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.

The effect of insulin on renal handling of sodium, potassium, calcium, and phosphate in man.

The effects of insulin on the renal handling of sodium, potassium, calcium, and phosphate were studied in man while maintaining the blood glucose concentration at the fasting level by negative feedback servocontrol of a variable glucose infusion. In studies on six water-loaded normal subjects in a steady state of water diuresis, insulin was administered i.v. to raise the plasma insulin concentration to between 98 and 193 muU/ml and infused at a constant rate of 2 mU/kg body weight per min over a total period of 120 min. The blood glucose concentration was not significantly altered, and there was no change in the filtered load of glucose; glomerular filtration rate (CIN) and renal plasma flow (CPAH) were unchanged. Urinary sodium excretion (UNaV) decreased from 401 plus or minus 46 (SEM) to 213 plus or minus 18 mueq/min during insulin administration, the change becoming significant (P smaller than 0.02) within the 30-60 min collection period. Free water clearance (CH2O) increased from 10.6 plus or minus 0.6 to 13 plus or minus 0.5 ml/min (P smaller than 0.025); osmolar clearance decreased and urine flow was unchanged. There was no change in plasma aldosterone concentration, which was low throughout the studies, and a slight reduction was observed in plasma glucagon concentration. Urinary potassium (UKV) and phosphate (UPV) excretion were also both decreased during insulin administration; UKV decreased from 66 plus or minus 9 to 21 plus or minus 1 mueq/min (P smaller than 0.005), and tupv decreased from 504 plus or minus 93 to 230 plus or minus 43 mug/min (P smaller than 0.01). The change in UKV was associated with a significant reduction in plasma potassium concentration. There was also a statistically significant but small reduction in plasma phosphate concentration which was not considered sufficient alone to account for the large reduction in UPV. Urinary calcium excretion (UCaV) increased from 126 plus or minus 24 to 200 plus or minus 17 mug/min (P smaller than 0.01). These studies demonstrate a reduction in UNaV associated with insulin administration that occurs in the absence of changes in the filtered load of glucose, glomerular filtration rate, renal blood flow, and plasma aldosterone concentration. The effect of insulin on CH2O suggests that insulin's effect on sodium excretion is due to enhancement of sodium reabsorption in the diluting segment of the distal nephron.

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.

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.

Nonosmotic stimuli alter osmoregulation in patients with spinal cord injury.

Studies on two quadriplegic patients who developed severe hyponatremia during episodes of acute respiratory distress were performed to determine whether differences in osmoregulation of vasopressin release could be identified in these patients compared to other quadriplegic subjects previously studied in a similar manner. Both patients were clinically stable and normonatremic, with no signs or symptoms of respiratory distress, when the studies were performed. However, both exhibited evidence of hemodynamic instability in the sitting posture. Linear regression analysis of the plasma vasopressin/plasma osmolality (Pavp:Posm) relationship during infusions of 0.85 M sodium chloride showed no significant differences in either the slope (sensitivity) or abscissal intercept (osmotic threshold) of this relationship compared to that of other quadriplegic subjects when the patients were supine. In contrast, when the patients were studied in the sitting posture there was a marked shift in the relationship of Pavp:Posm indicative of increased sensitivity and reduced osmotic threshold for vasopressin release. The slopes of the Pavp:Posm relationships were 0.249 and 0.178 for the two patients, respectively, compared to 0.092 +/- 0.03 ( +/- SD) for previously studied quadriplegic subjects. Oral water-loading studies performed on one patient revealed marked impairment of urine-diluting ability and free water clearance in the sitting posture compared with observations in similar studies performed when the patient was supine. Impairment of renal water excretion could not be attributed to an effect of vasopressin, which was reduced to unquantifiable levels by water loading. These studies have shown that hemodynamic stress related to autonomic dysfunction in quadriplegic patients may result in marked alteration of osmoregulation of vasopressin release in more severely affected individuals. Such altered osmoregulation, which may also be associated with vasopressin-independent impairment of renal water excretion in the sitting posture, may be a predisposing factor in the development of hyponatremia, especially in the presence of other potent nonosmotic stimuli.

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.

Acute renal failure in multiple myeloma.

1. The clinical manifestations, laboratory data and renal histologic features of acute renal failure occurring in 14 patients with multiple myeloma are reviewed and contrasted with the data from 29 previously reported cases. 2. Whereas other reports have stressed the role of intravenous pyelography and dehydration in the development of acute renal failure in multiple myeloma, the most common etiologic factor in our experience was hypercalcemia (7 patients). Other factors included potentially nephrotoxic antibiotics (3 patients) and volume depletion (2 patients). Intravenous pyelography could be clearly implicated in ony one patient. 3. The unusually high incidence of Bence Jones proteinuria in these patients is consistent with the possibility that Bence Jones protein excretion is associated with an increased susceptibility to renal injury. This could be due to an adverse effect of Bence Jones proteins on the renal tubules or their tendency to precipitate in tubular lumina during periods of reduced tubular flow. 4. The prognosis of patients with multiple myeloma who develop acute renal failure is poor; only 5 of our 14 patients survived the early period of acutely impaired renal function, and 4 of these subsequently died within 2 months. Preventive measures particularly the prompt correction of hypercalcemia and volume depletion, are the most important aspects of patient management.

Renal function in patients with multiple myeloma.

Renal tubular and glomerular functions were evaluated in 35 consecutive patients with multiple myeloma and were correlated with changes in renal histopathology and myeloma protein patterns. All nine patients without Bence Jones proteinuria had CCr greater than 50 ml/min. In contrast 16/26 patients with Bence Jones proteinuria had CCr less than 50 ml/min and the magnitude of the Bence Jones proteinuria correlated well with the degree of renal insufficiency. Frequent abnormalities in renal tubular acidifying and concentrating ability were observed only in patients with Bence Jones proteinuria and occurred in the absence of significant reductions of glomerular filtration rate. Severely deranged renal histology was seen only in patients with Bence Jones proteinuria and consisted primarily of tubular atrophy and degeneration; glomeruli appeared normal. These data suggest that Bence Jones proteins exert a direct nephrotoxic effect at the tubular level with resultant tubular dysfunction and tubular atrophy. Glomerular filtration rate remains relatively preserved despite the significant abnormalities of tubular function. Although obstructing tubular casts were observed only in patients with severely impaired glomerular filtration rate, many patients with similarly impaired renal function had no evidence of such casts. Instead, tubular atrophy and degeneration correlated best with renal dysfunction.

Chronic hyponatremia due to resetting of the osmostat in a patient with gastric carcinoma.

A 54-year-old schizophrenic patient who presented with hyponatremia and nephrotic-range proteinuria was subsequently discovered to have a gastric adenocarcinoma. Psychogenic water drinking, sodium depletion, and cardiac, adrenal, hepatic, and thyroid disease were excluded as causes of hyponatremia. The serum creatinine concentration was normal, and, although renal biopsy showed changes consistent with immune complex glomerulopathy, proteinuria remitted without treatment. Moderately severe hyponatremia persisted, and the diagnosis of gastric adenocarcinoma was made after the onset of early satiety 1 year later. Surgical exploration at the time of partial gastric resection revealed local metastatic lymph node involvement. Following the patient's uneventful recovery from surgery, studies of osmoregulation of vasopressin release and renal water handling were performed to determine the cause of chronic hyponatremia refractory to sodium chloride administration. Oral water loading studies revealed normal urinary diluting ability and appropriate suppression of plasma vasopressin concentrations. However, hypertonic sodium chloride infusion studies revealed a highly significant correlation between plasma osmolality and plasma vasopressin concentration, and a low osmotic threshold for vasopressin release based on linear regression analysis of the plasma vasopressin response to increasing plasma osmolality. Low osmotic threshold for vasopressin release was confirmed by exponential (log linear) and parabolic methods of data analysis. The findings in these studies are consistent with the typical features of the reset osmostat variant of the syndrome of inappropriate antidiuresis. To our knowledge, this is the first report of the occurrence of this syndrome in association with gastric adenocarcinoma.

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.

Risk factors for development of proteinuria in chronic spinal cord injury.

A retrospective, case-control study was performed to investigate the risk factors that may contribute to the development of proteinuria in patients with chronic spinal cord injury (SCI). During an 18-month period, 31 subjects with a 24-hour protein excretion of 1.0 g or greater were identified. Three control subjects with SCIs with a 24-hour urinary protein excretion of less than 1.0 g during the same time period were randomly selected for each study subject with proteinuria. Clinical data, including level and duration of injury, age, presence of indwelling bladder catheter, number of decubitus ulcer procedures, serum albumin and creatinine concentrations, hematocrit, creatinine clearance, and the presence of hypertension and diabetes mellitus, were obtained from medical records. Subjects with proteinuria had other evidence of renal dysfunction with greater serum creatinine concentrations and reduced creatinine clearances, serum albumin concentrations, and hematocrits. Proteinuric subjects were older, had a longer duration of injury, had undergone a greater number of decubitus ulcer procedures, and were more likely to have hypertension and indwelling bladder catheters. The independent predictors for the development of proteinuria using logistic stepwise multiple linear regression analysis were the use of chronic indwelling bladder catheters, number of decubitis ulcer procedures, presence of hypertension, and older age. These data suggest that inflammatory complications associated with complications of chronic SCI, rather than SCI per se, contribute to the development of proteinuria. SCI patients with proteinuria have more impaired renal function and increased mortality compared with SCI patients without proteinuria.

Coexistence of anti-neutrophil cytoplasmic antibody-associated glomerulonephritis and membranous glomerulopathy.

The association of renal Wegener's granulomatosis with other glomerular diseases is very rare. A case of anti-neutrophil cytoplasmic antibody-associated necrotizing glomerulonephritis superimposed on a membranous glomerulopathy in a patient with systemic Wegener's granulomatosis is reported. Renal failure was corrected by immunosuppressive therapy treatment, but a non-nephrotic-range proteinuria persisted for several months. The association of membranous glomerulopathy with anti-glomerular basement membrane disease and other autoimmune diseases is well described; however, anti-neutrophil cytoplasmic antibody-associated vasculitis superimposed on membranous glomerulopathy has not been reported previously.

Effect of acute metabolic acidemia on renal electrolyte transport in man.

The effect of acute NH4C1-induced metabolic acidemia on renal electrolyte excretion was examined in nine healthy subjects during steady state water diuresis. Following oral NH4C1, venous pH and bicarbonate concentration declined significantly (p less than 0.01) while inulin and PAH clearances remained unchanged. Mean sodium excretion (UNaV) increased from 142 +/- 16 mueq/min (mean +/- SEM) to 310 +/- 49 mueq/min (p less than 0.01) at 8 hr without change in plasma aldosterone or renin levels. Urine flow remained unchanged while CH2O/(CH2O + CCl) declined significantly, suggesting that acute metabolic acidemia inhibits sodium transport in the distal nephron. Similar results were observed in two subjects with central diabetes insipidus. Three subjects restudied following the ingestion of an equivalent amount of chloride administered as NaCl, failed to demonstrate a significant rise in UNaV. UKV fell acutely from 91 +/- 13 to 45 +/- 5 mueq/min (p less than 0.001) despite an increase in serum potassium concentration. No change in plasma insulin was observed. UCaV rose from 66 +/- 15 to 143 +/- 18 microgram/min and fractional excretion of calcium increased from 0.55 +/- 0.13 to 1.24 +/- 0.21% (p less than 0.001). Total serum calcium fell slightly, but ionized calcium rose from 3.99 +/- 0.05 to 4.30 +/- 0.03 mg/dl (p less than 0.001). No change in nephrogenous cyclic (cAMP) excretion was observed. In conclusion, acute metabolic acidemia in man (1) inhibits sodium reabsorption in the distal nephron independent of changes in plasma aldosterone concentration, filtered chloride load, or volume expansion; (2) inhibits potassium excretion despite a rise in serum potassium concentration; and (3) inhibits tubular calcium reabsorption independetn of changes in parathyroid hormone (as reflected by urinary cAMP).

Hemodynamic response to vasopressin in dehydrated human subjects.

BACKGROUND: Despite the known potent vasoconstrictor effects of vasopressin, the role of this hormone in the maintenance of blood pressure is incompletely understood. In studies performed in animals with increased plasma vasopressin concentrations, several complex cardiovascular effects have been noted, including decreases in heart rate and cardiac output, which may account for a lack of effect on arterial pressure despite the vasopressin-induced increase in total peripheral resistance. Only a few studies have been done to assess the cardiovascular effects of vasopressin in human subjects, and most of these have been limited to measurement of heart rate and arterial pressure only. The present study was designed to identify more fully the cardiovascular effects of vasopressin when plasma vasopressin concentrations are increased by osmotic stimulation without the superimposition of major nonosmotic stimuli associated with severe volume depletion. METHOD: Studies were performed on 11 normal human subjects in supine and erect posture before and after 24 hours of fluid deprivation, and following administration of a selective V1 receptor antagonist, [d(CH2)5Tyr(ME)]AVP, after dehydration. Cardiovascular parameters were measured noninvasively by thoracic electrical bioimpedance cardiography and blood samples for measurements of plasma concentrations of vasopressin and other hormones affected by dehydration and differences in posture were collected for subsequent analysis. RESULTS: After 24 hours of fluid restriction, plasma osmolality was increased from 287 +/- 0.9 to 294 +/- 0.7 mosm/kg H20 and plasma vasopressin concentrations (Pavp) were increased in both supine and erect posture. Mean arterial (MAP) and systolic blood pressure (SBP) were reduced by fluid restriction but were higher in erect than in supine posture both before and after fluid restriction. Heart rate (HR), diastolic blood pressure (DBP), and systemic vascular resistance (SVRI) were also higher in erect than in supine posture, while cardiac index (CI), stroke index (SI), end-diastolic index (EDI), and an index of total thoracic fluid content (TFC) were all reduced in erect posture, both before and after dehydration. Plasma renin activity (PRA) and plasma norepinephrine concentrations (Pne) were increased in erect posture, both before and after dehydration, but there was no effect of erect posture on plasma vasopressin concentrations (Pavp), either before or after dehydration. Administration of the V1 receptor antagonist after dehydration had no effect on hemodynamic parameters other than small reductions in DBP and cardiac preload. CONCLUSION: It is concluded from these studies that small increases in Pavp associated with moderate dehydration do not play a role in the maintenance of arterial pressure in normal human subjects in either supine or erect posture.

Polycythemia vera in an anephric man.

The effect of renal failure and bilateral nephrectomy on erythropoiesis and plasma erythropoietic activity was observed in a patient with polycythemia vera. For eight years the patient's hematocrit was maintained between 45 and 50 per cent by phlebotomy and in spite of the development of renal failure the hematocrit did not decline. Following rejection of a renal transplant, the hematocrit fell to 18 per cent but rose to 40 per cent with oral iron therapy. Following bilateral nephrectomy, the hematocrit fell to 29 per cent but subsequently increased to 37 per cent. After an episode of gastrointestinal bleeding the hematocrit was 21 per cent but subsequently rose to 32 per cent. Erythropoietin could not be detected in the plasma either before or after nephrectomy. In addition, erythropoietin failed to stimulate 59Fe incorporation into heme in vitro in the patient's marrow cells. The data incidate that, in polycythemia vera, erythropoiesis does not require erythropoietin.

Acute fulminant lactic acidosis complicating metastatic cholangiocarcinoma.

A patient with cholangiocarcinoma, metastatic to the liver and lungs, developed acute fulminant lactic acidosis in the absence of overt hepatic failure, sepsis, hypoxia, or circulatory failure. Despite extensive tumor replacement of hepatic parenchyma, no acid-base disorder was present during initial evaluation. The onset of acute lactic acidosis was temporally associated with the development of otherwise asymptomatic episodes of intermittent atrial arrhythmias. Once established, lactic acidosis was inexorably progressive, despite resolution of arrhythmias. Extensive areas of acute necrosis within the large hepatic metastases were demonstrated on postmortem examination, suggesting that local tissue ischemia, precipitated by cardiac arrhythmias, lead to excessive lactic acid production.

Reversible nephrotic range proteinuria and renal failure in atheroembolic renal disease.

A case is described in which atheroembolic renal disease was associated with nephrotic range proteinuria, sub-acute renal failure, severe hypertension and microhematuria, in the absence of typical peripheral stigmata of atheroemboli. Nephrotic range proteinuria has not been previously reported in atheroembolic renal disease. With sustained aggressive treatment of hypertension there was diminution and eventual clearing of the proteinuria accompanied by marked improvement in renal function. The histopathology, the indications for renal biopsy, and possible causes of proteinuria are discussed.

Case report: acute renal vein thrombosis in patients with spinal cord injury and secondary amyloidosis.

Chronic spinal cord injury, when complicated by chronic suppurative infections, has replaced chronic tuberculosis as a leading cause of secondary amyloidosis. Renal involvement with secondary amyloidosis is characterized by the presence of nephrotic range proteinuria and an increased incidence of renal vein thrombosis. Two cases of acute renal vein thrombosis associated with secondary amyloidosis in patients with spinal cord injury are presented. In both cases, a past history of extensive decubitus ulcerations and urinary tract infections preceded the development of nephrotic range proteinuria. In case 1, nonoliguric acute renal failure occurred after the development of acute bilateral renal vein thrombosis. The patient declined dialytic therapy and expired with uremia. In case 2, worsening renal function and increased proteinuria resulted after the development of acute unilateral renal vein thrombosis. These cases include the clinical and anatomic findings of acute renal vein thrombosis that occur as a complication of secondary amyloidosis. Acute renal vein thrombosis should be considered whenever an acute change in renal function or increase in proteinuria is noted in this setting.

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.