Direct and indirect cost of urea excretion

Abstract

Urea, the major end product of protein metabolism in mammals, is the most abundant solute in the urine. Urea excretion is thought to result from filtration curtailed by some passive reabsorbtion along the nephron. This reabsorption is markedly enhanced by vasopressin and slow urinary flow rate (V), the fraction of filtered urea excreted in the urine (FEurea) falling from approximately 60% at high V to only approximately 20% at low V. In concentrated urine, normal urea excretion can be maintained only if urea filtration is elevated. This can be achieved by increasing plasma urea concentration (Purea) and/or GFR. We have shown that both parameters do increase when normal rats are submitted to chronic alterations in the water intake/vasopressin axis within the normal range of physiologic regulation. This situation is very similar to that observed after alterations in protein intake. In both cases more urea needs to be filtered, either because more of it has to be excreted, or because the efficiency of its excretion is reduced. A common mechanism is proposed to explain the rise in GFR observed in the two situations. In summary, our studies demonstrate that the antidiuretic effects of vasopressin are responsible for a significant elevation of GFR. This GFR adaptation limits the rise in Purea, a favorable effect because urea is not as harmless as usually thought. However, this hyperfiltration might have deleterious consequences in diseased kidneys.

Vasopressin contributes to hyperfiltration, albuminuria, and renal hypertrophy in diabetes mellitus: Study in vasopressin-deficient Brattleboro rats

“…Hyperfiltration occurring in the early phase of DM (38)(39)(40) is known to lead to a delayed progressive deterioration of renal function (1). Now, chronic elevation in plasma VP, or in its selective V2 agonist dDVP, has been shown to induce distinct glomerular hyperfiltration (11,12,(41)(42)(43), rise in albumin excretion (suggesting an alteration of the glomerular filter) (14), and renal hypertrophy (15). In rats with 5͞6 nephrectomy, a reduction in VP level, brought about by a chronic elevation in water intake, slowed down the progression of chronic renal failure (10).…”

“…The effects of VP on glomerular filtration rate (GFR), albuminuria, and kidney hypertrophy are thought to result, indirectly, from its antidiuretic activity and the ensuing alterations in tubulo-glomerular feedback control of glomerular haemodynamics (12,15,18). In addition to its renal effects, VP also may influence vascular resistance through V1a receptors, expressed in smooth muscle cells.…”

Vasopressin V2 receptors, ENaC, and sodium reabsorption: a risk factor for hypertension?

“…Although the kidney needs to excrete a relatively large daily load of urea (on a normal protein intake), the vasopressin-dependent urea transporter UT-A1, located in the terminal inner medullary CD (54), allows significant amounts of urea to be reabsorbed. This improves urea accumulation in the medullary interstitium and favors overall urine concentration (33), but results in less efficient excretion of urea (like for sodium with the effect on ENaC), as illustrated by the fall in fractional excretion of urea with declining urine flow rate (8). Thus vasopressin's actions on ENaC in the cortex and outer medulla, on the one hand, and on UT-A1 in the inner medulla, on the other, can be viewed as two independent and additive means to improve water conservation (Fig.…”

“…7). The less efficient urea excretion due to vasopressin action is compensated for by an increase in plasma urea level that allows more urea to be filtered (8,17). The less efficient sodium excretion may secondarily induce pressure-natriuresis.…”

Structure and permeation mechanism of a mammalian urea transporter

“…In mammals, UTs are expressed in a wide variety of tissues, but their function is best understood in the kidney where they contribute to maintaining the high interstitial urea concentration necessary to limit the rate of water loss (1)(2)(3). During periods of water deprivation, the kidney develops a steep urea gradient from the cortex at 5-8 mM (roughly the concentration present in plasma), to as much as 100-fold higher in the inner medulla (4). While active transport of ions out of the renal tubules is currently thought to provide the main energetic driving force for creating this gradient, passive transport through UTs also contributes through a countercurrent exchange mechanism that slows the diffusion of urea away from the inner medulla (5).…”