Countercurrent Exchange and Transport Properties

General Concepts

It is broadly accepted that the microcirculation of the renal medulla is a countercurrent exchanger that traps NaCl and urea deposited to the interstitium by the loops of Henle and collecting ducts. Textbook illustrations generally show parallel vessels that equilibrate by diffusion. Most simply, DVR blood flow is concentrated by diffusive influx of NaCl and urea as blood flows from the corticomedullary junction toward the papillary tip. Conversely, blood flowing toward the corticomedullary junction in AVR is diluted by diffusive efflux so that solute is trapped and recycled. Recent studies have shown that this depiction of a purely diffusive "U-tube" exchanger is oversimplified. Osmotic removal of water from DVR across water channels occurs, sieving NaCl and urea to concentrate these solutes in DVR plasma. Thus, both molecular sieving and diffusion contribute to equilibration of DVR plasma with the interstitium. As discussed later, shunting of water from DVR to AVR in vascular bundles might play a role in optimization of urinary concentrating ability by reducing blood flow rate to the deep medulla.

Efflux of Water from DVR

DVR plasma protein concentration rises along the direction of blood flow, indicating water loss from plasma to renal medullary interstitium. Thus, DVR and nephrons deposit water to the renal medulla and AVR take up that water, accounting for overall mass balance. Water efflux from DVR raises two paradoxes. First, the purpose of depositing water from DVR plasma to the hypertonic medullary interstitium seems enigmatic. Second, Starling forces (hydraulic and oncotic pressure) do not account for the direction of DVR water transport because intraluminal oncotic pressure that favors water uptake exceeds the hydraulic pressure that favors efflux. NaCl and urea gradients generated by the lag in equilibration of DVR blood with interstitium favor water efflux and could account for osmotic water abstraction from DVR, but this requires the presence of a "small pore" pathway across which such small solutes exert effective osmotic driving force. The discovery of the aquaporins led to the molecular identification of that route (Figure 2A). Blockade of aquaporin-1 (AQP1) with mercurial agents or AQP1 knockout eliminates water efflux driven by abluminal hypertonic NaCl [3, 5]. Thus, transport of water across the DVR wall must be described by at least two parallel pathways, the properties of which are summarized in Table I. One is the highly water-selective AQP1 molecule. Another is a "large pore" route, likely paracellu-lar, that conducts the majority of water movement driven by Starling forces. Evidence is consistent with the notion that the paracellular pathway offers little or no restriction to con-vective small solute flux (small solute reflection coefficient nearly 0, oSS ~ 0) while the AQP1 pathway is completely restrictive (oSS ~ 1). In addition to AQP1, another mercurial insensitive pathway conducts water efflux across the DVR wall when the driving solute is urea, glucose, or raffinose.

Figure 1 Anatomy of the medullary microcirculation. Cortex: Interlobular arteries arise from the arcuate artery and ascend toward the cortical surface. Juxtamedullary glomeruli arise at a recurrent angle from the interlobular artery. The majority of blood flow reaches the medulla through juxtamedullary efferent arterioles; however, some may also be from periglomerular shunt pathways. Outer medulla: In the outer stripe, jux-tamedullary efferent arterioles give rise to DVR that coalesce to form vascular bundles in the inner stripe. DVR on the periphery of vascular bundles give rise to the interbundle capillary plexus that perfuses nephrons (thick ascending limb, collecting duct, long looped thin descending limbs, not shown). DVR in the center continue across the inner-outer medullary junction to perfuse the inner medulla. Thin descending limbs of short looped nephrons may also associate with the vascular bundles in a manner that is species dependent (not shown). Inner medulla: Vascular bundles disappear in the inner medulla and vasa recta become dispersed with nephron segments. AVR that arise from the sparse capillary plexus of inner medulla return to the cortex by passing through outer medullary vascular bundles. DVR have a continuous endothelium (inset) and are surrounded by contractile pericytes. The number of pericytes decreases with depth in the medulla. AVR are highly fenestrated vessels (inset). As blood flows toward the papillary tip, NaCl and urea diffuse into DVR and out of AVR. Transmural gradients of NaCl and urea abstract water across the DVR wall across aquaporin-1 water channels. Reproduced with permission from Ref. [2]. Renal Medullary Microcirculation in Encyclopedia of the Microcirculation, edited by David Shepro, Elsevier Inc.

Figure 2 Osmotic water permeability of murine DVR. (A) All Pf measurements are summarized (ordinate, mean SE) for AQP1 -/- (left) and +/+ mice (right). The solute used to drive water movement is shown on the abscissa. Transmural NaCl gradients failed to induce water flux across AQP1-deficient DVR; however, larger solutes (glucose, urea, raffinose) were effective. Reproduced with permission from Ref. [3]. (B) Simultaneous measurement of 14C-urea (Py) and 22Na (PNa) permeability was performed by dual isotope microperfusion of outer medullary (OMDVR), inner medullary descending vasa recta (IMDVR), or inner medullary ascending vasa recta (IMAVR). OMDVR were studied by in vitro perfusion while inner medullary vessels were perfused on the surface of the exposed papilla in vivo. OMDVR PU was always high, independent of PNa. This is due to expression of the UTB urea carrier in DVR endothelia. Reproduced with permission from Ref. [4]. Renal Medullary Microcirculation in Encyclopedia of the Microcirculation, edited by David Shepro, Elsevier Inc.

Figure 2 Osmotic water permeability of murine DVR. (A) All Pf measurements are summarized (ordinate, mean SE) for AQP1 -/- (left) and +/+ mice (right). The solute used to drive water movement is shown on the abscissa. Transmural NaCl gradients failed to induce water flux across AQP1-deficient DVR; however, larger solutes (glucose, urea, raffinose) were effective. Reproduced with permission from Ref. [3]. (B) Simultaneous measurement of 14C-urea (Py) and 22Na (PNa) permeability was performed by dual isotope microperfusion of outer medullary (OMDVR), inner medullary descending vasa recta (IMDVR), or inner medullary ascending vasa recta (IMAVR). OMDVR were studied by in vitro perfusion while inner medullary vessels were perfused on the surface of the exposed papilla in vivo. OMDVR PU was always high, independent of PNa. This is due to expression of the UTB urea carrier in DVR endothelia. Reproduced with permission from Ref. [4]. Renal Medullary Microcirculation in Encyclopedia of the Microcirculation, edited by David Shepro, Elsevier Inc.

The UTB urea transporter is expressed by DVR endothelia and exhibits mercurial insensitive water channel activity. The role of UTB to conduct water as well as urea flux across the DVR wall has yet to be examined. Simulation of these various transport pathways has been the underpinning of recent mathematical models of medullary microvascular exchange [7].

Mathematical simulations showed that DVR AQP1 might improve medullary concentrating ability by providing a route through which DVR water is shunted to AVR. The effect of that activity in the superficial medulla is to reduce blood flow to the deep medulla where interstitial gradients of NaCl and urea are most steep. A broadly unsettled question concerns regulation that might shift DVR equilibration between diffusive influx and water efflux/molecular sieving. High DVR solute permeability favors diffusive influx while low permeability favors water efflux across endothelial AQP1 water channels. If DVR permeability is acutely or chronically regulated, effects on "solute washout" and perfusion of the deep medulla would be expected to occur.

AVR Water Uptake

As required for overall mass balance in the medulla, AVR must remove the water deposited to the interstitium by nephrons, collecting ducts, and DVR. Transmural oncotic pressure gradients favor water uptake across the AVR wall and AVR hydraulic conductivity is very high [8, 9]. In vivo, transmural gradients in the AVR generated by the osmotic lag between blood and interstitium are directed to favor water uptake (luminal concentration greater than interstitial concentration). For AVR water uptake to be augmented by those gradients, the AVR wall must have nonzero reflection coefficients to NaCl and/or urea and transmural gradients of those solutes must be of significant magnitude. Rigorous measurements of AVR NaCl and urea reflection coefficients have been thus far impossible to obtain, but the general hypothesis that NaCl might augment transmural volume flux has been tested. In contrast to similar experiments in DVR, in vivo microperfusion of AVR with buffers made hypertonic or hypotonic to the papillary interstitium yielded no measurable water flux [10], suggesting that AVR reflection coefficients to small hydrophilic solutes is negligible (Sss - 0).

Vasa Recta Solute Permeability

As blood flows from the corticomedullary junction toward the papillary tip, rising interstitial concentrations of NaCl and urea are encountered. Those solutes equilibrate with the DVR lumen; however, the lag creates transmural gradients so that interstitial NaCl and urea concentrations exceed their respective concentrations in DVR plasma. Diffusive influx of NaCl and urea is favored. Additionally, the transmural gradient abstracts water across AQP1 water channels leading to molecular sieving of NaCl. Thus both diffusion and sieving across AQP1 contribute to DVR plasma equilibration. Quantification of diffusive permeabilities of the DVR wall to NaCl has been achieved by measurement of the rate of efflux of radiolabeled tracers from microperfused vessels. Those experiments have been performed both in vivo, on the surface of the exposed papilla, and in vitro, in isolated microperfused DVR. A summary of reported permeability measurements is provided in Table II. In vivo perfusion can underestimate permeabilities if the rate of diffusion of the isotopes away from the vessel in the surrounding interstitium is too low. In that case, 22Na or [14C]urea concentrations on the abluminal surface accumu

Table I Hydraulic Conductivity (Lp), Osmotic Water Permeability (Pf), and Reflection Coefficients of Vasa Recta.

Parameter

OMDVR

IMDVR

IMAVR

Driving force

Lp x 10-6 (cmsec-

'mmHg-')

1.4a

Albumin gradient

Lp x 10-6 (cmsec-

'mmHg-')

1.6

Albumin gradient

Lp x 10-6 (cmsec-

'mmHg-')

0.12b

NaCl gradient

Lp x 10-6 (cmsec-

'mmHg-')

12.5

Hydraulic pressure

Parameter

OMDVR

IMDVR

IMAVR

Method

salbumin

0.89c

Sieving

Salbumin

0.78

Sieving

Salbumin

0.70

Osmotic

SNa

<0.05d

0.00d

Osmotic

SNa

~0.03d

Osmotic

SNa

~1.0e

Sieving

SRaffinose

~1.0e

Sieving

a Assumes a reflection coefficient to albumin of 1.0.

b Evidence shows that transmural NaCl gradients drive water flux exclusively through water channels, whereas albumin drives water flux predominantly through water channels along with a small component via other pathway(s). c Not significantly different from 1.0. d Measurement of cNa for the vessel wall as a whole.

e 0Na, SRaffinose for the aquaporin-1 water channel pathway through which NaCl gradients drive water flux. References to original data in Ref. [6].

a Assumes a reflection coefficient to albumin of 1.0.

b Evidence shows that transmural NaCl gradients drive water flux exclusively through water channels, whereas albumin drives water flux predominantly through water channels along with a small component via other pathway(s). c Not significantly different from 1.0. d Measurement of cNa for the vessel wall as a whole.

e 0Na, SRaffinose for the aquaporin-1 water channel pathway through which NaCl gradients drive water flux. References to original data in Ref. [6].

late, violating the assumption of zero abluminal concentration. In vitro perfusion, due to the presence of a continuously flowing bath, is less likely to yield errors from such boundary layer effects, but necessitates the trauma of isolation and exposes the vessel to artificial buffers that could alter transport properties. In addition, DVR permeability is strongly dependent upon perfusion rate. Whether this rate dependence exists in vivo is uncertain but has important implications. If the true DVR NaCl permeability is very low, then abstraction of water across AQP1 might be the dominant mode of NaCl equilibration. That mode of equilibration may reduce blood flow to the deeper regions of the medulla and enhance interstitial osmolality. DVR urea permeability is the sum of transport via phloretin-sensitive transcellular, carrier-mediated route(s) and other, for example pericellular, pathways (Figure 2B). Histochemical evidence and in situ hybridization have identified the DVR urea transporter as the same as that expressed by the RBC-UTB.

AVR solute permeability has not been as thoroughly evaluated as that in DVR because AVR have not been isolated and perfused in vitro, owing to technical difficulties. Transport properties have been measured only by the difficult approach of in vivo microperfusion of vessels on the surface of the exposed papilla of rats and hamsters (Table II). The values so obtained exceed DVR permeabilities but, even so, are probably underestimated because the 22Na and 14C-urea tracers might have accumulated in the interstitium to significant levels.

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