Neal S. Bricker

On the pathogenesis of hyperparathyroidism in chronic experimental renal insufficiency in the dog

Healthy adult dogs were subjected to stepwise reduction of nephron population so as to create the transition from normal renal function to advanced renal insufficiency. Studies were performed at each level of renal function. Glomerular filtration rate (GFR), renal phosphate clearance, and serum radioimmunoassayable parathyroid hormone (PTH) levels were measured. Two groups of animals were studied. In one, phosphorous intake was maintained at 1200 mg/day. As GFR declined, fractional phosphate excretion rose reciprocally, and PTH levels increased over 20-fold. In the second group, phosphorous intake was maintained at less than 100 mg/day. As GFR fell, fractional phosphate excretion changed little, and no increment in PTH levels occurred. The data suggest that the control system regulating phosphate excretion contributes importantly to the pathogenesis of secondary hyperparathyroidism in advancing renal insufficiency.

On the Pathogenesis of the Uremic State: An Exposition of the Trade-off Hypothesis

MY comments represent an effort to summarize some of the very recent observations that my colleagues and I have made regarding the impact of chronic progressive renal disease on the functional char...

Control of phosphate excretion in uremic man

The present studies were performed in an effort to examine the characteristics of the control system governing phosphate excretion in uremic man. In a group of patients with glomerular filtration rates (GFR) ranging from normal to 2 ml/min, it was found that the lower the GFR the lower the fraction of filtered phosphate reabsorbed (TRP). On a fixed phosphate intake, phosphate excretion rate was the same in patients with GFRs ranging from 60 to 3 ml/min. When plasma phosphate concentrations were diminished to subnormal levels in hyperphosphatemic, hypocalcemic uremic patients, TRP values increased but did not return to normal. TRP failed to rise substantially when GFR, as well as plasma phosphate concentrations, were diminished. In patients with unilateral renal disease, TRP values were equal bilaterally, and values were substantially higher in the diseased kidneys than in patients with bilateral involvement. When plasma calcium concentrations were raised to normal for 2-3 wk in uremic patients in whom plasma phosphate concentrations had previously been lowered to subnormal levels, TRP values rose to an average value of 86%. Values remained in the normal range when phosphate concentrations were allowed to increase while normocalcemia was maintained. The data are interpreted to indicate that in advancing renal disease, the changing patterns of phosphate excretion are mediated by a control system in which parathyroid hormone serves as a major effector element. An increase in GFR per nephron, hyperphosphatemia, and intrinsic inability of the surviving nephrons to transport phosphate do not appear to be of primary importance in the progressive reduction in TRP.

Studies on the characteristics of the control system governing sodium excretion in uremic man

Sodium excretion was studied in a group of patients with chronic renal disease, (a) on constant salt intakes of varying amounts with and without mineralocorticoid hormone administration and, (b) after acute extracellular fluid volume expansion. The lower the steady-state glomerular filtration rate (GFR), the greater was the fraction of filtered sodium excreted on both a 3.5 and 7.0 g salt diet; and the lower the GFR, the greater was the change in fractional excretion in the transition from the 3.5 to the 7.0 g salt diet. This regulatory capacity did not appear to be influenced by mineralocorticoid hormone administration. After acute expansion of extracellular fluid (ECF) volume, the increment in sodium excretion exceeded the concomitant increment in filtered sodium in six of nine studies and in the remaining three studies, the increment in excretion averaged 59% of the Delta filtered load (i.e., only 41% of the increase in filtered sodium was reabsorbed). During saline loading, the decrease in fractional reabsorption of sodium tended to vary inversely with the steady-state GFR, although all patients received approximately the same loading volume. When an edema-forming stimulus was applied during saline infusion, the natriuretic response was aborted and the lag time was relatively short. When GFR and the filtered load of sodium were increased without volume expansion, the Delta sodium excretion averaged only 19% of the Delta filtered load; moreover, changes in fractional sodium reabsorption were considerably smaller than those observed during saline loading. The data implicate the presence of a factor other than GFR and mineralocorticoid changes in the modulation of sodium excretion in uremic man.

An abnormality in renal function resulting from urinary tract obstruction.

Abstract Observations have been described on four patients in whom an abnormality in renal function developed in association with mechanical obstruction of the urinary tract. Clinically, the presenting manifestations were those of acute renal failure (complete urinary suppression and symptoms and signs of renal insufficiency). Immediately following relief of the obstruction by appropriate instrumentation, polyuria occurred, varying in duration from several days to three and a half months. The maximum twenty-four-hour urine volumes ranged from 4.5 L. to 15 L. and the twenty-four-hour sodium excretion from 250 to 1,900 mEq. Renal function studies were conducted during the diuretic phase in all patients, and in two patients follow-up studies were performed after subsidence of polyuria. The initial studies revealed impairment of glomerular filtration rate, renal plasma flow and concentrating ability. The most impressive feature of the nephropathy, however, was the abnormality in salt and water excretion which was responsible for the polyuria. Analysis of this abnormality, based on current physiologic interpretations, led to the following conclusions: (1) the diuresis was similar to that seen in normal subjects during experimental osmotic diuresis; (2) the diuresis resulted primarily from the delivery into the urine of an excessively high percentage of the sodium and chloride filtered at the glomerulus; (3) the defect in sodium and chloride excretion could be related to suppression of tubular reabsorption; and (4) the latter was located predominantly in the proximal segment. The inability of the patients to decrease salt and water excretion in response to enforced fluid restriction favors the primacy of the tubular defect in the genesis of the polyuria. However, potentiation of the diuresis in one patient by the infusion of an isotonic saline solution suggests that concurrent fluid administration may influence the magnitude of the diuresis. Follow-up studies demonstrated improvement in the majority of parameters examined, indicating that the nephropathy attendant upon urinary retention includes multiple renal functions. Certain of the functional patterns noted in the present patients may also be observed in subjects with advanced Brights disease and with other renal salt and water wasting syndromes. The possibility has been considered, therefore, that qualitatively similar defects in sodium and chloride excretion may be operative in these states.

A natriuretic factor in the serum of patients with chronic uremia

Sera from chronically uremic and normal individuals were subjected to gel filtration with Sephadex G-25 and the same fraction of both was infused into rats with a decreased nephron population to determine the effects on sodium excretion. Sodium excretion rate and fractional sodium excretion increased slightly with the normal fractions; but the increase in both functional parameters produced by the uremic fractions was substantially and significantly greater. The natriuresis could not be explained by associated changes in glomerular filtration rate (GFR), para-aminohippurate (PAH) clearance, filtration fraction, hematocrit, or blood pressure. The possibility thus exists that the inhibitor affected some component part of the transepithelial sodium transport system. The elution characteristics of the fraction plus certain of its physicochemical properties suggest that the inhibitor of sodium reabsorption by the rat nephron may be identical with the inhibitor of PAH uptake by kidney slices and the inhibitor of transepithelial sodium transport by the frog skin and toad bladder previously found in the serum of chronically uremic patients.

Functional Profile of the Isolated Uremic Nephron: ROLE OF COMPENSATORY HYPERTROPHY IN THE CONTROL OF FLUID REABSORPTION BY THE PROXIMAL STRAIGHT TUBULE

An in vitro approach to the study of single nephron function in uremia has been employed in evaluating the control of fluid reabsorption by the renal superficial proximal straight tubule (PST). Isolated segments of PSTs from the remnant kidneys of uremic rabbits (stage III) were perfused in vitro and their rate of fluid reabsorption compared with normal PSTs and with PSTs derived from the remnant kidneys of nonuremic rabbits (stage II). All segments were exposed to a peritubular bathing medium of both normal and uremic rabbit serum thereby permitting a differentiation to be made between adaptations in function which are intrinsic to the tubular epithelium and those which are dependent upon a uremic milieu.Compared with normal and stage II PSTs, there was significant hypertrophy of the stage III tubules as evidenced by an increase in length and internal diameter, and a twofold increase in the dry weight per unit length. Fluid reabsorption per unit length of tubule was 70% greater in stage III than in normal and stage II PSTs, and was closely correlated with the increase in dry weight. Substitutions between normal and uremic rabbit serum in the peritubular bathing medium did not affect fluid reabsorption significantly in any of the three groups of PSTs. Perfusion of the tubules with an ultrafiltrate of normal vs. uremic serum likewise failed to influence the rate of net fluid reabsorption. It has previously been observed that net fluid secretion may occur in nonperfused or stop-flow perfused normal rabbit PSTs exposed to human uremic serum. Additional studies were thus performed on normal and stage III PSTs to evaluate whether net secretion occurs in the presence of rabbit uremic serum. No evidence for net secretion was found. These studies demonstrate that fluid reabsorption is greatly increased in the superficial PST of the uremic remnant kidney and that this functional adaptation is closely correlated with compensatory hypertrophy of the segment. Humoral factors in the peritubular environment do not appear to be important mediators of the enhanced fluid reabsorption.

The control of sodium excretion with normal and reduced nephron populations: The pre-eminence of third factor

Abstract It has long been realized that renal excretion of sodium (and water) largely determines the extracellular fluid volume. It also has been recognized for many years that extracellular volume must exercise a regulatory function on the rate of renal salt and water excretion. The views as to how volume influences salt excretion are in the process of being reassessed. Changes in glomerular filtration rate and in mineralocorticoid hormone activity may affect sodium excretion, but mounting evidence favors the view that a third factor, which is independent of both glomerular filtration rate and aldosterone levels, modulates sodium excretion. This third factor contributes decisively to the natriuresis observed following acute massive saline loading in normal animals. It also contributes importantly to the high rates of salt excretion per nephron in the diseased kidney and to the very large swings in sodium excretion per nephron which occur in the diseased kidney with only modest changes in salt intake. Moreover, third factor could prove to be responsible for the precisely controlled modulations in sodium excretion which permit the maintenance of sodium balance in health. Finally, in pathologic states characterized by edema formation, it seems possible that the third factor mechanism is inadequate due to some consequence of the underlying abnormality. The possibility even exists that in some salt and water losing states, third factor excesses may be involved.

The Presence of a Natriuretic Factor in Urine of Patients with Chronic Uremia. THE ABSENCE OF THE FACTOR IN NEPHROTIC UREMIC PATIENTS

A gel filtration fraction of serum from chronically uremic patients has been shown previously to produce natriuresis in the rat. In the present studies, the same fraction from urine of uremic patients and normal subjects was studied for its natriuretic activity. Urine samples were obtained from 17 chronically uremic patients (mean glomerular filtration rate [GFR], 8.7 ml/min; mean fractional sodium excretion [FE(Na)], 5.7%), and 14 normal subjects. The fraction from the uremic patients produced a significant increase in absolute sodium excretion (U(Na)V) and FE(Na); the fraction from normal subjects had no statistically significant effect on either U(Na)V or FE(Na); and the difference between the response to the uremic vs. normal fractions was highly significant for both parameters of sodium excretion. When a more concentrated urine fraction from uremic patients was administered, a striking natriuresis was observed with values for FE(Na) rising to levels as high as 12%. Studies also were performed on eight patients with far advanced chronic renal insufficiency and the nephrotic syndrome. The serum fraction was studied in each of these patients and the urine fraction in three. For the group, U(Na)V in the assay rats decreased by 0.87 mueq/min and FE(Na) decreased by 1.35% after infusion of the serum fraction. These results differ significantly from those of patients with chronic uremia without the nephrotic syndrome. The data are consistent with the view that the increased activity of the natriuretic factor in the serum of chronically uremic patients is not due to failure of excretion; rather it relates either to an increased rate of production and/or a decreased rate of degradation. The data also show that the inhibitor is detectable when FE(Na) is increased, but not when uremia is associated with a sodium-retaining state.

On the influence of extracellular fluid volume expansion and of uremia on bicarbonate reabsorption in man

The patterns of bicarbonate reabsorption during increasing plasma concentrations were studied in subjects with a range of glomerular filtration rates (GFR) from 170 to 2 ml/min. In a group of five subjects with GFR values above 30 ml/min, paired bicarbonate titration studies were performed first under conditions which minimized extracellular fluid (ECF) volume expansion, and second under conditions which were conducive to exaggerated expansion of ECF volume. In patients with GFR values below 30 ml/min, a single protocol was employed. Studies also were performed on two patients with far advanced renal disease who were nephrotic and exhibited a sodium-retaining state. When ECF volume expansion was minimized in the nonuremic subjects, values for bicarbonate reabsorption were well in excess of the usually accepted Tm level and over the range of plasma bicarbonate concentrations employed, no evidence of a Tm phenomenon was observed. A similar pattern emerged in the two nephrotic patients despite the presence of uremia. However, with both exaggerated expansion of ECF volume (GFR greater than 30) and in patients with advanced renal disease in the absence of exaggerated ECF volume expansion a tendency towards saturation kinetics for bicarbonate reabsorption was demonstrable. In comparing the minimized with the exaggerated expansion studies, evidence emerged for a decrease in both bicarbonate reabsorption per unit of GFR and the absolute rate of bicarbonate reabsorption. When ECF volume expansion was exaggerated in uremic patients after stable rates of bicarbonate reabsorption had been achieved, a decrease in reabsorption per unit of GFR and in absolute bicarbonate reabsorption occurred. The possible relationship of the factors controlling sodium excretion to the observed patterns of bicarbonate reabsorption is considered in the text.