New human physiology ch 25

New Human Physiology Ch 25 http://www.zuniv.net/physiology/book/chapter25.html

New Human Physiology | P a u l e v - Z u b i e t a 2 n d E d i t i o n

C h a p t e r 2 5 : R e n a l P h y s i o l o g y a n d D i s e a s e

HO ME PR EFAC E TAB LE O F C O NTE NTS S YMB O LS S E C TIO N INFO C O NTR IB UTO R S LINK S C O NTAC T US

Highlights

Study_O bjectives Chapter
Principles
25
Definitions
Essentials

Pathophysiology
Equat ions
Self- Assessment
Study Objectives
Answers
· To de fi ne the c onc ep ts: Ne phr on, glomer ular fi ltr atio n, tub ula r sec r eti on and r ea bsor pti on, r e nal
Further Reading lobulus, r ena l plasma c lear an c e, osmo lar c lea ra nc e, tubular passa ge f r ac ti on, r eabsor p ti on
f r ac ti on, exc r e ti on f r ac ti on, f i ltr ati on f r ac ti on, plasma extr ac tio n f ra c tio n, p r oxi mal and di stal
sy ste m, glome r ula r p r opulsi on pr essu r e, n et f i ltr a ti on p r essur e, r enal thr esho ld, and the maxi mal
tr ansf er ( Tma x ) fo r tub ula r sec r eti on and r ea bsor pti on.

· To de s c r i be the r enal c i r c ulati on and measur e ment of r enal bloodf low, a su per f i c ia l an d a
juxtamedullar y nephr o n, the juxtag lomer ular appa r atus, and the c on c entr ati ng mec hani s m o f the
ki dne y.

· To c a lc u la te the re la ti on be tween ha lf - li fe , eli mi na ti on r ate c o nstant, c le ar anc e a nd di str ib uti o n
volume of a substan c e tre ated i n th e ki dney s.

· To ex pla in the n or ma l r ena l f unc ti on i nc ludi ng the c ontr ol f u nc tio ns, use of endo genou s
c r e atini ne c le ar anc e as a r e nal test, the r ena l tr eatme nt o f the f i ltr a ti on- r ea bsor p ti on- and

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se c r etio n- f ami lie s of substanc e s, the g lo mer ular f i ltr ati on r ate ( GF R) , th e angi otens i n- r en in -
aldoste ro ne c asc ade, the tubulo- glomer ular fe edbac k, the p ro ximal and di stal tr a nspor t pr oc esses,
an d mi c tur i tio n. To explai n the pathop hy si ology of c ommo n r enal di sor der s i nc ludi ng r en al
oe dema.

· To us e th e above c o nc epts i n pr oblem solvin g and i n c ase h istor i es.

Principles
· The gl om er ul us a nd t he pr ox i m al tu bul e ar e r es po ns i bl e f or fi l t r at i on of pl as m a and f or m ajo r
r ea bs or pt i on of wa te r a nd s ol ut es . G lo mer u lar f i l t ra t ion is d ue t o a hy dr os ta ti c / c o ll oi d os mot i c
pr e s s ur e gr ad ien t .

· Tubul ar r eabs or pt io n is t h e move men t o f w at er and s ol ut e f r om t he t ubul ar l um en t o t h e t ubul e
c e ll s an d of t en f ur t her on t o t he per i t ubul ar c a pi ll ar y ne tw or k .

· Tubul ar s ec r e ti on r ep r es ent s t he n et a ddi t io n of s ol ut e t o th e t ubul ar f l uid in t he l um en.

· Al l s ubs t an c es t r eat ed by t h e k i dney s c a n be di vi ded i nt o t hr ee gr ou ps or f am il i es , n am el y t he
f i l tr a ti on gr oup, t he r eabs or pt io n gr oup an d th e s ec r et i on gr ou p.

Definitions
· Anu r ia r ef er s to a total stop of ur i ne pr od uc tio n f r equently c au sed by c i r c ulator y f ai lur e wi th
an oxi c damage of the tubular sy stem.

· ( Ren al plasma) Clear ance i s a c leani ng i nd ex fo r b lo od plasma p assi ng the ki dney s. The
ef f ic a c y of thi s c le ani ng pr oc e ss is d ir ec tly pr op or tio nal to the exc r etion ra te f o r the su bstanc e,
an d in ver sely pr opor ti ona l to i ts p lasma c on c entr ati on.

· Diur e sis is an i nc r eas ed u ri ne f low ( i e, volume of ur in e pr oduc ed per ti me uni t) .

· Exc r et io n fr act ion ( E F) fo r a substanc e i s the f r ac ti on of i ts g lo mer ular f i ltr ati on r ate, whi c h
pa sses to and i s ex c r e te d in the ur in e.

· Ext r a ct io n fr act ion ( E) f or a sub sta nc e i s the f r ac ti on ex t r ac t ed b y glo mer u lar f i ltr ati on f r om

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the total amo unt of substanc e d eliver e d to the kid ney dur i ng on e passag e of th e ar te r ia l blood
plasma.

· Fr ee w at er clear a nce i s the di ff er enc e between ur in e f low and osmolar c lear anc e ( see below) .
Th e f re e water c lear an c e i s a n in di c ator of th e exc r eti on of solute- f r ee water by the k id ney s.
E x c es s w at er i s exc r eted c ompar ed to so lu tes, when f r ee- wate r c le ar anc e i s posi ti ve. Ex c e s s

s o lu te s ar e exc r eted c ompa r ed to water, when fr e e- water c lear anc e is n egati ve. – Fr ee wa te r
c lear a nc e i s an esti ma te o f the r en al c a pac i ty f or exc r eti on of solute- f r ee water.

· Glomer ular filt r at ion i s due to a hy d ro stati c / c o lloi d osmoti c pr essur e g ra di ent - the S tar li ng
f or c e s.

· Glomer ular filt r at ion fr act ion ( GFF) i s the f r ac tio n of th e pla sma f lowi ng to the ki dne y s that is
ultr af i lter ed ( GFR/ RPF) . GF F i s n or ma lly 0. 20 or 1/ 5. - The GFF i s r educ ed dur i ng ac u te
glomer ulonep hr iti s.

· Glomer ulo neph r it is i s an autoi mmun e in jur y o f the glomer uli of b oth kid ney s.

· Glomer ular filt r at ion r at e ( GFR) i s th e volume o f glomer ular f iltr ate pr oduc ed per min .

· Glomer ular p r opulsion pr essu r e i n th e blo od of the glome ru la r c a pi llar i es i s the hy dr os ta ti c
mi nus the c olloi d osmo ti c pr e ssur e of the blood ( i e, 2- 3 kPa i n a he althy r e sti ng p er son) .

· Glomer ulo -t u bular ba lan ce r ef er s to the si multaneo us i nc r ease i n NaCl and wa te r r e absor pti on
i n the pr oxi mal tub ule s as a r esult o f a n in c r ease i n GF R and f i ltr a ti on r ate of NaCl . An almo st
c o nstant f ra c tio n of salt and water i s th us r eabsor b ed r egar dless o f the si ze of GFR.

· Nep hr on : A n ephr on c onsi sts of a glo mer u lus, a pr o ximal tu bule f or mi ng seve r al c oils ( par s
c o nvoluta) bef or e end in g in a str ai gh t se gmen t ( pa rs r e c ta) , the thi n par t of the Hen le loop and a
di stal tubule also wi th a par s r ec ta an d a par s c on volu ta .

· The n ephr o t ic s yndr o me r ef er s to a se ri ou s in c r ease i n the per meabi li ty o f the g lomer ular
ba r ri er to albumi n, r e sulti ng i n a mar ked loss of albumi n in the u r in e. The albumin ur ia ( mor e than
3 g p er d ay ) c auses hy poa lbu mi nae mi a and ge ner ali zed oede ma.

· Net u lt r afilt r at ion pr e ssur e i s the pr essur e gr adi ent gove rn in g th e glomer u lar f i ltr ati on - the net

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r esu lt of the so- c alled St ar l i ng f or c es ( see Fig. 25- 7) .

· Os molar clea r ance i s the plasma volume c lea r ed of osmole s (solu te s) eac h min ute. – Osmola r
c lear a nc e i s also def i ned as the f i c ti ve ur i ne f lo w that would have r e nder ed the u ri n e i so smolar
with plasma. - Osmola r c le ar anc e i s the di ff er en c e betwee n th e ur i ne f lo w and the f r e e wate r
c lear a nc e, and osmolar c lear an c e esti mates the r en al c a pac i ty to exc r ete solutes.

· Os molar it y i s the amount of osmo ti c a lly ac ti ve par ti c les di ssolved i n a litr e of soluti on.

· Pr ox imal t ubu le c onsi sts of th e pr oxi mal c on volu te d tu bule and par s r ec ta .

· Ren al th r esho ld fo r glucos e is the b loo d glu c ose c o nc entr ati on at whi c h the g luc ose c an b e
f i r st detec ted i n the ur i ne ( appe ar anc e thr eshold) or at whi c h the r eabs or ptio n c apac iti es of all
tubu les a r e satur ated ( satur ati on thr esho ld) .

· Ren al ult r afilt r at e i s also c ompar ed to pl as ma w at er , bec ause it i s c omposed li ke plasma mi nus
pr o te ins. Th e f ra c tio n of one litr e of plasma that is pu r e water i s ty pi c ally 0 .9 4. Thus, the
c o nc entr ati on of ma ny substan c es i n the ultr a fi ltr ate , C f il t r , i s equ al to C p / 0. 94.

· Sing le e ffec t g r adient i s a tr ansepi theli al c onc e ntr a ti on g r adi ent betwee n th e tu bular flui d and
the medullar y i nter stiti al flui d estab li she d at e ac h level of the thi c k a sc endi ng li mb b y ac ti ve NaC l
r ea bsor pti on.

· T m a x r ef er s to the maxi mal net tr ansf er r ate of substan c e by tubular sec r e ti on o r r ea bsor p ti on.

· Tubular pa ssage fr a ct io n. The f r ac ti on of the amount ultr a fi lter ed of subs tan c e passi ng a c r oss
se c ti on o f the n ephr on i s the pas s age f r ac t i on. The p assage f r ac ti on f or i nuli n does n ot va ry at a ll

thr ou ghout the neph r on. The passage f r ac ti on f or i nulin i s on e and r emai ns so.

· Tubular r ea bsor p t io n fr act ion. The r ea bs or pt i on f r ac t i on i s the r ever se o f the pa ssage f r ac ti on
( 1 mi nus the passa ge f r ac ti on) .

· Tubular r ea bsor p t io n ( ac ti ve or passi ve) i s th e net move ment of wa ter an d solute f ro m the
tubu lar lumen to th e tu bule c ells a nd of ten f ur ther on i nto the per i tubular c api llar y networ k.

· Tubular se cr et ion ( ac ti ve or passive) r ep r esents the net addi ti on of solute to th e tu bular lu men.

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· Tubulo- g lo mer u la r fe edbac k ( TGF ) c ontr ols the g lo mer ular c ap illar y pr essu r e and the pr oxi mal
tubu lar pr e ssur e – thus stabi li sin g deliver y of solute and volume to the d istal nep hr on. The mac ula
de nsa- TGF mec hani sm r e sponds to di stur ba nc es i n di stal tub ula r f lui d f low passing the mac u la
de nsa. - Rena l autor e gulation is c a used by my oge ni c f eedbac k and by the mac ula den sa- TGF
mec ha nism.

Essentials
Th is p ar agr aph d eals wi th 1. T he ne phr on , 2. C le ar ance a nd thr ee clea r ance families , 3 .

U ltr a filtr ation and th e in ulin family, 4. Tu bular r eab sor ption an d the gluco se family, 5. Tub ular
se cr etion an d th e PA H family , 6. Wa te r a nd solute s hunting b y vasa r ec ta , 7 . C once ntr ation or
dilution o f u r in e, 8. R enal bloo dflow, 9. M acula den sa- tubu lo - glome r ular feedba ck, 10. Non - io nic

diffu sion, 11. Tes ts fo r pr oxima l an d distal tu bular func tio n, 12. S tix te stin g with dipstics , and

13 . D iur etics.

1. Th e neph r on

Th e ki dney s tr ansp or t substanc e s b y th r ee vec tor i al pr oc esses. Vec tor i al pr oc esses ar e
c h ar ac ter i zed by the ir di r ec ti on an d size only ( Fi g. 25- 1) .

F ig . 25 - 1: Rena l t r an spor t . B la ck ar r ow s indicat e t hr e e vect or ial t r ans por t ing p r ocess es in a
n ephr o n: 1. Glomer ular ult r afilt r at io n is cause d by a hy dr ost at ic/ co llo id o smo t ic p r e ssu r e

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g r adient ( t he S t ar lin g for ces) , 2. Tubular r ea bsor p t io n is t he net movement of w at er and s olut e
fr om t he t ub ular lu me n t o t he t ubu le cells and t o t he p er it ubular ca pillar ies , an d 3. Tu bular
se cr et ion r ep r esent s t h e net add it ion of solut e t o t he t u bular fluid.

Th e f in al exc r etion ra te o f the su bstanc e s i n the ur i ne i s c alled net- f lux, J s , i n Fi g. 25 -1 .

1a . N ephr on anat om y

Th e f unc ti onal uni t is the ne phr on. Ea c h human ki dney c ontai ns 1 mi l l i on uni t s at bi r th . E ac h
ne phr on c o nsi sts o f a g lomer ulus ( i e, man y glomer u lar c a pi llar i es i n a Bowman 's c a psu le) , a pr oxi ma l
tubu le f or mi ng sever al c oi ls ( par s c on volu ta ) b ef or e endi ng i n a str ai ght segment ( pa r s r ec ta) , the
thi n par t of the Hen le loop a nd a di stal tub ule also wi th a par s r ec ta and a p ar s c on voluta. The d istal
tubu le e nds i n a c ol l ec t i ng duc t togethe r with tubu les f r om sever al other nep hr ons.

Th e ki dney ( ave ra ge nor mal wei ght 150 g) c o nsi sts o f a c or te x a nd a me dulla . Th e med u lla i s
c o mpo sed of r enal py r ami ds, th e base of wh ic h or ig in ates at the c or tic omed ullar y junc ti on . E ac h
py r ami d c on si sts o f an inn er zone ( the pap illa) and an o uter zone. The o ute r zone i s di vid ed i nto th e
ou te r medullar y r ay an d th e in ner r ay. Th e r ay s c onsist of c ollec ti ng duc ts and thi c k a sc endi ng li mb s
of the ne phr on.

A k id ney l obul us i s a medullar y r ay wi th adjac e nt c or ti c a l ti ssue. A ki dne y lob ule is a p y r ami d with
ad ja c ent c or ti c al ti ssue .

Th e lo op of Hen le i s a r egu la ti ng u nit. Ac tua lly, the H enl e l oop c on si sts o f the pr o ximal par s r ec ta,
the thi n He nle loo p and the di stal par s r ec ta, whi c h e nds at th e le vel o f mac ula den s a.

Th e th in d esc en din g li mb c ontai ns a water c hanne l ( c alled aqu apor i n 1) i n both the lu mi nal and the
ba solater al membr ane. The last seg ment of the thi c k asc e ndi ng limb i s c alle d th e mac u la d ensa. The
juxtaglomer ular ( J G) app ar atus i nc lude the mac ula densa and gr an ula r c ells of the aff er e nt a nd
ef f er ent ar ter io le s. Gr anular c ells ar e mo dif i ed smooth musc le c ells th at p ro duc e an d r elease r eni n.

Th e di stal tubu le i s c on volute d f ro m the mac ula densa of the J G app ar atus ( Fig. 25- 2) . The
i llu str a ti on sh ows a c o llec ti ng duc t, whic h r ec ei ves ur i ne f r om man y nephr on s. S ever al c olle c tin g
du c ts joi n to empty thr ough the du c t o f B elli ni i nto a r enal c up or c aly x i n the r ena l pelvi s.

Th e s uper f i c i al neph ro n ( r epr esen te d on the le f t si de of Fi g. 25- 2 A ) does not r eac h th e in ner zone

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of the medulla, bec ause its loop of He nle is sh or t. Th ese small, c or ti c al nephr on s ha ve a smaller

bloo d flow and glomer ular f i ltr ati on r a te ( GFR) than the d eep , j ux t am edul l ar y neph r ons ( whi c h a r e
loc a ted c lo se to th e medu lla and c omp ri se 1 5% o f all nephr o ns) . The total i nne r s ur f a c e ar ea of all
the glomer ular c api llar ie s is a ppr oxi ma tely 50 - 100 m2 . Mesang ia l an d endotheli al c ells i n the
glomer ulus sec r e te p r ostaglandi ns an d exhi bi t p hagoc y to sis. Many vasoc onstr i c tor s c on tr ac t the
mesang ia l c e lls, r educ e the g ome ru la r f i ltr a ti on c o eff i c i ent ( K f – see later ) and thus also GFR.

Th e pr ox i m al t ub ul es have an i nn er ar ea of 25 m 2 due to c har ac te r isti c mic r o villi o r b r ush bor de rs
( c o ntai nin g c ar boa nhy dr ase) .

F ig . 25 - 2: A: A sup er ficia l an d a dee p, ju xt ame dullar y nep hr on lea ding t o t he s ame c olle ct in g
d uct . B: A juxt amed ulla r y neph r on w it h r e la te d blood v essels.

Th e ju xta medu llar y ne phr on has a l on g, U - s hap ed Hen le loop. Th e bottom of thi s lo op extends towar ds
the ti p of the papi lla (a pex papi llae) at th e outle t of the c ollec ti ng duc t ( Fi g. 25- 2 ) . Th e ju xtamedu llar y
ne phr ons ha ve la r ge c or pusc le s wi th re la ti vely lar ge bloodf low. Th ese nep hr ons also r ec e ive b loo d
thr ou gh aff er en t ar ter i oles wi th lar ge di ameter s, and r etur n blood thr ou gh eff er en t a r ter i oles wi th
small d iameter s. W hen the blood h as passe d th e juxtamedu llar y glomer uli i t c onti nues to a pr i mar y
c a pi llar y ne twor k and to the vasa r ec ta i n the medulla. The blood c ollec ts i n vena a r c uata, vena
i nter lobar i s and f i nally i nto vena r ena li s.

1b . T he gl om er ul ar bar r i er

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Th e f iltr atio n bar r i er of th e glo mer ulus c o nsi sts of c api llar y e ndotheli um, basemen t membr ane and the
ep ithe li al la y er of Bowmans c apsule c on sisti ng o f po doc y tes with f oot pr oc esses. The h ole s or
f en estr ae of th e endothe li um have a r adi us of ap pr oxi mately 40 nm ( c over ed by a thi n di aphr agm)
an d ar e per meable to pepti des an d small pr otei n molec ule s. The base ment membr a ne c ons i sts of a
ne twor k of f ib r ils per meable to water an d small solutes. The pod oc y tes c ove r the b ase ment membr ane

with f oot pr oc esses sep ar ated by ga ps c alle d s pl i t- p or es thr ough whi c h the f i ltr ate i s r etar ded,
be c ause e ac h spli t i s c ove r ed by a memb ra ne.

A ll sma ll i ons and molec ules with an e ff ec ti ve r adi us below 1 .8 n m ( water, i ons, gluc ose, i nu li n etc )
f i ltr ate f r eely. S ubstanc es wi th a r adi us of 1. 8- 4. 2 nm ar e less f ilter able, and su bs tanc es wi th a
r ad iu s above 4. 2 nm c ann ot c ro ss th e bar r i er.

A ll c han nels of the glo mer ular bar r i er c ar r y n egat i vel y c har ge d molec u les tha t f ac i li ta te the p assage
of po siti vely c har g ed mo lec ule s ( eg, poly c ati oni c dextr ans, F ig .2 5- 3) . Dextr an mac r omolec ules c an
be ele c tri c a lly neu tr al or they ha ve negati ve ( ani oni c ) or po siti ve ( c ati oni c ) c ha r ge s.

F ig . 25 - 3: Filt r a tio n of dext r an molec ules acr o ss t he glomer ular ba r r ie r. T he bar r ier c ont ains
g ly copr o te in s wit h ne gat ive cha r ges. Po sitive c har ge d dext r a n mo lec ules ar e at t r ac t ed by t he
n egat ive ch ar ges an d filt er ea sily.

P osi ti ve c h ar ged molec ules wi th an ef fe c tive r a di us of 3 nm f i lter ea sie r tha n negati ve c ha rg ed
molec ules of the same si ze. These molec ules c a n ac t as eff ec ti ve osmoti c di ur etic s.

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I mmun olo gi c al o r i nf lammator y d amag es of th e glomer u lar ba r ri er r ed uc e the nega ti ve c h ar ge of the
ba r r ier. Her eby , nega ti ve pr o te in molec ules leave the plasma easi er an d pr otei nur i a oc c u rs i n a
nu mbe r o f glomer ular di sor der s.

1c . P r egnan c y and age

Th e glomer u li gr ow a nd the si ze and wei ght of the kid ney s i nc r ea se dur i ng pr egn anc y , ac c omp ani ed
by inc r eases i n both r en al bloo df low and f i ltr ati on r ate.

Th e number of glomer u li and thei r tubules de c r eas e with ag e. D r ugs that ar e exc re te d by r enal
mec ha ni sms c an easi ly c ause toxi c ac c umulati on i n the elder ly wi th poor ki dne y fu nc ti on.

2. C le ar ance

I n 19 26 Pou l Br a ndt Rehbe r g, a n assoc i ate of Au gust Kr ogh , f ou nd the mu sc le metabo li t e c r eat i ni ne
extr emely c onc entr ated i n human ur i ne ( C U mg per ml) c ompar ed to plasma ( C P mg per ml) . He a lso
measur e d th e ur i ne f low ( ur i ne pr oduc ti on p er mi n) .

Th us, th e c onc e ntra ti on i nd ex, C U / C P , i s lar ge f or c r eati ni ne. Multi ply i ng thi s in dex wi th the ur i ne
f low y i elds a r esu lt gr eater than simi lar r esu lts der i ved f or most other substan c es ( Eq. 25 -1 ) . B r andt
Rehber g u sed thi s c onc e pt ( later ter med c le ar anc e) as h is measu re o f r e nal fi l t r at i on r at e. The wo r k

with these matter s develope d in to the i de a of a fi l t r at i on- r eabs or pt i on ty pe of ki dney. Rehb er g was
the f i r st to r e ali se that the r eab sor pti on i n th e pr oxi mal tubules c on tr o ls the f i ltr ati on. A f ew y ear s

later Reh ber g´ s r ena l f i l tr a ti on r a te was c alled c r eat i ni ne c l ea ra nc e and u sed as a measur e o f the
gl om er ul ar f i lt r at i on r at e ( GFR) .

Th e r enal pl as m a c l ear anc e is a c le ani ng i ndex f or blood p lasma passin g th e ki dney s. Th e eff i c ac y
of thi s c leani ng pr o c ess i s di r ec tly pr opor ti onal to th e exc r eti on r ate f or th e subst anc e and i nver sely
pr o por tio nal to i ts plasma c onc e ntr a ti on ( E q. 25- 1) .

C le ar anc e i s the r ati o betwe en exc r eti on r ate and p lasma c o nc entr ati on f or the substanc e. Renal
c lea ra nc e c an a lso be thought of as the volume of ar ter ia l plasma c ompletely c le ar ed of the
su bstanc e i n the ki dney s wi thin one mi n, or the num ber of m l a r ter i al plasma c ontai ni ng the same
amoun t of sub sta nc e as c o ntain ed i n th e ur i ne f lo w per mi nu te ( E q. 25- 1) .

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2a . G l ome r ul ar fi l t r at i on r at e

Th e glomer u lar f i ltr ati on r ate, GF R, i s the volu me of glomer ular fi ltr ate pr oduc ed pe r mi n.

I n he althy a dults the GFR i s r emar kably c on sta nt a bout 180 l eac h d ay or 125 ml pe r mi n due to
i ntr ar ena l c o ntro l mec han isms. I n man y di seases the r en al b loo df lo w, RBF, a nd GF R wi ll f all, wher eby
the ab ili ty to eli min ate waste pr od uc ts and to r egulate bod y f lui d volume and c ompo si ti on will dec li ne.
Th e degr ee o f i mpai r ed r enal f unc ti on i s shown by the measur ed GFR.

GFR i s r outi nely me asur ed as the e ndogen ous c r ea ti ni ne c lea ra nc e.

Th e endog enous c re atin in e pr oduc ti on i s f r om the c r e atin e metabo li sm in musc les an d p r opor ti onal to

the musc le mass. In a 70- kg per so n c r eati ni ne i s pr oduc ed at a c onstant r ate of 1. 2 m g per mi n
( 17 30 mg d ai ly ) . Thi s pr od uc ti on i s re mar ka bly c onstant f r om da y to day, on ly sli ghtly aff ec ted b y a
no r mal pr otei n i ntake, and eq ual to the r ate of c r e ati ni ne e xc r etio n. Both the ser um c r eati ni ne and
the r en al c re atin in e exc r eti on f lu c tuate th r ougho ut the d ay. The r ef or e, it i s nec essa r y to c olle c t the
ur i ne f or 6- 2 4 hour s and measu r e th e c r eati ni ne exc r eti on r ate ( i e, th e ur i ne f lo w r a te multi plied by
the c r e atin ine c onc en tr a ti on i n the ur i ne) . A si ngle ven ous blood sa mple ana ly s ed f or c r eati ni ne i n
plasma i s all that i s neede d to p r ovi de the endo genous c r eatin in e c lear anc e ( E q. 25- 1) .

Th eor eti c ally, two small er r or s di stur b the pi c tur e, but both ar e o ver esti mates.

A t the no r mally lo w plasma c onc en tr a ti ons o f c r e atin ine , a mode st tubu lar se c r etio n o f c r eati ni ne
f r om th e blood i s detec table r esulti ng i n up to 15% over esti ma ti on o f the c r e atini ne e xc r eti on f lux.

Most la bor ator i es me asur e c r ea ti ni ne i n s er u m i nstead o f plasma, whi c h r es ults i n an ove r estimati on
of plasma c r eati ni ne.

Th us, c alc ulati on of a f ra c tio n wi th both an over esti mated nomi nator and den omi nator r esu lts i n a
value c lose to tha t of GFR i n almost all situa ti ons, wher e the r ena l f unc ti on i s nea r n or mal.

W i th pr ogr essive r e nal f ai lur e the plasma c r eati ni ne r i ses, and the c r e atin ine sec r et i on i nc r ease s th e
no mi nator i n the c lear anc e expr essi on e ven mo re , so the measur ed c lear anc e wi ll over e sti mate GFR.
S ti ll, the c lea ra nc e pr ovi de s a fa ir c li ni c al estimate of the r enal f i ltr ati on c apa c i ty ( GFR) .

I n most c ases a no r mal c r eati ni ne c lear an c e ( above 7 0 ml plasma p er mi n at any ag e) i s c o mpa ra ble
with the no r mal r ange f or ser u m c r eati ni ne ( ar ou nd 0. 09 mM i n Fi g. 25- 4) . The se r um c r ea ti ni ne
c o nc entr ati on i s i nver sely pr opo r ti ona l to the c r ea ti ni ne c lear a nc e, and also a g ood esti ma te o f GFR.

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Renal f ai lur e i s almost a lway s i r r ever s i bl e, whe n th e ser um c r eatin in e is a bove 0. 7 mM.

F ig . 25 - 4: Cr eat inine c le ar ance ver sus s er um cr eat inine. – A low ser um cr eat inine in dicat es
n or ma l kidn ey func t io n, but not alw ays ( see false n egat ive c oncen t r at ions) . – An e le v at ed
se r um c r eat inine indica te s kidney failur e, bu t not alwa ys ( see false po sit iv e conce nt r at ions ).

S er um [ c r ea ti ni ne ] an d ser um [ u re a] depend upon both pr o te in t u rn over and k idn ey f unc t i on. The
se r um [ c r eati ni ne] and [ ur e a] a r e la rg e af ter i ntake of meals extr emely ri c h i n ( f r i e d) me at, a lthou gh
the ki dn ey f unc ti on i s nor mal ( f alse positi ve c onc entr atio ns i n Fi g. 25- 4) . I n some mater i als up to
15 % of measur ed ser um c r e atini ne c onc en tr ati ons a re nor ma l, although the ki dn ey f unc t i on f ai ls
( f alse neg ative va lu es in F i g. 2 5- 4) . Long- ter m hospi talisa ti on o ften lea ds to musc ula r a tr op hy, wh ic h
r ed uc es c r ea ti ni ne p ro duc ti on and e xc r etio n. The ser um c r eati ni ne c on c entr ati on i s ma i ntai ned
no r mal bec a use of a si mi lar f all i n ki dney f unc ti on ( GFR) .

Half the osmolali ty o f no r mal ur i ne i s due to ur ea, and the oth er half i s mai nly due to NaC l . The
osmolar i ty of ur in e var i es tre men dously ( f r om 50 to 14 00 mOsmo l pe r l) .

P hy si ologi c al c han ges of the r enal bloodf low of ten pa r allel c han ges of GF R. A r educ ed GFR impli es a
smalle r tub ula r Na + - r eab sor ptio n and thus a smalle r O 2 dem and. W hen kid ney s ar e pe r fu sed by
an oxi c blood the tubular r eabsor ptio n is b loc ked f i r st, and the n th e GFR is r ed uc ed. As tub ula r Na +
- r ea bsor pti on i s th e mai n oxi da ti ve ene r gy demandi ng ac ti vi ty, a hi gh GFR i s c or r elat ed to hi gh

ox y gen c o ns um pt i on i n th e nor ma l ki dne y.

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Th e si ze of GFR is de te r mi ned by the f a c to r s shown i n F ig . 25 - 7. The r esi stanc e o f the glomer ular
ba r r ier i s extr emely small in h ealth y human ki dney s.

2b . I nu li n

I nu li n i s the i deal in di c ator f or deter mi na ti on of GFR, bec ause of the f ollo wi ng thr ee r elat i ons:

1. I nuli n i s a poly f r uc tose ( f r om J ewi sh ar ti c hokes) wi tho ut e ff ec t on GF R. I nulin h as a
sp her i c al c onf i gur ati on and a molec ular we ig ht o f 5 000. I nulin fi lter s f re el y th r ough the
glomer ular bar r i er. I nulin i s un c har ged a nd not boun d to p r otei ns in p la sma. I nuli n c r osse s
f r eely most c api lla ri es a nd y et does no t tr aver se the c ell memb ra ne ( di str ib uti on volu me i s
E CV) . Si nc e one litr e of plasma c ontai ns ar o und 0. 94 l of water, the ultra f iltr ate
c o nc entr ati on of i nuli n is C p / 0. 94.

2 All ultr af i lte r ed i nulin molec ules pa ss to the u r in e. I n o th er wor ds, they ar e n eithe r
r ea bsor bed n or sec r eted i n the tubules. I nuli n i s a n exogen ous substa nc e - not sy nthe si se d
or br o ken down in the b ody.

3. I nuli n i s n on- toxi c and ea sy to measur e.

Th us, under stead y - state c ondi ti ons, the r ate of in ulin leavi ng the B owman's c aps ule s must be e xac tly

eq ual to the r a te o f i nuli n ar r i vin g in the fi na l ur i ne. The mai n i dea i s to mea sur e the am ount of i nulin
exc r eted i n th e ur i ne dur i ng a ti mep er io d wer e the plasma [ i nulin ] i s main ta in ed c onstan t by c onstant
i nf usi on o f i nuli n. Af ter one ho ur the subjec t ur i nates, and the ur i ne volume and i nu li n c on c entr ati on
i n the ur i ne and p la sma i s me asur ed. Th e amou nt o f i nu li n f i lter ed thr o ugh the glomer ular ba r r i er per

mi n is: ( GF R × C p /0 . 94) .

A ll i nulin molec ules r emai n i n the pr eur i ne un ti l th e subjec t ur i nates. Thus , the amo un texc r eted i s
eq ual to the a moun t f i lte re d and Eq . 2 5- 4 i s developed ( se e la te r) .

S in c e the i nul i n c l ear anc e i s 18 0 l per 24 hour s f or y oun g, h ealth y males or 12 5 ml per mi n, the GF R

must be ( 125 × 0 .9 4) = 11 8 ml per mi n. The i nu li n c lear an c e i s 10% lower f or y oung f emales than f or
y o ung male s due to the di ff er enc e in a ver age bo dy wei ght and body sur f ac e ar ea.

Th e nor mal value s f o r b oth sexes dec re ase wi th age to 70 m l per mi n af ter the age o f 70 .

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I nu li n c l ear a nc e i s a pr ec i se exp er imental me asur e and the i de al stan dar d, but i nulin must be i nf used
i ntr aven ously, and the method i s not nec essar y i n c li ni c al r o utin e.

I f the c lear anc e of a substanc e has the s am e val ue as the i nuli n c lear an c e f or th e per son, then the

su bstanc e i s only sub jec t to ul t r af i lt r at i on. The or etic ally, re absor pti on mi ght balanc e tubu lar
se c r etio n and gi ve the same r esult.

I f th e c lear anc e o f a substanc e i s gr ea te r tha n th e in uli n c lear a nc e, then c lear ly thi s substanc e is

be in g added to the ur i ne a s it f lo ws along the tubu les; i n other wor ds, it i s bei ng s e c r et ed.

S imi la r ly, i f the c lear an c e of a substanc e is l es s th an the i nulin c lea r anc e, i t mean s tha t the

su bstanc e i s bei ng r ea bs or be d at a h ig her r ate th an any po ssi ble sec r eti on.

Th e extr ac ellula r f lui d volume ( ECV ) c an be measur ed wi th i nu li n as i nuli n does n ot p ass the c ell
membr ane ( see C hapt e r 2 4 and Eq . 2 4- 4) . The eli mi nati on of i nuli n is e xponen ti al - ie , the f r ac ti on
( k) of the r emai ni ng amount in the body that di sapp ear s per time uni t i s c onstant ( se e C hapt e r 1 ) .
S in c e the f iltr ati on f ami ly of substanc es i s eli min ated f r om the blood sole ly b y fi lt r atio n, the
eli mi na ti on d epends o nly on GFR, and the di str i butio n volume i s that of in ulin ( E CV) . Thu s, the
eli mi na ti on r ate c o nstant ( k= 0. 69/ T½ ) f or th e in uli n f ami ly i s r oug hly e qual to (GFR* C p ) / ( EC V* C p ).

2c . T he t hr ee c l ear a nc e- f am il i es

A ll substan c es tr eated by the ki dne y s c an be d ivi de d in to thr ee gr oups or f am i li es , na mely the
f i ltr ati on- , the r eab sor pti on- , and the sec r e ti on- f ami ly.

Th e ki dney tr eats the f i lt r at i on f am i ly o f su bstanc es ( se e la te r) just like i nu li n.

Th e f iltr atio n r ate ( J f il t r ) f or i nuli n equa ls the exc r eti on r a te ( J e xc r ) , and both in c r ease i n di r ec t
pr o por tio n to the r i se i n C p ( F ig . 25 - 5) . The c lear anc e is the slop e of the c ur ve, and i t is ob vio usly a
c o nstant value that is i nde pende nt o f C p .

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F ig . 25 - 5: The s tr a ig ht lin e show s a dir ect r elat ion ship bet w een t h e filt r at ion r at e a nd t he
co ncen t r at ion for t he inulin family o f s ubst an ces in plasma.

T he r eabs o r pt io n or glu c os e f am i ly c ontai ns ma ny vi ta l sub stanc es ( see later ) . For the r eab sor pti on
f ami ly o f c o mpo unds, the exc r eti on f lux i s equal to th e fi ltr atio n flux min us the r ea bso r ption flux. The
maxi mal r eab sor ptio n f lux ( Tma x ) is r ea c hed ab ove a c er tai n thr esho ld. A bove thi s satur ati on
thr esh old th e c le ar anc e f or the r ea bsor pti on f ami ly i s equal to ( th e in ulin c lea r anc e - Tma x /C p ) ,
ac c or di ng to the ma th ema ti c al ar gument i n Fig. 25- 8.

T he s ec r et i on o r PAH f ami l y c ompr i ses end ogenou s substanc es and dr ug s (see late r ) . F or ei gn
su bstanc es a re of te n di str i buted i n the E CV, but some of th em ar e a lso e nter in g c ells ( I C V) . At low
c o nc entr ati ons thei r eli mi nati on r ate c onsta nt ( k) i s r ough ly e qual to r e nal p la sma f low ( RP F) di vi ded
by ECV: ( RP F* C P / E CV* C P ) = RP F/ EC V. Thus, k equa ls RPF/ EC V or 1/ 20 mi n - 1 in most healthy
pe r sons. The k value c or r espond s to a h alf- li f e of 14 mi n ( T ½ = ln 2 /k) .

2d . E x c r et i on r at e and c le ar anc e .

E x c r et i on r at e c ur ve s f or i nu li n c a n be c han ged i nto c lear anc e by a si mple mathema ti c a l pr oc edur e:

D if f er enti atin g th e exc r eti on f lu x c ur ve f or th e in ulin f ami ly wi th r espec t to C p pr odu c e the r enal
plasma c lear an c e c ur ves f or these substanc e s. L et u s a ssume th at the c ur ves ar e f r om a r e sti ng
pe r son i n steady state wi th a nor mal in uli n c lea ra nc e ( the slope of the li ne i n Fi g. 25- 6, A) .

F or the inu li n f am i ly the e xc r eti on f lu x e quals ( ur i ne f lo w × C u ) , and by di visio n wi th C p we h ave the

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i nuli n c lear anc e.

F ig . 25 - 6: A, B, and C ar e t he filt r at io n- r eab sor pt ion - a nd sec r et io n- families of su bst anc es,
r es pect ively. - D show s t he clear a nce cu r ves.

F or all subs tan c es belong in g to the i nu li n f amily the exc re ti on f lux c ur ve s ar e li ne a r, so the ra t e of

c h ange ( wh ic h is the c lea r anc e) must be c onstan t i n a gi ven c o ndi tio n ( Fi g. 2 5- 6A) .

Th e r esults of the thr e e exc r eti on f lu xes ar e plotted wi th C p as the de pende nt va ri ab le ( x- axi s of Fig.
25 - 6, A BC ) .

Th e exc r eti on f lux c ur ves f or the thr ee f amili es of substan c es, whe n di ff er enti ated ( dJ e xc r / dC p ) ,
pr o vid e us wi th th e th r ee possi ble c lear an c e c ur ves ( F ig . 25 - 6, D ) .

F or the re abs or p ti on f am i l y, the c lear anc e is ze r o at f i r st, bec au se th e exc r eti on i s zer o ( Fi g. 25- 6
D ) . The c lear anc e in c r eases, an d fi na lly i t a ppr oac h es the i nulin c lea r anc e. Ther e fo r e, the
c lea ra nc e i s steadi ly i nc r easi ng towar ds i nulin c le ar anc e with i nc r e asi ng C p .

F or the s ec r et i on f am il y, th e c le ar anc e must also be equ al to the exc re ti on f lux di vi ded by C p . W hen
the [ PAH] i nc r e ases, mo r e and mo r e PA H i s elimi nated by f i ltr ati on, and the sec r etor y eli mi nati on i s
r elati vely suppr e ssed ( so- c a lled au to -s uppr es s i on) . The c lear an c e f or th e sec r eti on f amily i s f alli ng
with i nc r ea si ng C p , and a ppr oac hes that of inu li n ( Fi g. 25- 6 D ) .

Tab le 25- 1: Co mpo sit io n of ur ine

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Compon ent C once nt r at ion D aily r enal Find ing/ Disea se
ex cr et ion

< 5 00 ml/ Nep hr opathy, shoc k
W ater 50 0- 2500 ml
> 2 500 ml/ D iab etes

< 2 0 mmol d ai ly / Lo w di et
Potassi um 60 - 70 mM 90 mmol da ily
> 15 0 mmol d ai ly / Ric h di et

Sodi um 50 - 120 mM 15 0 mmol d ai ly

Pr otei n 20 mg* l- 1 30 - 150 mg dai ly Mic r oalbuminu r ia /D i abetes

Pr ot einu r ia /N eph r opat h y

Gluc osur i a/ Di abe te s mellitus
Gluc ose ze ro Neglig ib le
Gluc osur i a/ Pr oxi mal d ef ec t

Ur ea 20 0- 400mM 50 0 mmol d ai ly High exc r eti on/ Ur aemi a

High exc r eti on/ Lar ge m. mass
Cr eati ni ne 0. 1 15 00- 200 0 mg da ily
Lo w exc r eti on/ Musc ul. atr ophy

Osmolali ty > 600 mOsmol* kg- 1 A c c eptable c o nc . c apac ity

Th e c omposi tio n of ur in e in Table 25- 1 i s the basi s f or si mp le di ag nosti c s. Anur i a or oli gur i a ( < 500
ml d aily ) i ndi c ates the p re senc e o f hy potensi on or r en al di se ase. Poly ur i a ( > 25 00 ml of ur i ne dai ly )
i s the si gn of di abe tes – b oth di abetes melli tus and di ab etes i nsi pi dus. Mi c r oalbumi nur i a ( i e, 5 0- 150
mg per l) i nd ic ates glomer u lar ba r r ier di so rd er suc h as di ab etic g lomer ular di sease . Gluc osur i a wi th
hy per gly c ae mi a i s th e si gn of di abetes melli tus, and wi thou t hy per gly c ae mi a i t i s a s i gn of a pr oxi mal
r ea bsor pti on def ec t. Hi gh u r ea exc r eti on i s seen i n ur ae mi a, and hi gh c r eatin in e exc r eti on i ndi c ates
a lar ge musc le mass i n a healthy per so n. A lo w c r eati ni ne exc r e ti on i s the si gn of mu sc ular atr ophy
or ag ei ng.

3. U lt r a filt at ion an d t he inulin family

I n a he althy p er son at r est almost 25% of c ar di ac o ut put passes the two kid ney s ( 12 00 ml eac h mi n) .

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Th e blood r eac h es the f ir st par t of the nep hr on thr ough the a ff er ent ar ter i ole to the glomer ular

c a pi llar i es. I n the gl ome r ul ar c api l la r ies the hy dr ostati c pr essu re is ap pr oxi mately 60 mmHg at th e
star t and 5 5 mmHg at the end ( Fig. 25 -7 ) . The inu li n or f i l tr a ti on f a mi l y c onsi sts of i nulin ,
51 57
r ad io ac tive ind ic ator s( Cr - ED TA, Co- mar ked B 1 2 , 1 4 C- mar ked i nuli n, 3 H- ma r ked i nulin ,
i othalamate mar ked wi th 1 2 5 I or 1 3 1 I ) , mann itol, r aff i nose, suc ro se, th io c y ana te, an d th io sulfa te .
Th ese substa nc es ar e mor e or less evenly di str i buted i n the EC V.

3a . T he St ar l i ng f or c es

Th e pr essur e s g over ni ng the glomer ular ultr a fi ltr ation ra te ( GFR) ar e c alled the S t ar li ng f or c es ( see
eq uati on i n Fi g. 25- 7) . Nor mally, fi ltr ation c onti nues thr oug hout the enti r e le ngth o f th e glomer u lar
c a pi llar i es i n humans, bec a use the net ultr af iltr ati on pr essur e ( P n e t ) is po siti ve also at the eff er e nt
ar ter i ole. The ave r age values f or deter mi nants of GF R ar e gi ven i n the f i rst eq uati on of Fi g. 25- 7. The

hy dr ostati c pr essur e gr a di ent is an impor tant deter min ant of GFR. The gl ome r ula r f i l t r at io n
c o ef f ic ien t i s c alled K f . The K f i s equa l to the f i ltr ati on sur f ac e a r ea di vi ded by the r esi stanc e of th e
glomer ular bar r i er and thus a c onstant f or a gi ven bar r i er ( Fi g. 25- 7) . The va lue o f K f ( also c a lled

the r ec ip ro c al gl ome ru la r h y dr ody n ami c r es is ta nc e) i s r educ e d in d ia betes, glomer u lon ephr i tis a nd
hy per tensi on. Vasoac ti ve su bstanc es c onstr ic t or di latate the glome r ula r mesan gi al c e lls and c hange
the value o f K f .

I n othe r c o ndi tio ns, th e fo r c es oppo sin g f iltr atio n bec ome equ al to the f or c es f avo ur i ng f iltr ati on at
so me po int along the g lomer ular c ap illar i es. Thi s is c alled f i l t r at io n equi l ib r iu m.

Th e hy dr ostati c pr essur e in Bow mans s pac e b elo w the glome ru la r b ar r ie r i s abo ut 1 5 mmHg or 2 kP a
( P Bo w i n Fig. 25- 7) . Thi s pr essur e is a lmost equal to the pr oxi ma l tubu le pr e ssur e, si nc e ther e i s no
measur a ble pr essur e f all a lo ng this segme nt.

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F ig . 25 - 7: Net ult r afilt r at io n pr es sur es in affer en t a nd effer en t e nd of glomer ular ca pillar ie s .
T he St ar ling for c es det er mine t he final ult r afilt r at ion pr es sur e ( P n e t ) a cr oss t h e glomer ular
b ar r ier.

Th er e i s almost no c olloi d- osmotic pr essur e i n Bo wma ns spac e , b ut a n onc oti c pr essu r e of
ap pr oxi mately 25 mmHg i n th e in c omi ng p la sma, mai nly d ue to pr otei ns, whi c h ar e u p- c o nc entr ated,

when f lui d lea ves the the plasma fo r B owmans spa c e. Her eb y, the pr otei n- onc otic p re ss ur e ( p g c ) may
i nc r e ase f r om 25 to 35 mmHg at the end of the glomer ular c api lla ry (F ig . 2 5- 7) . The h i gher the r en al

plasma f low ( RP F) , the lower is the r i se i n p g c .

A s ele c tive i nc r ease i n the r esi stanc e o f the af f er ent ar ter io le r ed uc es bo th the RPF an d th e
glomer ular hy dr o sta ti c pr essur e ( P g c ) , but GF R dec r e ases mo r e th an RP F, so the f iltr ati on f r ac tio n ( =
GFR/ RPF) f alls. I n c on tr a st, a r i se i n the r esi stanc e o f the ef fe r ent ar ter io le r ed uc es RPF but
i nc r e ases P g c ( F ig. 25 - 7) . I nstan tly, GFR i nc r e ases sli ghtly, but GFR eventually dec r ea ses due to the

r i se i n p g c . As RPF f alls mor e than GFR the f i ltr ati on f r ac ti on i nc r eases. A c ombi ned i nc r eas e in
bo th the a ff er ent and the ef f er ent ar ter io la r r esistan c e ( as c aused by most va soc on str i c tor s) may
also r ed uc e RP F mo r e th an GFR, and i nc r ease the fi ltr ation fr ac ti on .

3b . T he net ul t r af i lt r at i on pr es s ur e

Th e net ul t r af il t r at i on pr es s ur e ( P n e t ) var i es f r om 20 to 5 mmHg thr ough the glomer ular c api llar ie s,
an d pr ovi des the f or c e f or ultr af i ltr ati on of a f at- a nd pr otei n- f r ee f lu id a c r oss t he glomer ular bar r i er

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i nto Bo wma ns spac e and f lo w thr ough the r en al tub ule s ( Fig. 25- 7) .

Th e ultr af i ltra te i s i sosmolar wi th plasma , almost pr otei n f re e, and c on tai ns low mol ec ular sub sta nc es
i n almo st the same c o nc entr ati on as i n plasma water.

Th e pr oxi ma l tubular r eab sor pti on takes plac e thr ou gh par a- and tr an s- c ellu lar pa th wa y s. I n the
pe r itub ula r c api llar i es, the Star li ng f or c es ar e se emi ng ly ad equate f or c ap illar y upt ake o f i nter sti tia l
f lui d ( Fi g. 25- 7) .

Th e hy dr ostati c net pr es s ur e i n the pr oxi ma l tubules – a nd wi th it the GFR - i s re mar ka bly well
mai ntai ned i n spi te of c hang es i n pr oxi mal r eabsor ptio n of salt and water.

A n ac ute def ec t i n the pr oxi mal r e absor pti on mec han ism r esults in a n in iti al r ise in p r oximal

hy dr ostati c pr essur e an d th e GFR is r ed uc ed. D ue to aut or egul at i on ( see par agr ap h 9) , the p r oxi mal
hy dr ostati c pr essur e i s r api dly nor mali sed at a new stea dy state. S y mp athetic sti mulation inc r eases
bo th the p r oxi mal r eabso r ption ra te a nd the per i tubular c ap illar y uptake ( F ig. 25 -7 ) . Her eby, the
hy dr ostati c pr essur e f alls in the p r oxi mal tubules and B owman's c apsule s o GFR may i n c r e ase. I n
r eve r se, angi otensi n I I sec r eti on i nhi bi ts th e pr oxi mal r eab sor ptio n r ate, inc r eases the pr o ximal

pr e ssur e and may r edu c e GF R. The t ot al di s t al f l ow re s i s t anc e be lo w th e pr oxi ma l tubules ( i e, i n th e
di stal sy stem) is lar ge an d impor tant. The d istal r esi stanc e h as two ma jor c o mpo nents namely a hi gh
r esistan c e i n th e Henle loop an d an even hi gh er re si sta nc e i n the r ema in in g di sta l sy s te m i nc ludi ng
the c o llec ti ng du c ts.

Th e r es i s t anc e o f t he glom er ul ar ba rr i er i s c alc ulated i n Fig. 25- 7 to be e xtr e mely small.

Nor mally, th er e i s h ar dly any hy dr ody na mi c r esi stanc e to glomer ular ultr a fi ltr ation .

4. Tu bular r eab sor pt ion and t he g lu cose family

Th e r eabs o r pt io n or glu c os e f am i ly c ontai ns vi ta l sub stanc es su c h as gluc ose , a mi no ac i ds, albumi n,
ac etoac etates, asc or bi c ac i d, beta- hy d r oxy buty r ate, c ar b oxy late, vi tami ns, lac ta te, p y r uvate, Na + ,
C l - , HC O3 - , phosphate, sulphate and ur ea.

4a . Tubu la r h andl i ng of gl uc os e

Tma x is the maxi mu m tr ansf er or net r eab sor ptio n f lux ( J r e a b s ) f or gluc ose ( mol. wt. 180 g p er mol) in
the pr o ximal tu bules. The opti mal value f or thi s gl uc os e tr a ns por t er i s 300 mg/ mi n or 300 /1 80 = 1. 7

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mmo l/ min f or he althy, y oung subjec ts wi th a body wei ght of 70 kg.

F or the re absor pti on f ami ly of sub stanc es, the exc r e ti on i s zer o a t f i r st sin c e the e nti r e f ilter ed load
i s r eab sor bed ( all glu c ose i s r eabso r bed, see Fi g. 25- 8 ) . Th e exc r eti on f lu x in c r ease s then li near ly
with i nc r ea si ng f iltr ati on f lux.

F ig . 25 - 8: Rena l G lucos e r at es as a fun ct io n of t he plas ma co ncen tr at io n ( C p ) .

Th e appea r anc e t hr es hol d is the b lo od plasma [ g luc ose] at whi c h the gluc o se c an be f i r st detec ted i n
the ur i ne ( n or mally 8. 3 mM or 150 mg% ). Th is oc c ur s whe n most bu t no t all nephr on s ar e satur ated
( Fi g. 25 -8 ) .

Th e ac tual s at ur at i on t hr es hol d, th e poi nt wher e all nephr o ns ar e gluc ose -satur ated, is muc h h ig her
( no r mally above 13 . 3 mM) . Th e c onc e ntra ti on d if fe r enc e ( 13 .3 - 8. 3 = 5 mM) r ep r esents a si mi lar
r ea bsor pti on r ate di ff er enc e ( 1. 7 - 1 . 0 = 0. 7 mmol/ mi n at nor mal GFR) c alled s pl ay . The r eabso rp ti on
c a pac i ty f or gluc ose i n the pr oxi mal tub ule c ells be c ome s satur ated at these hi gh blo od
c o nc entr ati ons ( Fi g. 25- 8 ).

4b . U r ea t r ans p or t

Th e water r eabsor ptio n in the p r oxi mal tubules i nc r eases th e ur ea c on c entr ati on i n th e f lui d. Si nc e
ur e a is u nc har ge d and di ff use s easi ly, i t will dif f use passi vely to the per i tubular c ap illar y blood. The
pa ssage f r ac ti on at the outlet of th e pr oxi mal tubule i s ar ound 0 .5 (5 0% o f the f i lte re d lo ad) .

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Ur ea i s thu s r eabsor b ed i n th e pr oxi mal tubules and also in the i nn er medu llar y c olle c ti ng duc ts an d
se c r eted i n th e th in d esc en din g and asc endi ng li mb of the He nle loo p ( see later ) .

Th e ki dney r euses ur ea by r ec ir c ula ti on i n the i ntr a- r enal ur ea r ec y c li ng c i r c ui t: I n ne r medu llar y
c o llec ti ng du c ts – medu llar y i nter sti ti um – lo op of Hen le – di stal tubules – c ollec ti ng duc ts.

Th e net r eabsor p ti on f lux i s ar ound 5 0% o f the f i ltr ati on f lux at nor ma l ur i ne f low. Th e nor ma l ur ea
c o nc entr ati on i n plasma is 5 mM, an d th e exc r eti on f lux fo r u r ea i s pr opor ti onal to th is ur e a
c o nc entr ati on.

4c . P r ox i ma l t ubu la r r e abs or pt i on

Health y pr oxi ma l tubules r ea bsor b app ro ximately 70% of th e f ilter ed wa te r, Na + , Cl - , K + and other
su bstanc es. Th e tu bular passag e fr a c tio n fo r the se substanc es at th e outle t of the pr oxi mal tub ule is
0. 3 ( 30 %) . The r e absor pti on of f lui d is i sosmoti c . Almost all f i lter ed gluc ose , p epti d es and ami no
ac id s ar e also r eabso rb ed by the pr oxi mal tub ules. The Cl- r eabso r ption is pa ssi ve. Thi s io n fo llows
the se c onda ry a c tive r e absor pti on of Na + in o rd er to mai ntai n elec tr i c al neutr ality. Reabsor ptio n of
water is pa ssi ve as a r esult of the osmo ti c f or c e c re ated by the r eab sor pti on of NaC l. All r eabsor p ti on
pr o c esses a re li nked to the f un c ti on o f the b asolater al Na + - K + - pump . Th e extr eme ly hi gh water
pe r meab ili ty of th e pr oxi mal tubule i s essen ti al f or its ne ar ly i sosmoti c volume r e ab sor pti on. The
ac ti ve r ea bsor pti on of solutes ma kes the f lu id sli ghtly di lute and the i nter stiti al f lui d sli ghtly
hy per toni c . I f i nuli n and PA H molec u le s ar e pr esent thei r c onc entr atio n in the f lui d wi ll r i se ( PAH a lso
be c ause o f pr o ximal sec r eti on) . The ac ti vely r eab sor bed solutes ha ve lo wer per meabi li ti es ( hi gh er
r ef lec ti on c oe ff i c ie nts) tha n NaC l.

I n the f i r s t hal f o f t he p r ox i ma l t ubu le , Na + - is r e absor be d wi th c ar boni c ac id a nd or gani c molec ules
be lo ngi ng to th e r eabso rp ti on f ami ly. - The pr oxi mal an d di stal r ea bsor pti on of bi c ar b o nate i s alr e ady
de sc r i bed i n Ch apt er 17.

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F ig . 25 - 9: Reab sor pt ion of NaC l in t he e ar ly and t he lat e p ar t of t he pr ox imal t ubu le. C A st an d s
for ca r boan hydr a se in t he br u sh bor d er s of t he ce ll.

Th e r eabsor p ti on f ami ly o f su bstanc es ( X ) e nter s th e tu bule c ells b y s pec i f i c s y m por t er pr ot ei ns
c o upled to the Na + - r ea bsor pti on ( 1. i n Fi g. 25- 9) . Thi s i s sec ond ar y ac ti ve tra nspor t showi ng
sa tu ra ti on k ine ti c s. Na + - r eabsor pti on i s also c ou ple d to H + - sec r eti on f r om the c ell by the f un c ti on o f
the N a + - H + - an ti po r te r p ro t ein (2 . i n Fi g. 25- 9 ) . Th is H + - sec r eti on i s li nke d to b ic ar bonate
r ea bsor pti on i n the uppe r p ar t of the pr oxi mal tub ules. The dr i vi ng f or c e f or the Na + - en tr y i s the Na +
- K + - pump loc ated i n th e basolater al membr an e, whi c h extr udes the Na + to the i nter c e llular spac e and
the bloo d ( 3. i n Fi g. 25 -9 ) . Glu c ose i s a ty pi c al example. The lumi nal me mbr an e c onta i ns a sod iu m-
gluc ose- c otr anspor ter ( SGLT 2) . A gen eti c de f ec t in thi s pr otei n pr od uc es f amili al r e nal gluc osur i a –
just as a gen etic d ef ec t in a simi la r i ntesti nal pr otei n ( SGLT 1) pr o duc es gluc o se- ga lac tose
malabsor pti on. - The pa ssage of gluc o se ac r oss the b asolater al membr ane i s by c a r ri er - medi ated
( f ac i li ta te d) di ff usi on.

I n the s e c ond ha lf of t he pr ox i m al t ubul e, Na + is r e absor be d to gether wi th Cl - ac r oss the c e ll
membr ane or thr ough par ac ellular r outes ( Fig. 25- 9, below) . I n thi s segment the tubular f lu id c ontai ns
a h igh c onc en tr a ti on of C l - and a mi ni mum of or gani c molec ules. Na + c ro sses the lumi na l memb ra ne
by the oper ati on of Na + - H + - ant i por t er s a nd Cl - - ani on ant i por t er s . I n the tubular lume n th e sec r eted
H + and ani on f or m a H+ - an io n c omp le x. Th e ac c umulati on of a li pi d- so lub le H + - ani on- c o mplex
esta bli she s a c onc e ntra ti on g r adi ent th at a llows H + - ani on -c omp le x r ec y c li ng ( Fi g. 25- 9) . Tr ansf er of

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the C l - - i on f r om the tub ula r f lui d to the blood c au ses the tubular f lu id to be c ome posi tive ly c h ar ged
r elati ve to th e blood.

4d . R eabs or pt io n in th e th ic k as c en di ng li m b

Th e Na + - K + - pump mai ntai ns a low i ntr ac e llular Na + , whi c h d r ive s th e simultaneou s, e lec tr on eutr al

r ea bs or pt i on of 1 Na + , 1 K + , and 2 C l - by the l um in al N a + ‑ K + - 2Cl - - s y m por t er . The C l - - c h annels ar e
on ly loc a te d in the b asolater al membr ane , so a c c umulate d Cl - re ac hes the I S F. The K + -c hanne ls ar e
loc a ted in a ll membr ane s and K + r ec ir c ula te s ( F ig. 25- 10) . Par a c ellular r eab sor pti on of posi tive io ns
by dif f usi on i s augmented by the po si ti ve c ha r ge of the tubular f lui d ( Fi g. 25 -1 0) .

Th e sec on dar y ac ti ve r eabs or pt i on of Na+ ( a nd Cl - ) is t h e bas i s f or t he t r ans ep it he li al s i ngl e ef f ec t
gr a die nt at e ac h tr ansver se leve l of the thi c k asc e ndi ng limb ( see later ) .

F ig . 25 - 10: Rea bsor p t io n of NaC l in t he th ick ascen ding limb o f t h e Hen le loo p. Ther e is a
luminal Na + K + - 2Cl - - sympo r t er and a ba solat er al Na + K + - pu mp . Th is mec hanism is essen tial for
d evelopment o f medu llar y h yper t o nicity by NaC l and t hu s fo r coun t er cur r en t mut iplica t ion
( se e la t er ) .

Th e elec tr oc hemi c al ener gy f or the f unc ti on o f the ba solater al Na + K + - p ump i s pr ovi ded by i ts

Na + - K + - ATP as e. The p ump thr ows Na + i nto the per i tubular f lui d. The K + an d Cl - i on s lea k out
pa ssi vely. The thi c k asc endi ng li mb i s i mpe r meab le to wa te r i n the ab senc e o f A DH, an d r e absor bs
Na + ac ti vely.

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Lo op di ur eti c s, whi c h ab oli sh the e ntir e osmolar gr adi en t i n the outer r ena l medulla, in hib it the
l um i nal Na + K + - 2Cl - - s y m por t er of the thi c k asc en din g li mb.

4e . R eabs or pt io n in th e di s t al t ub ul e and c ol l ec t i ng du c t

Th e di stal tubu le i s di vi ded i nto an ea r ly an d a la te segme nt, si nc e th e ear ly segmen t r eabsor b s NaCl
an d is i mper meable to water ( as the thi c k asc e ndi ng limb) , wher e as the la te segme nt f un c ti on s mor e

li ke the c ollec ti ng duc t. I n th e ear ly segment, th e NaC l tr ansf er i s me di ated by a Na Cl - s y m por t er
( Fig . 25 - 11) . Na + leaves the c ell thr ough the b asolater al Na + ‑ K + - pump, a nd Cl - le aves the c ell by
di ff u sio n ac r oss the ba solate r al C l - - c h annels. On ly a small f r ac ti on of the glomer ular f iltr ate r eac he s
the di stal tubules. Thi azi de di ur e ti c s i nhi bi t the NaC l- sy mpo rter.

F ig . 25 - 11: Cellular t r ans por t pr o cesse s in t h e dist al t ubule an d collect ing d uct .

Th e la te se gme nt i s c ompose d of two c ell ty p es ju st as the c ollec ti ng d uc ts. The lig h t p ri nc ip al c el ls
r ea bsor b Na + and sec r e te K + . The Na + - K + - pump i n th e basolater al me mbr an e dr aws Na + out i nto the
I SF and K + i nto the pr i nc i pa l c ells ( Fi g. 25- 11) . These c ells have sp ec i al i on c hanne ls i n the lumi na l
membr ane, whi c h i s pe rmeab le to Na + , b ut a lso to K + . The Na + -u ptake dep ola r ise s the lumi nal
membr ane ( - 70 mV) and makes the lumen elec tr oneg ati ve ( - 12 mV) c ompar ed to the i nter s ti tia l f lui d
( r ef er e nc e potenti al zer o) . K + r api dly di ff use s in to the tubu la r f lui d. Thi s sec r eti on of K + i nto the
tubu lar f lui d f r om the pr i nc i pa l c e ll i s thu s li nke d to the Na + - r eabsor ptio n. The amount of Na +
r ea bsor bed i n the di stal tubule sy stem is muc h less than i n the pr o ximal, b ut i t c an be i nc r eased by

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the ad r enoc o rti c al hor mone, aldoster on e. Aldoster one i s a min er aloc or ti c oi d, whi c h pr o motes the
r ea bsor pti on of Na + ( an d th us Cl - ) and the sec r e ti on o f K + ( and H+ ) i n pr i nc i pal c ells. Aldoster one
en te r s the c ell f r om the b lo od and bi nd s to an intr ac ellular r ec ep to r to f or m a c omple x. Th e c omple x
i nc r e ases the f or ma ti on o f membr ane pr otei ns i nc lud ing the Na + - K + -p ump a nd the lumi nal
Na + - c han nels. Thi s is the e ssenti al c ontr ol mec ha ni sm f or [ K + ] i n the EC V. S ec r eti on main ly o c c ur s
when the [ K + ] i n the EC V i s hi gher than nor mal.

A ld oster one also pr omotes the r eab sor pti on of Na + ( and thu s Cl - ) a nd the sec r eti on of K + ( a nd H+ ) i n
the c o llec ti ng du c ts o f sweat and sa li var y gland s just as i n the pr i nc i pa l c ells of th e di stal tubu les o f

the ki dn ey. Aldoster o ne- antago ni sts i nh ib it all a ldo ste r one eff ec ts. Th e dar k i nt er c al at ed c e ll s
se c r ete H+ ac r oss the lumi nal membr ane a nd r eabso rb K + .

I nter c a lated c ells ar e mi to c hond ri al- r i c h and most ac ti ve i n per sons wi th a low K + - pool. The H +
- se c r etio n by the H+ - pu mp i s pr ec i sely de te rmi ned by the [ H + ] i n the E CV.

Th e c ol l ec t i ng duc t c on ta in s p r in c i pal a nd i nter c alated c ells ju st as the late di stal segment, but the
i nter c a lated c ell di sapp ear s i n th e in ner me dullar y c ollec ti ng d uc ts.

Th e lu mi nal membr an e of the p r in c ip al c ells i n the c ollec ti ng duc ts c an be r egulated f r om n ear ly
water - imper meable ( i n the absen c e of anti di ur eti c hor mo ne, ADH) to water - per meable ( i n th e
pr e senc e of A DH) . The h or mon e in c r eases the water - per meabi lity by i nse r ti on o f water - c hann els

c a lled aq uapor i n 2. The water - c han nels ar e stor ed i n c y toplasmi c vesi c les that fu se wi th th e lu mi nal
membr ane. The b asolater al membr ane of the pr i nc i pa l c ell c ontai ns other aq uapor i ns an d th ey r emain
water - per me able even i n the absenc e of AD H. Mu ta ti ons i n the ge nes f or these c ha nnel pr otei ns
c a use nep hr ogeni c di abe t es i ns i pi dus .

5. Tubu la r s ecr et ion a nd t he PAH fa mily

S ubstanc e s sec r eted li ke PAH c on stitute the sec r eti on o r PA H f ami ly. The f i ltr ati on f lux ( J f i lt r ) as
usual i nc r eases i n di r ec t pr opo r ti on to the r i se i n C p ( Fig. 25 -1 2) . D i vid in g th e exc r eti on f lu x fo r PAH
with C p pr ovi des us with the PAH c le ar anc e . Th e c lear anc e i s the slope o f the exc r etio n flux c u r ve
( Fi g. 25 -1 2) . The sec r e ti on f lux appr o ac hes a maxi mu m ( T ma x ) . Most of the PA H molec u le s ar e f re e,
bu t 10 - 20% ar e bound to plasma pr otei ns.

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F ig . 25 - 12: Ren al PAH net r at es (flux es or J) as a fun ct io n of plasma con cent r at ion , C p .

Or gani c ac i ds a nd bases se c r eted i n the pr oxi ma l tubules i nc lud e endoge nous sub stanc e s an d dr ugs.
Th e endogenous su bstanc es i nc lud e adr ena li ne, bi le salts, c AMP, c r eati ni ne, dop ami ne, hi ppu r ate s,
no r adr enali ne, or ga nic ac i ds and ba ses, oxalate, pr ostaglandi ns, ster oi ds a nd ur ate. The dr ugs
c o mpr i se ac etazolami ne , ami lo r id e, a tr o pin e, bume ta ni de, c hlor othi azi de, c i me ti di ne, di odr a st,
f ur os emi de, hy d r oc hlor othi azi de, mor phi ne, ni tr of ur antoi n, par a- ami nohi ppu r ic a c id (PA H) , peni c i lli n,
ph enol r ed, pr oben ec i d, sulphona mi des, and ac ety lsalic y lic a c id . The sec r eti on i s of t en c ompeti tive .
A ll these sub stanc es ha ve var y i ng but hi gh af fi ni ty to an or gan ic a c i d- bas e s ec r et or y s y s te m i n the
pr o ximal tu bule c ells showi ng sa tur a ti on ki ne ti c s with a T ma x . The or ga nic c atio n sec r eti on i s
an alogous to the ani on sec r eti on.

5a . Tubu la r h andl i ng of PA H

Tma x is the maxi mu m sec re ti on r a te f or PAH i n the tubu le s ( F ig . 2 5- 13) . Nor mally, th e Tma x i s 0. 40
mmo l per mi n (8 0 mg/ mi n) fo r PAH.

At low PAH c onc en tr a ti ons i n the plasma ( Fi g. 25- 13 ), the slope o f the exc r etio n ra te c ur ve i s hi gh
( the c lear a nc e f or PAH i s hi gh) . Her e the PAH c lear anc e i s an a c c eptab le esti mate of the mi ni mal
r en al p lasma f low ( see ef f ec tive RPF later ) , bec a use the blood i s almost c lear e d by o ne tr ansi t.

Th e sec r eti on f lux is maxi ma l, wh en the plasma - [PA H] is h igh enough to a c hi eve satur a ti on. The weak
or g ani c ac i ds and b ases menti oned ab ove ar e si mi lar ly sec r eted i nto the pr oxi mal tub u le , an d have

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se c r etor y Tma x - values just like PA H ( Fig. 25- 14 ) . I n hu mans o f ave r age si ze ( wi th an ave ra ge body
su r fa c e ar ea of 1. 7 m 2 ) , the T ma x f or di odr ast and ph enol r ed aver ag e 57 and 36 mg/ min ,
r espec ti vely.

5b . Tubu la r h andl i ng of ur at e

Th e ac t i ve r eabs or pt io n of ur ate io ns i s ac c omplished i n the pr oxi ma l tubules b y an elec tr oneutr al
Na + - c otr ansp or t. Th e tu bular r eabsor p ti ve c a pac i ty is n or mally f ar gr eater than the amou nt deli ver ed
i n the glomer ular f iltr ate. Above a c ri ti c al c onc e ntr ation in the E CV o f ab out 0. 42 mM, th e ur ate
pr e c i pi tates i n the f or m of u r ic a c i d c r y stals, p r ovi ded the envi r onment i s ac i d. Pr e c i pi tati on i n th e
joi nts i s te rmed go ut ( a rthr i ti s ur i c a) , of te n aff ec ti ng seve ra l joi nts. Ur ate i ons ar e ac c umu lated i n the
E CV of go ut p atien ts, an d of te n also in patie nts wi th u r aemia. High doses of pr ob enec i d c ompete with
ur a te f or the pr o ximal r eabsor p ti on mec ha ni sm. Use o f thi s dr ug to pati ents wi th ac u te g out in c r eases
the exc r etio n of u r ate in the u r ine .

Th e ac t i ve sec r eti on of ur ate i ons o c c ur s f r om the b loo d plasma to the tubu lar f lui d by the or gan ic

ac id - bas e s e c r et or y s y s t em , whi c h h as a lo w c apa c ity f or ur ate.

Th us, th e r enal tu bules have a c apac i ty of both ac ti vely r eabso r bin g ur ate i ons and a c tively se c r etin g
them.

5c . Tubu la r h andl i ng of c r eat i ni ne

E ssenti ally a ll c r eati ni ne i n the glome r ula r f i ltr a te p asses on a nd i s exc r eted i n th e ur i ne. The
molec ule i s la r ger th an that of ur ea, and no ne of it i s r eabso r bed. Con tr ar y, c r eati ni ne i s sec r eted
i nto the pr oxi mal tub ule s, so th at the c re atin in e c onc e ntr a ti on i n the ur i ne i nc r e ase s mor e th an
10 0- f old.

5d . T he s ec r e ti on m ec h ani s m

Th e molec u le s o f the se c r eti on f ami ly leave the blood plasma of the per i tubular c ap il lar i es and bi nds
to basola te r al r ec eptor s wi th sy mpor ter s on the tubule c ell ( Fi g. 2 5- 13) . These c hann e ls ar e d r ive n by
en er gy f r om the b asolater al Na + - K + - pump tr an spor tin g th e molec u le s agai nst thei r c hemic al gr a di ent
ac r oss the baso later al membr a ne. In si de the c ell the molec ules ac c umu la te u nti l they c an d if fu se
towar ds the lumi nal me mbr an e. Her e, an an ti por ter tr ansf er s the i ons i nto the tubular f lui d. All these

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molec ules c ompete f or tr anspo rt, so i ntake of the dr ug p r obenec id c an r educ e th e peni c i lli n sec r eti on
loss.

F ig . 25 - 13: Sec r et io n of or ga nic anions a cr oss t h e pr oximal tu bules

Th e lu mi nal membr an e c ontai ns s pe c i fi c r ec e ptor pr otei ns f or nut r i ti ve m ono - an d di - c ar box y la te s .
Th ese r ec ep to r f un c tio ns ar e also c oup le d to Na + - tr ansf er.

6 . W at er and s olut e shu nt ing by va sa r ect a

Th e nor mal pe r fu sio n of th e r enal med ulla i s ty pi c ally 5- 10% of RBF. Th is b loo df lo w i s lar g er tha n th e
f lui d f lo w thr ough the loop o f Henle. Both the vasa r ec ta a nd the c losely loc ated loo ps o f Henle ( f ro m
juxtamedullar y neph ro ns) c onsi sts of two par a llel li mbs wi th c ounter - c u r r ent flui d f l ow i n the me dulla.

Vasa r ec ta a r e desi gned as a c ounter c u r re nt b lo odf lo w and ac t as w at er- s o lu te s hunt s that pr otec t
the medullar y hy pe r osmo ti c gr ad ie nt. Th e endothe li al li ni ng o f va sa r ec ta i s hi ghly p er me able f or
small molec ules ( wa te r, ur e a, NaCl, oxy ge n and c ar b on di oxi de) . Va sa r ec ta also ser ve as a n utr iti ve
so ur c e to the med ulla.

Vasa r ec ta r e c ei ve blood f r om the e ff er ent ar ter i oles and c on seque ntly ha ve an elevat ed c o lloi d
osmoti c pr essu r e and r educ ed hy dr o sta ti c pr e ssur e ( Fig. 25- 14 ). Th e net fo r c e i n th ese vasc u lar
loop s f a vour s net f l uid re abs or p ti on .

Le t us c onsi der the si tuati on wi th a hy pe ro smoti c medullar y gr adi ent and A DH p r esent, so a

28 of 61 18-10-2012 01:04


c o nc entr ated ur i ne i s pr od uc ed. The blo od i n th e desc en di ng limb of vasa r ec ta i s f i r st pa ssed on i n
the di r ec ti on o f i nc r ea si ng med ullar y o smolar i ty. Ac c or di ngly, thi s blood must gr adua lly supp ly water
to the hy p er osmola r, i nter sti tia l f lui d by passi ve osmosi s, and p assi vely r eabsor b s o lu te s (NaCl and
ur e a) by di ff usi on. He re by, the i nter sti ti um i s tempor ar i ly di lute d and the blood i s c o nc entr ated. I n
the asc endi ng p or ti on the b loo d passes r e gi ons wi th f alli ng osmolar i ty, and the bloo d gr adually
ab sor bs wa te r o smoti c ally and deli ver s solutes to the i nter stiti um by di ff usi on. The f low i n the
asc endi ng va sa r ec ta i s lar g er tha n in the desc en di ng li mb, bec au se water f r om the He nle lo op i s also
r ea bsor bed .

F ig . 25 - 14: A: Pas sive cou nt er - cur r e nt exch ange o ccur s in va sa r ect a, w it h d iffus io n of solut es
alo ng black a r r ows . P assive os mo tic flux of w at er fr om th e blood t o th e hyp er osmolar
int er s t it ium occu r s along s t ip pled, blue ar r o ws. – B : T he act ive co unt er - cu r r ent mult ip lier in
t he th ick ascen ding limb w it h a single effect at ea ch hor iz o nt al le vel.

Th e gr oss eff e c t o f the pa ssi ve c ounter - c u r re nt e xc hang e in the vasa r ec ta i s th at o f a w at er s hun t
pa ssi ng the me dulla ry ti ssue , wher eas so lutes r e c y c le and thus a re mai ntai ned i n medu lla. W ater i s
sh unted f r om li mb to li mb withou t di stur bi ng the i nn er medu lla. The pa ssi ve c ounter - c u r r ent exc hang e
an d lo w bloodf low thr oug h th e vasa r ec ta c u rtai l th e med ullar y h y per osmoti c gr adi ent ( Fi g. 25- 14) .
Th e mea gr eness o f the medullar y blood f low, r educ ed by AD H, c ontr i bute to the ma in ten anc e of the
medullar y hy pe r osmo ti c gr ad ie nt, bu t r ed uc e the nutr i tive supply to th e in ner me dulla .

7 . Co ncen t r at io n or dilut ion of ur in e

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Th e th in a sc end ing li mb of Henle i s imper meable f or water, but hi ghly per meable f or Na Cl and less so
f or ur ea . The thic k asc end in g li mb is a lso i mper meable f or water and a lso f or ur e a. The water
pe r meab ili ty of th e c or tic al a nd me dullar y c ollec ti ng d uc ts in c r ease with i nc r ea sin g c onc e ntr ation s of
an ti di ur eti c hor mone ( A DH) i n the per i tubular blood . C onc en tr a ti on o f u ri ne . I ni ti ally, the osmo lar i ty
of the tubu lar f lui d, th e vasa r ec ta blood, an d th e in te rsti ti al f lui d i s 300 mOsmol * l - 1 . The asc endi ng
li mb of the Henle lo op i s i mper meable to water and a c tive ly tr ansp or ts NaCl f r om the p r eur i ne i nto th e
su r ro undi ng i nter sti ti um. Thus solute an d flui d i s sepa ra te d and the tubular f lui d be c omes di luted. At

ea c h hor i zontal level of the thi c k a sc endi ng li mb , a hy per osmoti c gr adi ent ( a s i ngl e ef f ec t ) of
ty pi c a lly 200 mOsmol * l - 1 i s establi shed ( Fig. 25 - 14B) . En er gy i s nec ess ar y to establish th e
hy per osmoti c gr adi ent. The ene r gy i s fr o m Sko u´ s basolater al Na + - K + - pump, wor ki ng i n c on jun c tio n
with the Na + - K + - 2C l — sy mpor ter of the thi c k asc en di ng li mb ( Fig. 25- 10) .

Th e to ta l osmolar i ty in the i nn er medu llar y i nter sti ti al tissue c an be as hi gh as 140 0 mO s m ol p er l,
when the ur i ne i s ma ximally c onc en tr a te d.

Th e r enal c or tex f lu id i s i sotoni c with the plasma. W hen the i sotoni c f luid fr o m the pr oxi mal tubu les

pa sses down thr ough the hy per toni c me dulla i n the de s c end in g t h in l i mb of the Henle loop, water
moves ou t i nto the me dulla r y in ter sti ti um by o smosi s, maki ng the tubular f lu id c onc en tr ated . Th is i s
be c ause the e pi the li al c ells of the thi n de sc endi ng li mb a r e hi ghly per meable to wate r but less so to
so lutes ( NaCl and ur e a) . W ater i s r eabsor b ed and r etur ne d to the b ody vi a vasa r ec ta a nd the r enal
vei ns . A t the be nd of the lo op the f lu id h as an osmolar i ty e qual to tha t of the sur r ou ndi ng medulla r y
i nter sti tia l f lui d. Howe ver, the tub ula r f lui d has a g re ater c onc e ntr a ti on o f NaCl an d a smalle r
c o nc entr ati on of ur ea than the sur r oundi ng s.

I n c o ntra st to the thi n and thi c k asc endi ng li mb, most c ell memb r anes i nc ludi ng thos e of the p r oxi mal
tubu les a nd the thi n desc en di ng limb of the Hen le loop, ar e water - per meable unde r a ll c i r c umsta nc es.

Th is i s bec ause these c ell memb ra nes c on tai n water - c hann el p ro te in s c alled aquapo r in s .

A s new f lui d enter s the desc endi ng li mb of the He nle loo p, the hy per osmoti c f lu id i n the bo ttom of the
loop i s pus hed i nto the asc en di ng limb, wher e NaCl i s separ ated f r om water.

Th e osmola r ity of the i sosmotic tub ula r f lui d r unni ng i nto the thi n desc endi ng loop o f the ou te r
medulla i s 300 mOsmol* l - 1 and the o utp ut to the di stal tubule i s 100 mOsmol* l - 1 ( Fig. 25- 14 , B ) . A t

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New human physiology ch 25

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