingestion and was significantly correlated (r = 0.62, P < 0.01) with the amount of carbohydrate administered. Despite this fall in ketoacids, the concentration of blood ketoacids, plasma free fatty acids, and serum insulin remained constant throughout the study. Urinary ammonium excretion, closely correlated with ketoacid output (r = 0.95, P < 0.001), also fell significantly after carbohydrate ingestion. No significant changes were present in extracellular or urinary pH. Urea nitrogen excretion did not change when urinary ammonium output fell. These results indicate that: the excretion of ketoacids and ammonium in starving man is exquisitely sensitive to minute amounts of ingested carbohydrate; the change in ketonuria appears to be due to increased renal ketoacid reabsorption after carbohydrate ingestion; and the nitrogen-sparing effect of reducing renal ammonium output in starvation can be dissociated from nitrogen sparing occurring because of changes in urine urea excretion.

The regulation of aldosterone secretion in anephric man.

The regulation of aldosterone secretion in anephric man was investigated in studies on nephrectomized patients who were being intermittently hemodialyzed while awaiting renal transplantation. The effects of supine and upright posture on the concentration of plasma aldosterone on the 1st day postdialysis and on a 3rd or 4th day postdialysis were compared to the effects of postural variation in normal subjects who were on a low sodium intake and on a high sodium intake. In contrast with the normal subjects who exhibited higher concentrations of plasma aldosterone after 2 hr of upright posture than in the supine position and low concentrations of plasma aldosterone on a high sodium intake, the anephric patients showed less consistent variations in plasma aldosterone due to changes in posture and exhibited higher concentrations of plasma aldosterone on the 3rd or 4th day postdialysis, despite an increase in body weight, than on the 1st day postdialysis. The increase in the concentration of plasma aldosterone in the anephric patients between the 1st day postdialysis and the 3rd or 4th day postdialysis indicates that aldosterone secretion is not responding primarily, in this situation, to volume-related stimuli. There was a high degree of correlation between the concentration of plasma aldosterone and the corresponding levels of serum potassium concentration, which also rose significantly between the 1st day postdialysis and the 3rd or 4th day postdialysis. Furthermore, when potassium accumulation between dialyses was prevented in three of these patients, the concentration of plasma aldosterone fell to minimally detectable levels. The results of these studies suggest that the primary regulator of aldosterone secretion in the absence of the kidneys is potassium.

Biosynthetic studies with isolated kidney glomeruli.

Glomeruli were isolated from rat kidneys and were found active in protein and glycoprotein synthesis in vitro. The incorporation of proline, galactose and fucose into macromolecules was linear for at least 8 h. The intracellular pool of free proline and lysine was 52 and 32 nmol/mg glomerular protein respectively. Vinblastin and cytochalasin B, two agents which interfere with normal cellular secretory processes, inhibited galactose and fucose incorporation, possibly by a feedback mechanism. Experimental nephrotic syndrome was induced in rats by the injection of puromycin aminonucleoside; the rate of proline and galactose incorporation was reduced in glomeruli isolated from the nephrotic animals. The system of isolated glomeruli is deemed suitable for future studies of selected kidney diseases which affect the glomeruli.

Therapeutic implications of gentamicin accumulation in severly diseased kidneys.

We evaluated the influence of severe disease in human kidneys (12 patients) on gentamicin sulfate accumulation characteristics in such tissue and compared the results with intrarenal tissue concentration data derived from the study of healthy dogs (54 kidneys) during variation in hydration and urinary pH. Our results indicate that, in the management of pyelonephritis complicating preexisting renal disease, if the minimal inhibitory gentamicin concentration for an infecting organism is greater than the usual therapeutic an nontoxic serum levels of the compound, then it may be appropriate to use alternate antibiotics that demonstrate lesser reduction in tissue drug accumulation in diseased kidneys.

Influence of renin levels on the treatment of essential hypertension with thiazide diuretics.

Initial plasma renin activity (PRA) was measured in 213 patients with untreated hypertension before beginning thiazide (chlorothiazide and hydrochlorothiazide) therapy alone to test whether patients with low-renin hypertension exhibited a greater response to diuretic therapy. Diastolic blood pressure response to treatment in the low, mid-range, and high PRA groups did not differ significantly (delta diastolic blood pressure, -13.6 +/- 1.6, -11.6 +/- 1.5, and -10.8 +/- 2.6 mm Hg, respectively). Moreover, eight subjects with the highest PRA values exhibited the same magnitude of decrease in diastolic blood pressure as did the low PRA group (15.0 +/- 4.2 vs 13.6 +/- 1.6, respectively). This study thus provides no evidence for increased sensitivity to diuretic therapy among patients with low-renin essential hypertension.

Mechanism of deterioration in renal function in patients with renovascular hypertension treated with enalapril.

Azotemia produced by converting enzyme inhibition in renovascular hypertension was studied in six patients by measurement of glomerular filtration rate (GFR) and effective renal plasma flow (ERPF). Patients with unilateral renovascular hypertension lowered GFR acutely to 40% of control values at 4 hours, but after 4 days it only returned to 75% of control even though ERPF exceeded control values. Calculated filtration fraction (GFR/ERPF) decreased from 0.31 to 0.19 in 4 hours (p less than 0.05) and remained at 0.20 after 4 days of treatment despite increases in GFR and ERPF. In bilateral renovascular hypertension, neither the decreased GFR nor lowered ERPF induced by enalapril showed any tendency to return toward normal with continued treatment. These data are consistent with selective glomerular efferent arteriolar dilation in response to enalapril and suggest that angiotensin converting-enzyme inhibition interferes with the autoregulatory capacity of the kidney in the presence of severe renovascular hypertension.

Relation between blood pressure and renin, renin substrate, angiotensin II, aldosterone and urinary sodium and potassium in 574 ambulatory subjects.

Five hundred and seventy-four ambulatory subjects with blood pressures ranging from 94/58 to 250/145 mm Hg were studied on their usual dietary and sodium intake. Renin, renin substrate, angiotensin II, aldosterone and urinary sodium and potassium were compared with blood pressure to access the contribution of these variables to the blood pressure variance. Our analyses revealed that renin substrate was highly and positively correlated with diastolic blood pressure (r = +0.39; p < 0.00001) but all other components of the renin-aldosterone system exhibited a significant negative correlation with blood pressure. A highly significant relationship between potassium, the renin-aldosterone system and blood pressure was found but no such relationship could be demonstrated for sodium. Subjects with higher blood pressures had lower urinary potassium concentrations and lower potassium/creatine ratios. These findings raised the possibility of a significant pathogenetic relationship between potassium and high blood pressure. Multiple linear regression reveals that influences of the renin-angiotensin-aldosterone system can only account for less than 20% of the variance exhibited by the blood pressure in these subjects.

Hypertension following coronary artery bypass surgery. Role of preoperative propranolol therapy.

Over a 9-month period, the incidence and characteristics of hypertension following coronary artery bypass surgery were studied in a group of 52 patients. Hypertension occurred in 61% of the patients and was characterized by an increase in arterial blood pressure of 35 +/- 2 mm Hg mean +/- SEM during the early postoperative period. Preoperative blood pressures and hemodynamic variables were similar in those who developed hypertension of those who remained normotensive. Ninety-four percent of those who developed hypertension as compared to only 40% of those who remained normotensive received propranolol during the 24 hours preceding surgery (x2 = 15.4; p less than 0.001). Maximal blood pressures during the first 5 hours following the termination of cardiopulmonary bypass were significantly positively correlated with preoperative propranolol dosage (p less than 0.01). Hypertension was not associated with significant changes in plasma renin activity or angiotensin II levels, but concomitant plasma catecholamine concentrations were elevated significantly (p less than 0.005). However, a similar rise in plasma catecholamine concentrations was found in those who remained normotensive. Hypertension was associated with an increase in systemic vascular resistance (p less than 0.001) and left ventricular stroke work index (p less than 0.05), and a fall in stroke volume (p less than 0.005) and cardiac index (p less than 0.001). These studies suggest that hypertension following coronary artery bypass surgery is common, results from an increase in systemic vascular resistance, is not renin-angiotensin mediated, and may, in part, be related to preoperative propranolol administration.

Angiotensinogen genotype, sodium reduction, weight loss, and prevention of hypertension: trials of hypertension prevention, phase II.

The angiotensinogen gene has been linked to essential hypertension and increased blood pressure. A functional variant believed to be responsible for hypertension susceptibility occurs at position -6 in the promoter region of the gene in which an A for G base pair substitution is associated with higher angiotensinogen levels. To test whether an allele within the angiotensinogen gene is related to subsequent incidence of hypertension and blood pressure response to sustained sodium reduction, 1509 white male and female subjects participating in phase II of the Trials of Hypertension Prevention were genotyped at the angiotensinogen locus. Participants had diastolic blood pressures between 83 and 89 mm Hg and were randomized in a 2x2 factorial design to sodium reduction, weight loss, combined intervention, or usual care groups. Persons in the usual care group with the AA genotype at nucleotide position -6 had a higher 3-year incidence rate of hypertension (44.6%) compared with those with the GG genotype (31.5%), with a relative risk of 1.4 (95% confidence interval [0.87, 2.34], test for trend across all 3 genotypes, P=0.10). In contrast, the incidence of hypertension was significantly lower after sodium reduction for persons with the AA genotype (relative risk=0.57 [0.34, 0.98] versus usual care) but not for persons with the GG genotype (relative risk=1.2 [0.79, 1.81], test for trend P=0.02). Decreases of diastolic blood pressure at 36 months in the sodium reduction group versus usual care showed a significant trend across all 3 genotypes (P=0.01), with greater net blood pressure reduction in those with the AA genotype (-2.2 mm Hg) than those with the GG genotype (+1.1 mm Hg). A similar trend across the 3 genotypes for net systolic blood pressure reduction (-2.7 for AA versus -0.2 mm Hg for GG) was not significant (P=0.17). Trends across genotypes for the effects of weight loss on hypertension incidence and decreases in blood pressure were similar to those for sodium reduction. We conclude that the angiotensinogen genotype may affect blood pressure response to sodium or weight reduction and the development of hypertension.

A corpus callosal deficit in sequential analysis by schizophrenics.

This preliminary study evaluated interhemispheric (i.e., corpus callosal) information processing by chronic schizophrenic and normal subjects. In right-handed normals the left hemisphere has been reported to be superior in temporal sequential analysis. Consequently temporal information presented to the right hemisphere requires time to cross to the left hemisphere for analysis. Measurement of hemispheric laterality and corpus callosal transfer time were evaluated by a two-pulse temporal discrimination task. Two dot stimuli were presented with decreasing temporal separation during bilateral and unilateral conditions. Subjects were required to judge perceived simultaneity and nonsimultaneity of dot onset. The results indicate that left hemisphere function in chronic schizophrenic and normal controls is superior to the right hemisphere in temporal analysis. Corpus callosal transfer time was significantly slower for chronic schizophrenics than for normal controls.

The syndrome of inappropriate antidiuretic hormone secretion (SIADH): pathophysiologic mechanisms in solute and volume regulation.

1. Studies on eight patients were performed to clarify the mechanism(s) of altered sodium metabolism and volume regulation in SIADH. The mechanism controlling water excretion was also studied to determine whether there is evidence that altered osmoregulation may be the basis for inappropriate ADH secretion in some patients. 2. These studies show that cumulative sodium balance and aldosterone secretion rates in patients with SIADH are negatively correlated with water intake. There is also a negative correlation between aldosterone secretion and urinary sodium excretion. In the absence of normal urine diluting ability, this increased excretion of sodium becomes a mechanism that allows an increased quantity of water to be excreted despite the persistence of an ADH effect on the renal tubules. 3. Within the range of hyponatremia observed in our studies, changes in serum sodium concentration were accounted for by changes in solute and water balance. One patient, who was potassium deficient during the studies, retained large quantities of sodium and potassium that could not be accounted for by an increase in either serum osmolality or body weight. These observations suggest that intracellular osmotically active solute is either lost or "inactivated" in some manner as intracellular potassium is replenished. 4. Marked impairment of urine diluting ability was demonstrated in all patients. However, two patients with SIADH associated with pulmonary tuberculosis exhibited graded responses to water loading, which suggests that ADH secretion may have been suppressed as serum osmolality was progressively reduced. Whether this can be attributed to a basic alteration or "re-setting" or osmoreceptor function, or is merely an indication that greater than normal reductions of serum osmolality are required to inhibit potent nonosmotic stimuli, remains to be determined.

Plasma levels and hepatic extraction of renin and aldosterone in alcoholic liver disease.

Arterial plasma levels and hepatic extraction of renin and aldosterone (ALDO) were measured in 24 patients with alcoholic liver disease and in 14 normal subjects being evaluated as prospective kidney donors. Patients with liver disease had higher plasma concentrations and lower fractional hepatic extractions of both renin and ALDO than the normal subjects. The quantity of renin extracted by the liver was highly correlated with plasma renin in both normal subjects and patients. Plasma ALDO concentration was positively correlated with plasma renin (p less than 0.001) but not with serum sodium, potassium or albumin concentration, inferior vena cava pressure, corrected hepatic venous wedge pressure, plasma volume or sulfobromophthalein storage or transport. Sixteen patients were restudied after one month. Six had received 40 mg/day of prednisolone, and the remaining 10 had received a placebo. Neither group had a change in plasma volume, corrected hepatic venous wedge pressure, plasma concentration or hepatic extraction of renin or ALDO. Serum albumin concentration increased and inferior vena cava pressure decreased with prednisolone therapy. These studies document high plasma levels and impaired hepatic extraction of renin and ALDO in patients with liver disease that are not corrected by short-term prednisolone therapy.

Studies of marked and persistent sodium retention in previously fasted and sodium-deprived obese subjects.

To further delineate the effects of fasting and sodium deprivation on the handling of sodium when sodium intake is resumed, balance studies were performed on seven obese female subjects. All subjects underwent a period of total fasting, which continued for 27 to 29 days prior to resumption of sodium intake. Natriuresis in the first week of fasting and continued sodium chloride deprivation resulted in cumulative deficits of 383 +/- 47 mEq (SEM) and 371 +/- 41 mEq of sodium and chloride, respectively. Chloride space decreased from 21.2 +/- 2.7 L to 18.7 +/- 2.5 L, and aldosterone secretory rates (ASR) increased from 43 +/- 13 micrograms/24 h to 597 +/- 138 micrograms/24 h. Following resumption of sodium intake and simultaneous refeeding on low calorie diets in studies on four subjects (group I), cumulative sodium balances during the first seven days ranged from +586 mEq to +1,109 mEq; sodium retained/previously existing sodium deficit = 2.4, 3.2, 2.0, and 1.6 in the four subjects, respectively. Continued sodium retention resulted in cumulative sodium balances ranging from +670 mEq to +1,249 mEq at the end of 19 to 22 days in studies on three subjects whose cumulative sodium balance was +1,249 mEq, sodium retained/sodium deficit = 3.6. During the first five days of sodium intake and refeeding ASR decreased to 74 +/- 26 micrograms/24 h. Sodium chloride administration without refeeding in studies on three subjects (group II) also resulted in retention of more than enough sodium to replenish previously existing sodium deficits.(ABSTRACT TRUNCATED AT 250 WORDS)

Creatinine filtration, secretion and excretion during progressive renal disease. Modification of Diet in Renal Disease (MDRD) Study Group.

The Modification of Diet in Renal Disease (MDRD) Study is a multicenter, randomized, controlled trial to determine acceptance, safety, and efficacy of low protein and phosphorus diets in patients with progressive renal disease. During the feasibility phase, 96 patients aged 18 to 75 years, with previously declining reciprocal serum creatinine concentration (1/PCr) and current glomerular filtration rate (GFR) from 7.5 to 80 ml/min/1.73 m2, were randomly assigned four study diets. After randomization, 91 patients were followed for a mean duration of 14.1 months. GFR, 1/PCr and creatinine clearance (CCr) were measured every three months. In an earlier report, we demonstrated relatively weak correlations of rates of change in GFR and 1/PCr during the feasibility phase; the proportion of variability in 1/PCr slopes that was explained by variability in GFR slopes (r2) was only 0.49 to 0.55. In this study, we examined the relationship of GFR and 1/PCr to other determinants of the serum creatinine concentration, including filtration (GFCr), secretion (TSCr), and total renal excretion (UCrV) of creatinine. Our results show that these parameters varied widely among individuals and changed over time. These findings may explain, in part, the relatively weak correlations. These results strengthen our previous suggestion that the rate of change in 1/PCr may not be an accurate index of the rate of change in GFR and raise questions about the validity of conclusions from other studies in which the efficacy of dietary modification in retarding the progression of renal disease was based principally on measurements of 1/PCr.

At risk nephrons and the decline in renal function in response to treatment of hypertension.

An examination of change in renal function following blood pressure lowering in more than 4,400 individuals in several clinical trials revealed that renal function declined following initiation of antihypertensive treatment in both essential hypertension and hypertensive diabetics for a period of two years before stabilizing at or near zero change. This initial decline can be related to the severity of preexisting hypertension but does not appear related to the type of antihypertensive regimen used. This phenomenon appears most readily explained by progressive obsolescence of previously damaged nephrons and not by the type of antihypertensive therapy employed. These finding raise questions about validity of interpretation of clinical trials designed to test efficacy of specific drug regimens in preserving renal function when outcome results are predominantly influenced by events during the first two years of intervention.

Hepatitis B infection in patients with end stage renal disease: some characteristics and consequences.

Susceptibility to hepatitis B infection appears to be in part genetically determined. The HLA specificity Bw35 is commonly associated with a higher frequency of both transient and persistent hepatitis B surface antigen in the serum. Persistent hepatitis B surface antigenemia occurring in patients with end stage renal disease while on dialysis is associated with a poor prognosis and markedly decreased survival regardless of whether the individual is treated subsequently by chronic dialysis or by transplantation. We conclude that persistent hepatitis B surface antigenemia is not a contraindication to transplantation since outcome is not improved by management on hemodialysis.

Exfoliative cytology in the diagnosis of immunologic rejection in the transplanted kidney.

Urinary cytology was used in the study of 57 patients who received renal allografts. In general, there was close correlation between the cytologic and clinical evidence of rejection and, at least in some instances, rejection was detected cytologically prior to the onset of clinical signs and symptoms. A cytologic profile associated with rejection was established. This had as its main feature an increased number of tubular cells, particularly those that were small and degenerating. An associated background of cellular debris and casts was found to be of major significance. Intranuclear inclusions suggestive of viral infections were present in 15 patients. Cellular atypias caused by factors other than immunologic rejection were seen but none were of a malignant nature. It was considered of importance that the method described in this study could be carried out in a routine diagnostic cytopathology laboratory by cytotechnologists and cytopathologists who had received only a brief period of special training in the field of transplant cytology.