Search

Diuretics have been used in acute renal failure in an attempt to increase urine flow and ameliorate the reduction in glomerular filtrate rate. A beneficial response occurs in some experimental models of acute renal failure when diuretics are administered prophylactically or very early in the course of renal failure and may require a renal vascular bed capable of responding partially, at least, to vasodilating stimuli. In chronic renal insufficiency the most important indications for diuretic use are for the treatment of systemic hypertension and for the correction of the congested state. However, the precise effect of diuretic therapy under these conditions is unpredictable and dependent on the functional state of the renal vessels. Diuretic administration may at times prove detrimental, resulting in a deterioration of glomerular filtration rate. In hemodynamically unstable conditions the slow removal of extracellular fluid by continuous arteriovenous hemofiltration may prove preferable to diuretic administration or standard forms of dialysis.

Studies were performed to evaluate the effects of the chronic administration of furosemide on hydrogen and electrolyte excretion in dogs on a normal electrolyte diet and in the absence of electrolyte or volume depletion. Control daily excretion in five dogs averaged 64 meq for Na, 51 meq for K, 66 meq for Cl, and 17 meq for net H. Furosemide, 40 mg, in the drinking water 3 times daily was given for 4 days. On day 1 Na excretion averaged 128 meq, but thereafter was not significantly different from control levels. Over 4 days cumulative net H excretion increased 63.6 meq and plasma HCO3 rose 6.6 meq/liter. The same dogs were restudied by the same protocol except that, to obviate electrolyte depletion, NaCl and KCl were administered daily in quantities sufficient to replace urinary losses. All dogs remained in positive Na, K, and Cl balance. Body weight, hematocrit, plasma albumin, creatinine, and plasma renin activity were unchanged, indicating the absence of electrolyte or volume depletion. Nonetheless, cumulative net H excretion increased 61.2 meq and plasma HCO3 increased 4.3 meq/liter. Two adrenalectomized dogs receiving steroid replacement showed similar changes in net H excretion and plasma HCO3. These experiments suggest that chronic furosemide administration may enhance H excretion and generate alkalosis even in the absence of volume or electrolyte depletion and without increased aldosterone secretion.

Free-flow micropuncture and clearance studies were performed to evaluate the transport of allantoin inthe rat kidney. Inn all studies [2-14C]uric acid and [methoxy-3H]inulin were administered. With a two-step column chromatographic technique, radiolabeled uric acid and allantoin were separated in plasma, urine, and tubular fluid, and the [2-14C]allantoin concentration was determined. Tubular fluid collections were obtained under hydropenic and control coneated animals in the control and volume-expanded states. Clearance data were obtained in oxonic acid-treated animals under the same experimental conditions. These studies indicate that allantoin is not bound to plasma protein and is, therefore, freely filterable. Neither net reabsorption nor net secretion of allantoin was evident along the length of the nephron. The bubular handling of allantoin was demonstrated to be dissociated from that of uric acid in all experimental states. No significant intrarenal production of allantoin from uric acid was observed.

Clearance experiments were performed in male Sprague-Dawley rats to determine the effect of mannitol on phosphate (Pi) transport. Solutions of 10 per cent mannitol or normal saline were infused at progressively increasing flow rates with or without parathyroid extract (PTE) infusion into the following animals: Group I: Intact Rats-Mannitol Infusion: A--Intact, hypocalcemic; B--Intact, normocalcemic, normomagnesemic; Group II: TPTX Rats: A--Mannitol infusion; B--Mannitol + PTE infusion; C--Hydropenia + PTE infusion; and D--Saline + PTE infusion. In contrast to previous reports, mannitol increased Pi excretion in intact rats. When Ca + Mg were maintained constant in intact rats or after TPTX, mannitol failed to increase Pi excretion. In TPTX rats receiving mannitol + PTE, increased Pi excretion was again noted. Comparison of Pi excretion during PTE infusion during hydropenia and volume expansion with mannitol or saline in TPTX rats revealed significantly higher Pi excretion with volume expansion. Pi excretion paralleled Na excretion in intact mannitol-loaded and PTE-infused TPTX animals undergoing a mannitol or saline diuresis. Pi and Na excretions, however, were dissociated in mannitol-loaded TPTX rats, intact animals receiving simultaneous Ca and Mg infusion, and TPTX hydropenic animals receiving PTE. These studies indicate that (1) mannitol increases Pi excretion in intact rat, (2) the phosphaturia is PTH-mediated, (3) Pi and Na excretions can be dissociated, and (4) volume expansion with either mannitol or saline enhances the effect of PTH on Pi transport in the renal tubule.

After the relief of 24 hr of complete unilateral ureteral obstruction in the dog, the experimental kidney is characterized by a decrease in filtration rate and an increase in fractional and often absolute excretion of sodium before and after the administration of mannitol. In the hydrated state, the failure to conserve sodium is associated with increases in fractional free water clearance and fractional sodium supply to water-freeing sites signifying that the augmented sodium excretion is derived from a proximal source. In the hydropenic state there is decreased fractional free water reabsorption, and sometimes free water excretion, in the postobstructive kidney. An early plateau in free water reabsorption is associated with an increased fractional excretion of sodium. These findings are attributed to the early development of distal nephron impermeability to water as a result of enhanced distal tubular supply and transport of sodium. There is a decrease in maximal tubular reabsorptive capacity (Tm) of glucose in the post-obstructive kidney which is, however, less marked than the decrease in filtration rate. The fall in filtration rate is to some extent likely due to a dropping out of nephrons from the circulation while the remaining nephrons are hypoperfused. The magnitude of the sodium reabsorptive defect is markedly exaggerated as the concentration of nonreabsorbable solute (mannitol) in the glomerular perfusate is increased. It is concluded that the postobstructive increase in sodium excretion during mannitol administration is in part due to a limit in the capacity to reabsorb sodium against a concentration gradient in the proximal tubule.

We performed studies on dogs under hydrated conditions, utilizing the rate of free water formation (C(H2O)) as an index of the rate of distal tubular sodium transport. Since C(H2O) could be progressively increased with no evidence of a maximal rate during loading with hypotonic (2.5%) mannitol, it was concluded that there is no limit on distal tubular sodium transport during mannitol loading. In contrast, during hypotonic (0.45%) saline loading C(H2O) rose initially, but as urine flow (V) exceeded 25% of the filtered load C(H2O) attained maximal levels (up to 20% of the filtered load) and remained stable as V increased to 50% of the filtered load. It was concluded that saline loading progressively inhibits proximal sodium reabsorption. Initially, the distal tubule absorbes a large fraction of the proximal rejectate and sodium excretion rises slightly. Eventually, an alteration in distal sodium transport appears which culminates in a maximal rate or transport limit. This distal transport limit provoked by saline loading could not be characterized by a classical Tm as seen with glucose and does not seem to be consequent to high rates of flow through the distal tubule. Regardless of the precise nature of this limit, the major increment in sodium excretion develops during saline loading only after saline alters the capacity of the distal tubule to transport sodium.