Challenges and intriguing problems in comparative renal physiology
Department of Physiology, College of Medicine, University of Arizona, Tucson, AZ 85724-5051, USA
e-mail: dantzler{at}u.arizona.edu
Accepted 14 December 2004
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Summary |
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Key words: glomerular ultrafiltration, epithelial fluid transport, urate transport, avian kidney, reptilian kidney
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Introduction |
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Quantification of glomerular ultrafiltration |
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Pressure profiles
In a classical anatomical study of the renal glomerulus, William Bowman
(1842) examined kidneys from
mammals (including humans), birds, reptiles, amphibians and fishes in order to
evaluate the structural relationships between them. Differences between
mammalian and avian glomerular capillary networks were evident in Bowman's
drawings and are shown even more clearly in more recent studies of structure
(Spinelli et al., 1972
;
Casotti and Braun, 1995
). In
mammals, the glomerular capillaries form a complex network of thoroughfare
channels that anastomose freely (Spinelli
et al., 1972
), whereas in birds a single unbranched glomerular
capillary coils around the periphery of the renal corpuscle
(Casotti and Braun, 1995
).
Indeed, in the small, superficial loopless avian nephrons (sometimes called
`reptilian-type' nephrons), there may be only a single capillary loop
(Fig. 1). This simple structure
offers a unique opportunity to examine pressure profiles in a high-pressure
glomerular filtration system as described below.
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Ultrafiltration at the renal glomerulus produces an essentially
protein-free filtrate of the plasma, with which it is in Donnan equilibrium
(Navar, 1978;
Renkin and Gilmore, 1973
). If
the total capillary network is considered a cylinder of equivalent surface
area, the single nephron filtration rate (SNGFR) may be described by
the following version of the Starling equation:
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In this equation, l is the length of the cylinder, x is
the distance along the cylinder, A is the glomerular capillary area
available for filtration and Lp is hydraulic conductivity. Since
random micropuncture measurements of the glomerular capillary hydrostatic
pressure (PGC) in mammalian glomeruli show little
variation (Brenner et al.,
1971), PGC apparently decreases little along
the length of the capillaries. Although the small decrease in
PGC along the length of the capillaries is essential for
flow to occur, it can be ignored in the simplest treatments of the above
relationship and PGC can be considered to be constant
throughout the length of the cylinder. The transmural hydrostatic pressure
difference is then equal to the difference between PGC and
the hydrostatic pressure in the space outside the capillaries (Bowman's
space), which is continuous with the lumen of the proximal tubule. This
pressure in Bowman's space (PBS) is also considered to be
constant. Because the protein that is filtered and enters Bowman's space is
negligible, it can be ignored and the colloid osmotic pressure of the plasma
(PCOP) alone can be considered the net colloid osmotic
pressure that opposes the hydrostatic pressure driving filtration. Although
PGC apparently decreases only slightly along the length of
the capillaries, the PCOP rises markedly as filtration
occurs. This results from the fact that the protein concentration in the
capillaries increases reciprocally with the fraction of water remaining in
them and PCOP increases as an exponential function of the
increasing protein concentration (Landis
and Pappenheimer, 1963
). Filtration will occur only as long as the
net outwardly directed hydrostatic pressure
(PGC-PBS) exceeds the opposing
PCOP. The difference between these two opposing pressures
is the net ultrafiltration pressure (PUF).
Models based on mammalian micropuncture studies
(Brenner et al., 1972) indicate
that if filtration equilibrium is reached along the length of the capillaries,
the glomerular filtration rate is proportional to plasma flow along the
capillaries. Changes in plasma flow under these circumstances alter the shape
of the rising PCOP curve. However, the complexity of the
capillary network in the mammalian glomerulus prevents determination of the
precise site of each pressure measurement or of the exact profile of the
PCOP curves along the length of the capillaries from the
afferent to the efferent end. No such pressure measurements have yet been made
in avian glomerular capillaries, but the simplicity of the single loop of
glomerular capillary in the superficial loopless nephrons
(Fig. 1) should permit direct
determination of the pressure profiles in glomeruli from any species that are
accessible to micropuncture. This will take some exploration and careful,
meticulous work, but it should be possible for the interested investigator.
Birds, like mammals, are homeotherms with high arterial pressures. Therefore,
it appears likely that such measurements, which cannot be made in mammals,
would provide very important information concerning glomerular function in
both vertebrate classes.
Capillary area available for filtration
The integrated rate of glomerular ultrafiltration is determined not only by
PUF but also by the glomerular capillary area available
for filtration (A in the above equation) and on the water
permeability of the capillary wall (hydraulic conductivity, Lp). With
the apparent exception of the single loop of glomerular capillary in the avian
superficial loopless nephrons, the glomerular capillaries in other avian
nephrons are moderately complex and in mammals form a highly complex branching
network. The total area available for filtration in these complex networks is
a function of the length, diameter, and number of the capillary branches.
Moreover, the specific morphology of the capillary network, including the
capillary dimensions and branching pattern, as well as the microrheological
properties of the blood, determine the distribution of blood flow and, thus,
the area used for filtration. Because the area available for filtration is
unknown in such complex glomerular networks, A and Lp are
usually treated together in the equation above as the ultrafiltration
coefficient, Kf. However, in superficial avian glomeruli
found accessible to micropuncture, it should be possible not only to make the
pressure measurements discussed above but also to determine the area available
for filtration in this single loop and, thus, to calculate a specific value
for Lp, at least for one type of high pressure glomerulus. This
information, together with the pressure profiles in the same glomeruli, would
be enormously valuable for obtaining a quantitative understanding of
glomerular ultrafiltration.
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Fluid reabsorption by proximal renal tubules |
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In reptiles, however, the reabsorptive process for solutes and water in the proximal tubule appears to be quite different from that in mammals and amphibians. In fact, studies of this process in reptiles have raised a number of intriguing, unanswered questions about the coupling of solute and water transport across epithelia, the answers to which might materially advance our general understanding of transepithelial transport. However, the answers to these questions will only be obtained through further studies in this vertebrate class.
The initial micropuncture and microperfusion studies on lizards and snakes,
mentioned above (Dantzler and Bentley,
1978a; Stolte et al.,
1977
), indicated that water and sodium are (or at least can be)
reabsorbed at osmotically equivalent rates, but they did not demonstrate that
water reabsorption is dependent on sodium reabsorption. In fact, studies with
isolated, perfused garter snake (Thamnophis sp.) proximal tubules
indicate that neither sodium nor chloride is essential for normal fluid
reabsorption (Dantzler and Bentley,
1978a
). These studies involved replacement of sodium or chloride
or both with a number of substances commonly used as substitutes for them
[e.g. choline, tetramethylammonium (TMA), or lithium for sodium; methyl
sulfate for chloride; or sucrose for both sodium and chloride]. The critical
results of these studies are summarized in
Fig. 2. When sodium in the
perfusate is replaced with choline, net fluid reabsorption nearly ceases
(Fig. 2). However, when sodium
in the bathing medium is also replaced with choline so that the composition of
the two solutions is identical, net fluid reabsorption returns to the control
level (Fig. 2). The results are
the same when sodium is replaced with TMA, when chloride is replaced with
methyl sulfate, and when both sodium and chloride are replaced with sucrose
(Fig. 2). However, net fluid
reabsorption does not change when sodium is replaced with lithium in the
perfusate or in both the perfusate and bathing medium
(Fig. 2). Fluid reabsorption at
the control rates, regardless of the composition of the perfusate and bathing
medium, is isosmotic (at least within the margin of error of the cryoscopic
measurement system used) and can be at least partially inhibited by cyanide
and cold (Dantzler and Bentley,
1978a
). However, even when sodium is the primary cation in the
media, fluid reabsorption is not inhibited by removal of potassium from the
bathing medium or by addition of ouabain or other cardiac glycosides (highly
specific inhibitors of Na+-K+-ATPase) to it (Dantzler
and Bentley,
1978a
,b
).
This latter observation apparently reflects the lack of sensitivity of the
Na+-K+-ATPase in these reptilian tubules to cardiac
glycosides (Dantzler, 1972
).
Moreover, even with sodium as the primary cation, net fluid reabsorption is
independent of the buffer system (bicarbonate, phosphate or Tris) used, but it
is reduced about 18-25% by the removal of colloid from the peritubular fluid
(Dantzler and Bentley,
1978a
).
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These studies on snake renal tubules are fascinating because, in contrast
to studies on all other vertebrate species, they indicate that isosmotic fluid
reabsorption in the proximal tubule can occur in the absence of sodium and
chloride. However, they do not provide any information on the mechanism
involved in such transepithelial transport. One suggestion has been provided
by quantitative structural studies on these isolated, perfused tubules
(Dantzler et al., 1986).
Within a few minutes of the replacement of sodium in both the perfusate and
bathing medium with choline, the cells double in size and the intercellular
spaces nearly quintuple. During this time, the areas of the lateral and apical
cell membranes approximately double, but their surface densities remain
constant. This observation means that although the larger cells in the absence
of sodium have proportionally larger surface areas, the volume-to-surface area
ratio remains constant. The source of the membrane utilized in the rapid
increase in membrane area (perhaps intracellular vesicles) is unknown, but
certainly merits examination. In any case, these changes in membrane surface
area are correlated with the maintenance of the control rate of net fluid
reabsorption when sodium is replaced by choline
(Dantzler et al., 1986
),
suggesting that they may be related to the mechanism involved in such fluid
reabsorption. For example, they may permit a small, previously insignificant
driving force (perhaps even the osmotic pressure gradient across the
epithelium generated by the colloid in the bathing medium) to be sufficient to
produce a control level of net fluid reabsorption
(Dantzler et al., 1986
).
However, there is no direct evidence for such an occurrence. It is merely
speculation. Moreover, it does not provide an intellectually satisfying
explanation for the maintenance of such a constant rate of net fluid
reabsorption in the presence and absence of sodium. The process remains a
mystery that should intrigue the inquisitive investigator. Devising
experimental strategies to determine the mechanism(s) and to measure the
actual force(s) involved will, of course, test the ingenuity of such an
investigator. However, the solution of the problem, which could provide unique
insight into the coupled transport of solutes and water across epithelia, is
certainly exciting enough to warrant whatever effort it takes.
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Urate secretion by proximal renal tubules |
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Although urea is the major end product of nitrogen metabolism excreted by
the kidneys of all mammals, a small amount of uric acid is produced and urates
do appear in the urine (Roch-Ramel,
1979). In most mammals, filtered urate undergoes net reabsorption
by the renal tubules (Roch-Ramel,
1979
). However, in a few mammalian species (pigs, rabbits), net
secretion of urate by the renal tubules commonly occurs
(Chonko, 1980
;
Roch-Ramel et al., 1980
). In
humans, tubular reabsorption of filtered urate predominates, but tubular
secretion also occurs (Roch-Ramel,
1979
). Understanding the mechanism of urate secretion by the renal
tubules of reptiles and birds, where it dominates, may aid in the
understanding of the mechanism of urate secretion in mammals such as humans,
where it normally plays a minor role in urate excretion. Most of the
physiological information on the tubule secretory process has come from
studies with isolated perfused snake and chicken renal tubules
(Brokl et al., 1994
; Dantzler,
1973
,
1976
;
Randle and Dantzler, 1973
) and
is summarized in the descriptive models shown in Figs
3 and
4.
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Transepithelial transport
In snakes and chickens, net transepithelial secretion occurs in the
proximal tubule only (Brokl et al.,
1994; Dantzler,
1973
,
1976
). Secretion occurs
equally in all segments of snake proximal tubules, but possible variation
along the proximal tubules has not yet been determined in chickens
(Brokl et al., 1994
;
Dantzler, 1976
). There is no
evidence of net transepithelial reabsorption of urate in snake and chicken
tubules; however, in contrast to the transepithelial transport of other
organic anions in these tubules, there is a substantial passive reabsorptive
backflux that appears to move between the cells (Figs
3 and
4;
Brokl et al., 1994
; Dantzler,
1973
,
1974
,
1976
). In snake tubules and
probably also chicken tubules, the magnitude of this backflux varies directly
with the luminal perfusion rate, resulting in net secretion that also varies
directly with perfusion rate (Dantzler,
1973
; Brokl et al.,
1994
). The overall pattern of transepithelial transport in snake
renal tubules is remarkably similar to that observed for urate secretion in
isolated perfused rabbit proximal renal tubules
(Chonko, 1980
;
Dantzler, 1973
). The
similarity of these patterns has implications for physiological and possibly
pathological function in rabbit tubules and the molecular basis of transport
in snake tubules (see paragraphs discussing mammalian pathology and mechanism
of basolateral urate transport below).
Net transepithelial secretory transport of urate is a saturable process,
but the Km for this process in snake tubules (150
µmol l-1) is well below the normal plasma urate concentration in
these animals (
400-500 µmol l-1;
Dantzler, 1982
). This
observation indicates that the transepithelial secretory process is normally
about 60-70% saturated and suggests that changes in plasma urate concentration
have little effect on net secretion. This probability suggests, in turn, that
changes in the rate of flow of filtrate (or perfusate) along the proximal
tubule may be particularly important in determining net transepithelial
secretion and final urinary excretion
(Dantzler, 1995
). It appears
very likely that flow rate plays the same role in urate secretion by chicken
tubules, although this has yet to be shown definitively.
In both snake and chicken tubules during the process of transepithelial
secretion, urate is transported into the cells at the basolateral membrane
against an electrochemical gradient and then moves from the cells to the lumen
down an electrochemical gradient (Figs
3 and
4;
Brokl et al., 1994;
Dantzler, 1973
). These are, of
course, the same basic steps observed for the transepithelial secretion of
other organic anions in these and other vertebrate species
(Dantzler, 1988
).
However, in snake renal tubules the apparent permeability of the
basolateral membrane to urate is much greater than that of the luminal
membrane (Fig. 3), just the
opposite of the situation for other organic anions (Dantzler,
1973,
1974
,
1976
). The arrangement of
these membrane permeabilities provides an inefficient system for net transport
to go in the secretory direction and, considered in isolation, appears to be
highly non-physiological. Nevertheless, net secretion does occur in perfused
nephrons. Moreover, this high permeability of the basolateral membrane may
account, in part, for the much lower intracellular concentration of urate
established at steady-state in nonperfused than in perfused snake tubules
(Brokl et al., 1994
;
Dantzler, 1973
), a situation
just the opposite of what is observed for other organic anions
(Brokl et al., 1994
; Dantzler,
1973
,
1974
,
1976
). In addition, the
apparently higher rate of urate transport into the cells at the basolateral
membrane in perfused than in non-perfused tubules may be related to a luminal
anion that is absorbed and exchanged for urate at the basolateral membrane
(see discussion of the basolateral transport mechanism below).
In reptiles and birds, what appear to be non-physiological observations
that (1) urate transport into the cells at the basolateral membrane is
dependent on perfusion of the lumen with filtrate (or an appropriate
substitute), (2) the basolateral membrane has a higher passive permeability to
urate than the luminal membrane, and (3) substantial passive paracellular
urate reabsorption can occur, all may actually have substantial physiological
significance when considered in the context of the intact kidney. The small
loopless (reptilian-type) nephrons in the avian kidney and all nephrons in the
reptilian kidney can filter intermittently. At the time when one of these
nephrons is not filtering, these three apparently non-physiological
characteristics of urate transport may actually perform the important
physiological function of preventing accumulation and precipitation of poorly
soluble urate in the tubule lumen or cells, thereby also preventing blockage
of the tubule lumen or damage to the cell structure. Similarly, if net urate
secretion by rabbit proximal tubules also includes a balance between an
energy-requiring secretory flux and a substantial passive backflux, as seems
likely (Chonko, 1980), this
backflux may prevent accumulation and precipitation of urate in the lumens of
nephrons that stop filtering during pre-renal acute renal failure. This might
occur at the same time that secretion of hippurate by the general organic
anion secretory system (see below for brief discussion of organic anion
secretory system) is actually producing fluid secretion and helping to
maintain some flow in the lumen, as suggested by Grantham and Wallace
(2002
). A similar pattern
might also occur under these circumstances in human tubules, although there is
no information on this process.
Basolateral transport mechanism
The mechanism by which urate is transported into the cells against an
electrochemical gradient at the basolateral membrane has not been completely
determined for either reptilian or avian nephrons and merits intensive study,
especially since it may provide insights into the secretory process in
mammalian nephrons, including human nephrons. In reptilian nephrons, the
process is completely separate from the general physiological process for
other organic anions (Dantzler,
1988). However, inhibition of the basolateral urate transport step
by anion-exchange inhibitors (e.g. the disulfonic stilbene SITS; Mukherjee and
Dantzler, 1995) suggests that the process may involve anion-exchange transport
(Fig. 3). Although this seems
likely, the possible counter anion for which exchange of urate might occur has
not been identified, despite attempts to promote exchange with numerous mono-,
di- and tricarboxylates, by analogy with the general organic anion transport
system (see below; Y. K. Kim and W. H. Dantzler, unpublished observations).
Thus, the details of this process in the reptilian nephron remain a
mystery.
In avian nephrons, urate transport into the cells against an
electrochemical gradient at the basolateral membrane appears to involve both a
process independent of that for other organic anions (as in the reptilian
nephrons) and the accepted process for other organic anions (generally
monovalent organic compounds of molecular mass less than 0.4 kDa, e.g.
p-aminohippurate (PAH; Fig.
4). The accepted physiological process for other organic anions is
a tertiary active transport system, the terminal step of which involves the
transport of the organic anion into the cells against its electrochemical
gradient in exchange for -ketoglutarate moving out of the cells down
its electrochemical gradient (Fig.
4). The outwardly directed gradient for
-ketoglutarate is
maintained in turn by metabolism and by
-ketoglutarate transport into
the cells against its electrochemical gradient via coupling to the
movement of sodium into the cells down its electrochemical gradient
(sodium-dicarboxylate cotransport; Fig.
4). Finally, the inwardly directed gradient for sodium is
maintained by its transport out of the cells via basolateral
Na+-K+-ATPase, the primary, energy requiring step in the
tertiary active transport process (Fig.
4). This general process was first proposed by Burckhardt and
Pritchard, essentially simultaneously, from data obtained with basolateral
membrane vesicles from rat kidney (Pritchard,
1987
,
1988
;
Shimada et al., 1987
). It was
then demonstrated to function this way in intact rabbit, chicken, snake and
flounder renal tubules (Brokl et al.,
1994
; Chatsudthipong and Dantzler,
1991
,
1992
;
Dantzler et al., 1995
;
Miller and Pritchard, 1991
).
It appears quite possible that urate may be transported by an independent
system in one portion of a given avian proximal tubule and by the common
organic anion transport system in another portion of the same tubule, but the
difficulty of teasing avian tubules from fresh tissue has not yet permitted
this to be determined. It is also possible that one transport system dominates
in one group of nephrons and the other transport system in another group of
nephrons. Internephron heterogeneity, depending on the distribution of the
transporters, could be important for urate secretion during intermittent
nephron function. In any case, the possibilities of intra- and internephron
heterogeneity for the urate transport systems in the avian kidney certainly
merit examination.
Nothing is known about the molecular basis of either the pure basolateral
urate transport process or the general basolateral transport process for other
organic anions in either reptiles or birds. However, in all mammals studied,
the terminal step in the basolateral tertiary active transport system
(-ketoglutarate/organic anion exchanger) involves two members of the
Organic Anion Transporter (OAT) family, OAT1 and OAT3
(Wright and Dantzler, 2004
).
These two transporters have different specificities for organic anion
substrates and these specificities vary for the same transporter cloned from
different species. Of particular interest for the present discussion, rabbit
OAT3, when expressed in a heterologous cell line, can transport urate in
exchange for
-ketoglutarate (X. Zhang and A. Bahn, unpublished
observation; noted in Wright and Dantzler,
2004
) but has almost no affinity for PAH
(Wright and Dantzler, 2004
).
OAT3 may be the critical basolateral transporter in the urate secretory system
in rabbit proximal tubules, although this has yet to be studied directly. If
this turns out to be the case, it is possible that orthologs of OAT3 are the
critical basolateral transporters for urate in reptiles and birds, given the
physiological similarities between the rabbit urate secretory system and the
reptilian (and probably avian) urate secretory systems noted above
(Chonko, 1980
; Dantzler,
1973
,
1976
). This is an area in
which appropriate molecular and physiological studies could provide
significant information about the details of the urate secretory process in
reptiles, birds, and mammals.
Luminal transport mechanism
Much less is known about the urate transport step at the luminal membrane
than at the basolateral membrane, although movement from the cells into the
lumen is very clearly down an electrochemical gradient (Figs
3 and
4). Absolutely nothing is known
about this transport step in avian nephrons. It has yet to be studied.
Moreover, those studies that have been performed on reptilian nephrons present
a very confusing picture of this process. In isolated, perfused snake proximal
renal tubules, transport of radiolabeled urate from the cells to the lumen is
not affected in any way by the addition of probenecid (inhibitor of organic
anion transport), SITS or unlabeled urate itself to the lumen, thus providing
no evidence for mediated transport
(Dantzler and Bentley, 1979;
Mukherjee and Dantzler, 1985
).
Studies with brush border membrane vesicles (BBMV) from snake renal tubules
also provided no evidence for mediated transport
(Benyajati and Dantzler, 1988
).
These data, in conjunction with the relatively low urate permeability of the
luminal membrane (Fig. 3), are
compatible with completely passive diffusion of urate from cells to lumen.
However, it is very difficult to reconcile the rather large flux of urate
across the luminal membrane during net transepithelial secretion with simple
passive diffusion. Perhaps urate is sequestered in vesicles during the
transcellular portion of the secretory process and then extruded into the
lumen by exocytosis, as suggested by Miller and his colleagues for the
transport of fluorescein in teleost and some other tubules
(Miller and Pritchard, 1994
;
Miller et al., 1993
). But
exocytosis does not appear compatible with the observed rate of transport of
urate. Determining the nature of this transport step is going to require
unusual and creative approaches, but it is critical to the understanding of
the transepithelial transport and excretion of this very important anion.
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Conclusion |
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Acknowledgments |
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References |
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