Glomerulotubular Balance, Tubuloglomerular Feedback, and Salt Homeostasis
Scott C. Thomson and
Roland C. Blantz
Department of Medicine, Division of Nephrology-Hypertension, University of California San Diego, and VA San Diego Healthcare System, San Diego, California
Correspondence: Dr. Scott C. Thomson, Department of Medicine, University of California, and VA San Diego Healthcare System, 3350 La Jolla Village Drive 9111H, San Diego, CA 92161. Phone: 858-552-7528; Fax: 858-552-7549; E-mail: rblantz{at}ucsd.edu
The homeostasis of NaCl is critical to complex organisms withclosed blood systems. Kidneys regulate this salt excretion bymodulating the rapport between glomeruli and tubules. The tubulesrespond to glomeruli with glomerulotubular balance, whereasglomeruli respond to tubules through tubuloglomerular feedback.These relationships are dynamic, mysterious, and amenable tomathematical analyses. The biology underlining what is knownabout these interactions is observational, fragmentary, andsomewhat inconclusive. Discussed here is a simple tetheringof these interrelated concepts.
We discuss here the relationship among glomerulotubular balance(GTB), tubuloglomerular feedback (TGF), and NaCl (salt) handlingby the kidney. GTB refers to the direct positive effect of tubularflow rate on tubular reabsorption. TGF operates in the juxtaglomerularapparatus and confers an inverse dependence of single-nephronGFR on tubular fluid salt reaching the macula densa. GTB andTGF form a negative feedback system that stabilizes both single-nephronGFR and distal salt delivery. Most of our points are made bydeduction.
Tubular reabsorption is a random process, subject to statisticallaws. Accordingly, more delivery translates to more chancesfor reabsorption, which translates to more total reabsorption.Ergo, GTB exists. But increasing the flow through a nephronsegment also increases the opportunity for an individual moleculeto transit the segment without being reabsorbed. From this wededuce the most perfect GTB can do no better than maintain aconstant fractional reabsorption. In reality, GTB in the proximaltubule is approximately 70% efficient at holding fractionalreabsorption constant.1 To put this in context, if a personin balance on a 180 mEq/d sodium intake with GFR 180 L/d andfractional reabsorption of 80% up to the macula densa were toexperience a 10% increase in GFR, then 44% of the incrementin filtered load would arrive at the macula densa. GTB downstreamfrom the macula densa is difficult to quantify, but assumingconstant fractional reabsorption (to wit perfect distal GTB),this 10% increase in GFR would effect a 22% increase in saltexcretion.
The mechanisms of GTB have been argued since the 1930s and arenot entirely clear, even today. GTB depends partly on parallelchanges in peritubular capillary oncotic pressure that accompanychanges in filtration fraction. Recently, a luminal mechanismhas also been identified in which shear strain on the proximaltubule brush border activates apical co-transporters.2 In theloop of Henle, GTB is expected to result from the relativelylow affinity of the bumetanide-sensitive salt transporter forchloride; however, our arguments here rely only on the existenceand inherent limitations of GTB, which are deduced independentof present or future knowledge of its mechanisms.
The inherent limitation of GTB also does not apply to tubulareffects of "natritropic" nerves and hormones regulating thetotal body salt through negative feedback. Instead, the natritropes,which include angiotensin, aldosterone, natriuretic peptides,and renal nerves, are constrained by the immutable requirementfor salt balance to nullify any long-term disparity betweensalt intake and salt excretion. This requirement is immutablebecause the alternative advances an untenable notion of infinitetotal body salt.
Because of the limitations of GTB, a portion of any change inGFR will pass along the nephron to elicit a TGF response, whichwill offset part of the original disturbance. The uncompensatedportion of the original disturbance remains as an error signal.The ratio of the compensation to the error signal is termedthe open loop gain (OLG). The OLG of any feedback loop equalsthe product of the slopes of its pair-wise relations (see Appendix).Typically, the negative OLG for the GTB-TGF system is approximately2, which means that the system compensates for approximately66% of an outside disturbance,3 so an outside disturbance thatwould increase GFR by 10% and salt excretion by 22% in the absenceof TGF winds up as a 3% increase in GFR and a 7% increase insalt excretion. Current thinking on the mechanism of TGF isthat the macula densa releases ATP in proportion to the tubularfluid salt concentration and this ATP binds to vasoconstrictorpurinergic receptors on the afferent arteriole and/or convertsto adenosine, which activates vasoconstrictor adenosine A1 receptorson afferent arterioles. The sensitivity of this feedback issusceptible to modulation by a variety of mediators, includingnitric oxide, prostaglandins, and angiotensin II, among others.4
After a change in salt intake, salt excretion asymptoticallycatches up to the new intake and balance is restored at a newtotal body salt. Over time, total body salt varies directlywith the salt intake, and the slope of this relationship isinversely related to how rapidly balance is restored after achange in salt intake. When balance is restored rapidly, thetotal body salt is less sensitive to long-term salt intake thanwhen balance is restored slowly, so the efficiency of salt homeostasisboils down to how long it takes to restore balance after a changein salt intake. The most parsimonious explanation for observedbehavior is a system in which salt excretion is driven not bysalt intake but by the total body salt.5 This likens salt excretionto radioactive decay. The construct allows for the 4 to 7 drequired to achieve salt balance while also allowing salt excretionto change rapidly after a sudden change in total body salt.In addition, this construct provides a fair literal representation,because activation of the major natritropes is tied to changesin the total body salt. The natritropic hormones and nervesmake for a more stable total body salt, but, to the extent thatthey act by changing GFR or proximal reabsorption, their effectivenessis attenuated by TGF. In other words, when the object of homeostasisis the total body salt, TGF is antihomeostatic.
This, too, can be deduced: Any change in salt excretion equalsa change in delivery to the macula densa minus a change in reabsorptiondownstream from the macula densa. Hence, there is potentialfor natritropes to speed up the salt balance by impinging bothupstream and downstream from the macula densa. But TGF makesthe distal delivery resistant to change. If GTB-TGF were perfectlyefficient (OLG infinite), then total responsibility for saltbalance would be relegated downstream from the macula densa.This competition between TGF and the natritropes results ina compromise between the efficient compensation for changesin salt intake and control of the distal salt delivery. Theintegration of this compromise is inherent and its details arerevealed by solving a simple system of equations developed fromthe individual pair-wise relations between total body salt,the natritropes, and their effects on the various nephron segments(see Appendix).
ADVANTAGES TO COMPROMISING ON THE EFFICIENCY OF SALT HOMEOSTASIS
A stable internal environment is essential for normal functioningof the organs, so why incorporate TGF, which naturally lessensthe efficiency of sodium homeostasis? Sodium is not the onlyimportant constituent of the body fluids. There is also potassium,acidity, and calcium to consider. Homeostasis of all of thesemoieties involves regulated transport downstream from the maculadensa, which makes random fluctuations in distal delivery disruptive.Furthermore, not all changes in salt delivery to the maculadensa help to stabilize total body salt. For example, if GFR,hence macula densa salt, were passively allowed to track short-termfluctuations in BP that occur independent of total body salt,then fluctuating salt excretion would follow, irrespective oftotal body salt. Or if proximal reabsorption were to declinein the aftermath of some injury to the tubule, then macula densasalt would increase independent of total body salt. The kidneyinvokes TGF to lessen the impact of such transient events onGFR and salt excretion,6 but this inevitably requires some sacrificeof salt homeostasis.
The relative contribution of proximal and distal nephrons tooverall salt balance must vary according to the relative OLGof the GTB-TGF and natritropic feedback systems. A model forthis is developed in the Appendix. When numbers derived fromthe published literature are applied to this model, it is revealedthat eliminating TGF would lessen by 30% the impact of dietarysalt on the total body salt.
Because of the inverse relationship imposed by TGF, glomerularfiltration and distal salt delivery cannot change in the samedirection unless there is resetting of the TGF curve. For example,acute plasma volume expansion, which increases both GFR anddistal delivery, must cause rightward resetting of TGF.3 Furthermore,the natural tendency for tubular flow to align with the steepestpart of the TGF curve suggests resetting at the level of eachnephron, a phenomenon that has been confirmed.7,8 If TGF resetsrightward during prolonged activation, then this will lessenits apparent OLG for buffering long-term (hours/days/weeks)relative to short-term (seconds/minutes) disturbances. Hence,the degree to which TGF interferes with salt homeostasis willbe tempered to the extent that TGF resets rightward on a high-saltdiet. The full details of TGF resetting are not known, but severallines of evidence point to nitric oxide synthase in the maculadensa,9–12 and blocking this enzyme makes the BP sensitiveto salt intake, which is tantamount to demonstrating that morepersistent TGF causes less efficient salt homeostasis.13
TGF helps to overcome inherent limitations of GTB in stabilizingdistal salt delivery. The added stability bestowed on nephronfunction by negative feedback from TGF inevitably incurs somecost in terms of less efficient salt homeostasis, but this costis tempered by TGF resetting. These implications of the GTB-TGFinteraction are revealed, mainly, by deduction.
GTB and TGF place the following conditions on GFR and maculadensa chloride,
where GFR and MDsalt refer to residualchanges in GFR and macula densa NaCl after compensation by GTB-TGFfor an outside disturbance, , in GFR. p is the change in MDsaltper unit change in GFR as a result of GTB. β is the negativeslope of the TGF curve (see Figure 1A). The straightforwardsolution is as follows:
where pβ is the negativeopen loop gain. There are constraints on p as a result of thenature of GTB. These are discussed in the main text. Theoretically,β can assume any value from 0 to infinity where β= 0 is the absence of TGF. Typically, pβ is approximately2 in the rat.
Figure 1. (A) GFR and MDsalt refer to residual changes in GFR and macula densa NaCl after compensation by GTB-TGF for and outside disturbance () on GFR. p is the change in MDsalt per unit change in GFR as a result of proximal GTB. pβ is the negative slope of the TGF curve. (B) Model for role of GTB-TGF in salt homeostasis. Variables (total body salt [TBsalt], natritrope activity, GFR, Jprox, Jdist, MDsalt, and urinary sodium voided [UNaV]) represent changes from initial steady state before outside disturbance (). Parameters (, p,d, β, and 1 to 3) all are positive and represent partial derivatives of downstream variables with respect to upstream variables. Negative effects are shown with dashed arrows. Natritrope activity is the sum of all nerves and hormones that contribute to salt homeostasis by negative feedback. Jprox is the reabsorption upstream from the macula densa. Jdist is the reabsorption downstream from the macula densa. (C) Unit increase in salt intake occurs at time 0. Return to salt balance mimics exponential decay with rate constant k. The area above each curve, which equals 1/k, represents the ultimate impact on total body salt. Eliminating TGF makes salt homeostasis 33% more efficient. These curves are derived from the model in B with published data on lithium, creatinine, and salt balance in humans on low- and high-salt intake14 and TGF and GTB efficiencies from rat micropuncture.1,3
The model in Figure 1B depicts the impact of GTB-TGF on salthomeostasis. The seven internal variables (e.g., total bodysalt [TBsalt], GFR, natritrope activity) represent changes asa result of outside disturbance (). In other words, for thesystem in steady state with no disturbance, these all are 0.Positive and negative influences are written such that all parameters(p,d, β,, 1 to 3) are positive numbers. These representslopes of the pair-wise relations. By conservation of mass:
The solution to the homogeneous equation is the simple decayingexponential:
where k is obtained from the modelby algebraic substitution to express urinary sodium voided (UNaV)as a function of TBsalt. If is applied as a bolus at time 0,then C = and TBsalt will decay from to 0 with time constantk. Similarly, if is applied as a step increase in salt intake,then TBsalt will exponentially approach a new steady state valuewhere TBsalt = /k, so salt balance is achieved more rapidlyand salt homeostasis is more efficient when k is large.
Note the dependence of k on pβ, which is the negative OLGfor GTB-TGF. This is the main point of the exercise and revealshow GTB-TGF competes with the natritropes for control of GFRand macula densa salt. As GTB-TGF becomes more powerful relativeto natritropes that act upstream of the macula densa (1 to 2),overall salt homeostasis becomes less efficient and more dependenton feedback from TBsalt through natritropes acting on the distalnephron (3). The impact on salt homeostasis of eliminating TGFis shown in Figure 1C, for which model parameters were givenvalues derived from the literature.
This work was performed with funds provided by National Instituteof Diabetes and Digestive and Kidney Diseases grants DK28602and DK56248 and by the Department of Veterans Affairs ResearchService.
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
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Top
ADVANTAGES TO COMPROMISING ON...
TGF ADAPTATION: LIMITING THE...
GFR and 
, in GFR. 
p is the change in MDsalt per unit change in GFR as a result of GTB. β is the negative slope of the TGF curve (see Figure 1A). The straightforward solution is as follows:
, 
1 to 3) are positive numbers. These represent slopes of the pair-wise relations. By conservation of mass:
