Dependence of saline-induced natriuresis upon exposure of the kidney to the physical effects of extracellular fluid volume expansion.

In many previous studies, the natriuresis induced by saline loading has been demonstrated to persist even though glomerular filtration rate (GFR) has been decreased to below pre-expansion levels by a reduction in renal artery pressure. In such studies, however, the kidney has been exposed to the effects of volume expansion for varying periods of time before renal artery pressure was controlled. The present experiments were designed to evaluate whether this period of exposure induces critical changes in intrarenal factors that are responsible for the natriuresis.Experiments were carried out in rats, in which renal artery pressure was decreased to 70 mm Hg either at the onset of saline loading (immediate clamping experiments) or after 45 min of saline loading had elapsed (delayed clamping experiments). In the delayed clamping experiments, consonant with previous studies, mean sodium excretion, 3.2 mueq/min, remained markedly increased above control, despite a reduction in GFR to 91% of the hydropenic control value. In contrast, when renal artery pressure was comparably reduced at the onset of saline loading mean sodium excretion was only trivially increased, 0.4 mueq/min, although GFR increased to 140% of the hydropenic control value. These results exclude an important role for either a circulating hormone or a reduction in plasma oncotic pressure in the natriuretic response to saline loading, and indicate that intrarenal factors are the critical determinants of the natriuresis. We have used the difference in response to saline loading in the immediate and delayed clamping experiments to evaluate the role of two intrarenal factors, interstitial hydrostatic pressure and renal plasma flow. Interstitial pressure changes were estimated from changes in tubular pressure and diameter by using the in situ compliance characteristics of the tubules. In a group of rats saline loaded without aortic clamping, interstitial pressure increased by 4-5 mm Hg and renal plasma flow increased by 2.5 ml/min. During the period of reduced renal artery pressure, however, neither interstitial pressure nor renal plasma flow was detectably increased above control in either the immediate or the delayed clamping experiments. The only noteworthy difference between the experiments in which a natriuresis occurred (unclamped and delayed clamping studies) and the experiments in which no natriuresis occurred is that in the former group the kidney was at least transiently exposed both to an increase in renal plasma flow and interstitial pressure. These findings indicate, first, that extracellular fluid volume expansion can induce a natriuresis only if the kidney has been exposed to at least a transient increase in either interstitial hydrostatic pressure or renal plasma flow (or both); and, second, that a sustained increase in interstitial pressure and renal plasma flow is not required for the natriuresis to persist.

A definition of proximal and distal tubular compliance. Practical and theoretical implications.

Micropuncture studies were carried out in the rat to evaluate the in situ distensibility characteristics of the proximal and distal tubules under a variety of experimental conditions. In the first phase, we determined the response of tubular diameter (D) to changes in tubular pressure (P) induced by partially obstructing single tubules. The response observed under these conditions (i.e., when interstitial pressure is presumed to be constant) has been defined as the compliance of the tubule. Over the range of tubular pressures studied (10-35 mm Hg for the proximal tubule, 5-25 mm Hg for the distal tubule) the compliance characteristics of the proximal and distal tubule were found to be markedly different; the proximal tubular pressure-diameter relationship was linear, DeltaD/DeltaP = 0.45 mum/mm Hg, whereas the distal pressure-diameter relationship was curvilinear, DeltaD/DeltaP = c(-0.1xP+2.2). In the second phase we used the compliance data to construct a series of theoretical pressure-diameter curves that define the response of the tubule to increments in interstitial as well as intratubular pressure. These curves indicate that changes in distal diameter should provide a sensitive index of a rise in interstitial pressure under conditions in which the transtubular pressure gradient is increased by a small amount, but that proximal diameter should provide a more sensitive index of changes in interstitial pressure when the transtubular pressure gradient is increased by a large amount. In subsequent experiments in which furosemide was administered, we observed that the pressure-diameter relationships for both the proximal and distal tubule were indistinguishable from the compliance curves, a finding consistent with the interpretation that interstitial pressure was not appreciably changed from control. By contrast, when mannitol was administered, both proximal and distal tubular pressure-diameter relationships were significantly altered in a fashion consistent with a large increase in interstitial pressure. Neither with furosemide nor mannitol administration did it appear likely that significant changes in tubular compliance could account for the observed behavior of the tubule.Finally, we propose that a knowledge of tubular compliance will be useful in exploring the interrelationships between tubular and peritubular pressures, tubular anatomy, and transtubular ionic permeability. Recent studies linking changes in the geometry of lateral intercellular spaces of the tubule to changes in passive ion movement suggest that an investigation of such anatomical-functional correlates should be productive.

Impaired renal vasodilation and urinary cGMP excretion in Dahl salt-sensitive rats.

We previously have shown that Dahl salt-sensitive rats increase renal vascular resistance in response to excessive salt feeding before total peripheral resistance increases and hypertension occurs. Failure of renal vasculature to dilate, as normally occurs in Dahl salt-resistant rats fed a high salt diet, may play a role in the development of hypertension in Dahl salt-sensitive rats. We also showed that renal vasculature in salt-sensitive rats is hyperreactive to vasoconstrictors and hyporeactive to vasodilators. Atrial natriuretic peptide, by stimulating cell-bound receptors, and nitroprusside, by generating nitric oxide, cause renal vasodilation by generating cGMP. Studies were undertaken to determine whether defective renal vasodilation in Dahl salt-sensitive rats is due to impaired production of cGMP. We examined the influence of nitroprusside infusion and salt intake on renal vascular resistance and cGMP excretion in salt-sensitive rats. Results demonstrate that salt feeding and nitroprusside infusion increase cGMP excretion and decrease renal vascular resistance in salt-resistant rats (P < .01), and, although this relationship was less clear in salt-sensitive rats, there was a reciprocal relationship between renal vascular resistance and cGMP excretion in all animals studied. Salt feeding and nitroprusside infusion caused less of an increase in cGMP excretion in salt-sensitive than in salt-resistant rats (P < .01). In conclusion, these studies support the concept that impairment in cGMP generation may play a primary role in the inability of the kidneys of Dahl salt-sensitive rats to vasodilate in response to increased salt intake. Such an impairment could contribute to salt retention and the development of hypertension.

Reversible hypertension due to carcinoma of the ureter.

A patient who presented with hypertension of recent onset was found to have unilateral hydronephrosis. Increased activity of the renin-angiotensin system was documented with renal-vein-renin concentrations. The hydronephrosis was due to a primary transitional cell carcinoma of the ureter. Following nephroureterectomy, blood pressure returned to normal and has remained so for two years.

Persistent hypophosphatemia following parathyroidectomy in end-stage renal disease: report of three patients.

Immediate and persistent hypophosphatemia following subtotal parathyroidectomy, despite discontinuation of phosphate binders, developed in three chronic hemodialysis patients. Although the serum phosphorous level is regularly reduced by parathyroidectomy in such patients, prolonged hypophosphatemia has not previously been reported. This observation supports the concept that parathyroid overactivity in end-stage renal disease is a major determinant of hyperphosphatemia.

Proteinuria in congestive heart failure.

To clarify the association between proteinuria and congestive heart failure (CHF), 24-hour urinary protein determinations were obtained from 27 patients with objectively documented CHF, before and after therapy of the CHF. The results demonstrate that modest proteinuria is a frequent feature of CHF and that this proteinuria reverses promptly with successful CHF therapy. Proteinuria exceeding 500 mg/day occurred only in patients with acute pulmonary edema. However, there was no other correlation between severity of proteinuria and type or chronicity of CHF. When proteinuria exceeds 1 g/24 h or when proteinuria does not reverse within 2 weeks of successful CHF therapy, intrinsic renal disease should be suspected.

Glucose and glycerol compared as osmotic agents for peritoneal dialysis.

The potential utility of glycerol as an osmotic agent for peritoneal dialysis was evaluated by conducting both isosmotic and hyperosmotic exchanges in anesthetized rats. Similar exchanges were conducted using glucose, and the results with the two agents were compared. During hyperosmotic exchanges both agents produced significant osmotic flow of water, but at initial molar concentrations that were equal the flow observed with glycerol was nearly 40% less than that observed with glucose. The lower volume transport generated by glycerol was found to be due to its surprisingly rapid removal from peritoneal fluid when it was present at hyperosmotic concentrations, but paradoxically during isosmotic exchanges, when its concentration was low, glycerol was absorbed only slightly faster than glucose. The observed increase in peritoneal permeability when glycerol was used resulted in a twofold increase in the caloric load imposed per unit of water removed in comparison with glucose.

Formulating and evaluating quantitative models of control of sodium stores.

Numerous factors that influence sodium handling have been identified, and many have been studied in minute detail; however, relatively little information is available regarding either the steady-state relationship between dietary sodium intake and sodium stores or the transient response of intact animals to challenges to sodium homeostasis. In this paper the principles of elementary feedback control theory have been used both to obtain and analyze quantitative models of the feedback control of sodium stores. It has been assumed that the sodium content of the body determines the rate of urinary sodium excretion, and a mass balance has been used to obtain differential equations that describe the dynamics of sodium stores. Both first- and second-order models are considered, and their predictions for both steady states and transients are compared critically with observations from the literature, using data from human studies whenever possible. The results indicate that a relatively simple proportional feedback controller describes most available data well; however, gaps in the available information are identified, and opportunities for future experimental investigation are described.

Errors in estimates of peritoneal fluid volume.

Inherent limitations in the suitability of drainage volumes for monitoring intraperitoneal fluid volume have resulted in the frequent use of indicator dilution techniques, but little attention has been given to confirming the adequacy of the estimates that volume markers provide. In a series of experimental exchanges in rats, volume estimates were compared based on the dilution of blue dextran and hemoglobin with direct collections of surgically exposed intraperitoneal fluid. Significant systematic and random errors in the indicator dilution volume estimates were observed. The systematic errors appeared to be due to the rapid removal of a fixed amount of marker from peritoneal fluid, while the random errors were caused by the rapid appearance of a variable amount of endogenous chromogen. The behavior of the markers observed in this study was not consistent with the assumptions commonly used to analyze volume transport in peritoneal dialysis.

A graph theory model of the glomerular capillary network and its development.

Graph theory methods were used to analyze the topology of the renal glomerular capillary network using data both from a serial reconstruction of a rat glomerulus and from the literature. The graphs obtained were tested for planarity, and all but one were found to be nonplanar. This result indicated that the development of the glomerular capillary network must include a nonplanar growth process, and new growth models were proposed. In addition, the statistical properties of capillary branching patterns were analyzed, and a node degree distribution function estimate was obtained.

The use of polyelectrolytes as osmotic agents for peritoneal dialysis.

Various small and large molecules have been studied as osmotic agents to replace dextrose in peritoneal dialysis. Macromolecules are attractive because of their slow absorption from intraperitoneal solutions; however, it has been assumed that they are only marginally effective as osmotic agents unless they function as polyelectrolytes at physiological pH. In experimental exchanges conducted in rats we measured volume changes induced by Gelifundol (5.5% oxypolygelatin) and Ringers lactate to which was added either nothing, 4.25% dextrose, or 5% albumin. In the control exchanges using Ringers lactate, intraperitoneal fluid volume remained unchanged for eight hours. The volume changes induced by 4.25% dextrose were complete within two hours and resulted in a two-thirds increase over the amount of fluid administered. In both series in which polyelectrolytes were used volume transport was sustained throughout an eight hour dwell. With 5% albumin the total increase in fluid volume was about 40% of that installed, while Gelifundol caused fluid volume to double. Qualitatively similar results were obtained in transport studies conducted in vitro. Physical studies of the oxypolygelatin solutions indicated that the fixed charges per liter were comparable to those in the albumin solutions. Thus the different volume transport the two proteins induced could not be attributed to Donnan effects. However, since the molecular weight of albumin is triple that of Gelifundol the van't Hoff pressures of the two macromolecules can explain the observed differences in volume transport. These results suggest that neutral macromolecules deserve further study as potential osmotic agents for peritoneal dialysis.

Renal tubular transport of penicillin G and carbenicillin in the rat.

The pattern of transport of penicillin G and carbenicillin was examined directly in the rat kidney by means of micropuncture studies. Samples of plasma, tubular fluid, and urine were assayed for antibiotic content by an agar diffusion technique. Secretion accounted for 67% of the penicillin G but for only 37% of the carbenicillin present in the proximal tubule. No further net secretion of either agent could be detected in the distal nephron. Net secretion of penicillin G decreased from 67% in the distal tubule to 60% in the urine (P less than 0.05%); this reduction correlated with reabsorption of water from the collecting ducts. Both penicillin G and carbenicillin were secreted by the proximal tubule of the rat nephron, but the latter was secreted at a lower rate than the former. A significant fraction of penicillin G was reabsorbed from the collecting ducts under conditions of maximal antidiuresis.

Dissociation of saline-induced natriuresis from urea washout in the rat.

Medullary urea washout has been postulated to play a major role in the natriuretic response to volume expansion (VE). To examine this hypothesis, renal tissue solute composition was measured in a natriuretic and nonnatriuretic model of VE. Renal tissue composition was analyzed during hydropenia, acute VE, acute VE with renal artery pressure reduced to 70 mmHg at the onset of saline loading (immediate clamping), and acute VE with renal artery pressure reduced to 70 mmHg after 45 min of saline loading (delayed clamping). Immediate clamping, a nonnatriuretic model of VE, prevented VE-induced urea washout and the increase in sodium and water content in the cortex and outer medulla. Delayed clamping, a natriuretic model of VE, produced a pattern of tissue composition very similar to immediate clamping. Tissue urea content was not significantly different in the two protocols and only minor differences in sodium and water content were noted. Thus, under these experimental conditions, VE-induced natriuresis can be dissociated from medullary urea washout, and other mechanisms must be invoked to explain the increased sodium excretion.

Effect of variations in dietary sodium intake on sodium excretion in mature rats.

Sprague-Dawley rats weighing 400 g or more were studied to determine whether their continued weight gain affects renal sodium handling. Rats maintained on a wide range of sodium intakes gained 3.9 +/- 0.4 g/day. The intercept of a linear regression of intake against urinary excretion provided an estimate of the minimum daily requirement for sodium intake of 247 +/- 33 microEq/day. When more than this required amount was ingested, the animals excreted the excess quantitatively in the urine. When less was ingested they continued to gain weight at a slower rate, 1.6 +/- 0.6 g/day, and remained in positive sodium balance. Nonetheless, they developed a sodium deficit manifested as retention of a sodium challenge. Thus, on an adequate dietary intake the normal physiological state of Sprague-Dawley rats of this size is one of chronic sodium retention rather than neutral sodium balance. In contrast, when inadequate sodium is ingested a deficit develops in the absence of external losses. These observations have important implications for the interpretation of studies of renal sodium handling in these animals.