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ANATOMICAL ASPECTS OF NEPHRON A. CORTICAL /. Form 85% of Total Glomeruli Situate i! outer "#$ %i !e&
S'ort loo( NOT e)te! i!* i!to Me ulla +Salt lo,i!*- fu!.tio!all&.
012TA 3 ME41LLARY Form 5" 6 55% !e('ro!, Situate at Corti.o Me ullar& fu!.tio!
Lo!* loo(, of He!le (e!etrati!* me ulla 7a,a re.ta .lo,el& relate Fu!.tio!all& 'a8e9 i: ii: iii: Hi*' Glomerular filtratio! Rate, +Salt retai!i!*- feature, +;ater retai!i!*- feature,. to loo( of He!le.
GLOMER1L1S 3 Fu!.tio!al A!atom& 1. !. Tuft of CAPILLARIES between afferent ARTERIOLES held together by mesangial ells. and efferent
"O#$A%&S CAPS'LE ( E)ithelial layer ( single layer with foot )ro esses or Podolytes interdigitating with ea h other. Endothelia layer with fenestrations or )ores *++(1+++ , in diameter.
-. .ILTRATIO% PAT/#A0 $ole ule $# 1 2+++3 14R radius 5 'C "owman&s s)a e E(it'elial Po o.&te, Slit mem<ra!e =">? @ Ai e:
L. RARA E! ot'elial Cell /ASEMENT : Gl&.o(rotei!, .o!tai!i!* ,iali. a.i 7. .'a .olla*e! MEM/RANE :
MaBor Se*me!t, of Ne('ro! 1. !. 6lomerular Ca)sule Pro7imal Con8oluted tubule ( S1 initial )art of )art on8oluta ( S! intermediate segment in luding )ars beginning of PARS RECTA. ( S- rest of PARS RECTA.
on8oluta 5
-.
Loo) of /enle ( thin des ending Segment ( loo) ( thi 9 as ending Segment Thi 9 as ending )art in onta t with the afferent : efferent arterioles to form ;'<TA = 6LO$ER'LAR APPARAT'S >istal Tubule Colle ting Tublule -)ts. ?a@ Corti al ?b@ Outer $edullary
4. 2.
? @
Inner $edullary
GLOMER1LAR FILTRATION RATE 1. !. -. 4. 2. *. %ormal A 1!2mlBmin C 1+(!++mlBmin o8er !4hrs. - million glomeruli filtering 4+ nmolBmin 1+D lower in .E$ALE 1E+LBday with F G2D reabsorbed 6lomerular Ca)illary "ed A1.2m! .a tors and Renal "lood .low .ACTORS CO%TROLLI%6 6 . R P. 1 P ( b.
1.Afferent arteriole
!. 6lomerular 2+(*+ Ca)illary -. Efferent arteriole *+ !+ 4. Peritubular 1+ = !+ Ca)illaries $ean 1! b@ 1. !. -. 4. Tubules Site Pro7. Con8ol. Tubule >istal Con8ol. Colle ting >u ts Interstitial .luid ! *
/ydrostati
12 = 1E mm/g 2
Smaller diameter than afferent arterioleI /igh Resistan e Afferen e arteriole -+(42D T. Renal Has . R. Efferent Arteriole 4- = 2+D Peritubular CAP 1*D
-. Protein Content efferent arteriole blood is !+D higher than afferent arteriole blood. 4YNAMIC OF GLOMER1LAR FILTRATION AN4 PERIT1/1LAR REA/SORPTION Afferent Art G+
!2 -2
Efferent Arteriole
-2
2+ (*+
!2
-+
1+ ( 12
+ PERIT'"'LAR CAPILLARIES I%TERSTITIAL 1+ Ps 1+(12 -+ -2 1 COLLOI> O%C.PRES. 12
E..ERE%T R F A..ERE%T R
6.R
J. 6 K ? P6C( PT@
6C
J.6 1 .ILTRATIO% CoE.. 1 E = 1*mlBminBmm/gBm! Ca).area P6C 1 $ean 6lom. CAP. /ydrostati P A 2+ = *+ mm/g PT 1 $ean tubular )ressure 1 1+(12 mm/g
6C
1 $ean CAP. Osmoti )ressure in glomerulus ?-+mm/g@ 1 Colloid O%C. Pressure of Tubular .luid A +
!.
P ( 1. >e)ends on ARTERIAL PRESS'RE And A..ERE%T : E..ERE%T ARTERIOLAR TO%E RESISTA%CE. !. PT ( Tubular )ressure -. b ( >ilution or loss of )lasma )roteins ( C Plasma .low Rate.
" Length along 6lom. Ca) along 6 a)illary %et filtration Pf de reases smaller fra tion To + at 1B- a)illary length b less . greater along 6l. Ca) filtra tion a@ Afferent Arteriolar E7 retion Constri tion 6lom.Ca). )ressure 6.R Length .low filtered . Pf
5 Reabsor)tion
Peritubular Ca)illary P
6lomerular Ca)illary P
Peritubular Ca)illary P I%CREASE> E<CRETIO% ? @ E..ERE%T ARTERIOLE Constri tion of Eff. Arteriole b filtration Peritubular Reabsor)tion Ca)illary P
P.T.C.
Absor)tion
6.R
ARTERIOLAR TO%E ?a@ Sym)atheti %eural Control ?b@$ild inherent smooth mus le ontra tion inde)endent of %eural effe ts ( le8el of tone is low high blood flow Bgm tissue ( fra tional a)a ity to in rease L is lower than other organ ( absolute is onsiderable due to high L at resting le8el3 i.e. 2+D of high flow A !+D C.O is high.
T1/1LO3GLOMER1LAR FEE4/ACC La is Cells = $yoe)itheloid Cells. Afferent Arteriole Efferent Arteriole $a ula >ensa Smaller : renin granule
>istal Tubule
/y)othesis M $AC'LA >E%SA ( re e)tor or sensor monitor for T.6. feedba 9 $AP 6.R %a 5 e tubular At $a ular >E%SA N Release of intra(renal RE%I% Llo al angiotensin I Angiotensin II 6.R 5 R". Auto Regulation Afferent Arteriolar CO%STRICTIO% /E%CE T.6. feedba 9 refers to the Tubular regulation of 6.R in the fa e of mar9ed hanges in $.A.P. GLOMER1LOT1/1LAR /ALANCE Reabsor)tion of Solute by the )ro7imal tubule is )ro)ortional to the load deli8ered to the tubule by filtration. A onstant .iltration fra tion is )resent so that the total amount reabsorbed rises when 6.R rises and 8i e(8ersa. $EC/A%IS$ .iltration .ra tion eg. $.A.P.
Peritubular Ca)illary Colloid On oti P .iltrate in Lumen Reabsor)tion %a 5 /!O 6LO$ER'LOT'"'LAR "ALA%CE PCT
PRESS1RE 3 4I1RESIS INCREASE M.A.P. 1RINE O1TP1T 3 ;HY D i: ii: GFR Aell 5E? autore*ulate R/F 5"? 8? REG1LATION >? 5? MAP =mmH*: Re,(o!,e MAP 5?? 55? GFR 1RINE FLO; A1TO F 8?3"??mmH* "?? Litte R/F or GFR 3 autore*ulatio! Mar% uri!e out(ut ue to filtratio! fra.tio! a! alteri!* +Glomerulo3tu<ular /ala!.eGFR Le,,
FF
+Glomerulo3Tu<ular
FL1I4 1PTACE IN PERIT1/1LAR CAPILLARIES A)ro7. 1E+L B day Pro7. C Tubule a)illaries ')ta9e 1. -. 4. .ILTRATIO% .RACTIO% .. 1 6.R 1 1!2 1 !+D RP. *2+ !+D )lasma flowing through 9idney is filtered. .. due to dis)ro)ortionate 6.R due to 1. through PCT leading to ?a@ Colloid O.P. ?PTC@ ?b@ 'rine out)ut. RENAL CLEARANCE The 8olume of Plasma whi h would be om)letely leared of a substan e by the remo8al of that amt. of substan e by the 9idney in one minute. Renal learan e 1 Con .urine 7 8olume flow rate urine Plasma Cons. I%'LI% learan e 6.R Inulin $# 2!++ Inert3 %ot metabolised .ILTERE>3 not absorbed or se reted C1 1 '1 H i P $annitol or Sorbitol may be used . Creatinine Ce ( slightly higher 8alue due to mild se retion Hit. "1! Co labelled /y)ague I labelled Tubular load Low hydrostati Pressure in Peritubular
E>TAChromium21 labelled. RENAL HAEMO4YNAMICS 1. "lood .low !2D Cardia out)ut -(2ml gm(1 min =1 A(HO! differen e 1(! Hol D !2D HO! for basal metabolism O2D HO! for %a a ti8e Absor)tion !. Intra renal blood flow Corti al blood ( /igh flow /igh )ressure Low resistan e $edullary Region ( Low flow +.-mlg(1min(1 /igh resistan e. 4ISTRI/1TION H 1. !. -. 4. Corti al "lood .low E+(E2D Corti o $edullary Region 1+D Hasa Re ta ?urine Con @ !D A = H Shunts ?TR'ETA@ -D %o Sym)atheti Tone #ith Sym)atheti stimulationI .low is distributed 12 ;u7ta( medullary %e)hrons.
RENAL CIRC1LATION 6 F1NCTIONAL ANATOMY 1. ARRA%6E$E%T O. HESSELS Renal ART Interlobar A Ar uate $edulla Afferent Arteriole a@ CORTICAL %EP/RO%S 6lomerular Ca)illaries Heins b@ ;'<TA($E>'LLAR0 %EP/RO%S .rom Efferent Long bran hes forming HASA RECTA losely Arterioles related to loo) of /enle PPortal SystemQ ! Ca)illary "E>S in series se)arated by efferent arteriole M 1st a) "E> ( 6lomerular a)illaries !nd a) "E> ( Peritubular Ca)illaries. Efferent Arteriole Henules Corti al a)illaries A between Corte7 :
inter lobular A.
6.R :
R"..
C Re e)tors F R re e)tors )redominant C stimulation with ate holamine >o)aminergi re e)tors dilatation Other /ormones Angiotensin II Haso onstri tor Jalli9rein "rady9inin >ilator Prostaglandin E! >ilator
AFFERENT ARTERIOLES i! a@ CORTICAL %EP/RO%S Thi 9 $us le #all %o Autoregulation /igh Resistan e 1+(12D Perfusion through Jidney
b@ E..ERE%T ARTERIOLES Thi 9 $us le wall at both orti al and ;u7ta $edullary %e)hrons ( Sensiti8e to Sym)atheti Haso onstri tor A ti8ity CONTROL Autoregulation ( Intrinsi Control Constant .low o8er $AP O+ = 1E+mm/g ( An intrinsi me hanism inde)endent of neural or ir ulating humoral influen es. Theories a@ Plasma S9imming P R due to )lasma s9imming with loss of )eri)heral )lasma.
His osity 5 b@ @ d@
Resistan e results.
Renal interstitial )ressure $yogeni theory )ressure smooth mus le ontra tion ;6A feedba 9 loo) )erfusion P %aCe deli8ery to ma ula densa out)ut Angiotensin II 8aso onstri tion. RE%I%
+Autore*ulatio!-
58?
5. S&m(at'eti. Ner8e Su((l& ". A!*iote!,i! II 7a,o.o!,tri.tio! $. Pro,ta*la! i!, E" G A" (re,e!t PG E" 8a,o ilator Natriure,i,
MEAS1REMENT IN4IRECT RPF K 1) . 7 RA) R7) Cleara!.e PAH u,e All PAH i, e)tra.te L 'e!.e R7) i, ?. R/F K RPF = 5 53 P7C :
4IO4RAST .leara!.e <ut 5??? a..urate 4IRECT FloA (ro<e, Colle.tio! of 7e!ou, Efflue!t. TRANSPORT MECHANISM
5.
MASSI7E 4IFF1SION $ost sim)le where random mo8ement of ion or mole ule dri8en by its thermal energy without intera tion with the ell memb. Com)onent or other solute. $o8ement C 6radient : )ermeability E7am)le 'REA reabsor)tion Pro7 C.T. /!O reabsor)tion urea Con .
Passi8e diffusion into P.T... Ioni subst. Through Sona o ludens ( has least resistan e ". fluid. %on(ioniTed li)id Soluble. %o energy reUuired E7am)le %/5 >rugs Luinine3 )ro aine. CO3TRANSPORT SYSTEMS Trans)ort of one substan e is lin9ed to another. ?a@ $ore of one substan e down a gradient ?ele tro hemi al@ dri8es the mo8ement of another. AT luminal memb. %a 5 glu ose entry is fa ilitated by arrier mole ule. Ele tro hemi al gradient for %a is maintained by %a = J = ATPase )um) at the basolateral memb. PASSI7E TRANSPORT OF ;EAC ELECTROLYTES Chemi al 6radients established due to altered )/ in Tubular
/en e3 %a = 6lu ose trans)ort me hanism is a SECO%>AR0 a ti8e trans)ort mesh. Called P S0$PORTQ %a %a = 6 J S0$PORT ?b@ %a ACTIHE P'$P A%TIPORT
A%TIPORT System ! ions of the same harge are e7 hanged a ross the memb. %a 5 J = ATPase System
Trans)ort of Substan e from Tubular Lumen to Peritubular fluid against an ele tro( hemi al gradient utilising energy. ! Ty)es M ?a@Trans)ort $a7ima V Reabsor)tion Trans)ort fi7ed and limited Uuantity of Solute )er unit timeI i.e. CAPACIT0( LI$ITE>. 'sually asso iated with CARRIER = $E>IATE> trans)ort systemsI with s)e ifi ity 5 om)etition eg. 6lu ose3 $alate3 R or butyrate a etoa etate3 Hit.C. Saturation o urs when arrier mole ule is saturated so that e7 ess is e7 reted through urine. SAT'RATIO% PT 1 $A<. RATE O. TRA%SPORT 1 TRA%SPORT $a7imum V ?b@ 6RA>IE%T = TI$E limited Trans)ort Sys. Absor)tion me h. Limited by Con . 6radient that ould be established within time of onta t. Eg. %a3 Cl3 /CO-. Tubular .luid .low ( Rate affe ts 6radient Limited me hanism limit ba 9 flu7. A high rate of /!O reabsor)tion limits ba 9 .lu7 : hen e reabsor)tion. PRO2IMAL T1/1LE REA/SORPTION AN4 SECRETION 5. Ele.tri.al Gra ie!t T$P 1 (O+mH due eletrogeni )um). Peritubular fluid 58e to lume by =!mH Lumen ( (!mH Cell (O+mH PTE 5 +mH
".
Pro). Tu<ular Fu!.tio! ACTI7E REA/S. PASSI7E REA/S. SECRETION =ACTI7E: Cation en l.
%a E+D Cl E+D /5 J E+D /CO- E+D %/! /PO4 E2D SO4 /!O E+D 'rate 6lu ose 1++D 'rea 2+D PA/ Amino A ids Peni illin Proteins. %". O+(E+D %a3 Cl3 /CO- : /!O reabsorbed in )ro7. Tubule. .L'I> E%TERI%6 >ESC. T'"'LE is I
a@ b@ @
ISO(OS$OTIC to PLAS$A indi ating ISO(OS$OTIC reabsor)tion P/ 1 O #ATER is reabsorbed follow on . 6radient reated by %a 5 Cl reabsor)tion. "ASE$E%T $E$". J %a /! J %a5 %a3 Cl3 /!O "'LJ .LO# %a5Cl
%a REA"SORPTIO% L'$E% Cl
1.
Primary trans)ort system for %a 5 /!O reabsor)tion is %a = J = ATPase system at basolateral memb. #hi h )um)s %a into )ara ellular s)a e : interstitial fluid. !. This reates a mar9ed redu tion in ellular %a and an ele tro hemi al gradient fa8ouring %a mo8ement into the ell3 as luminal memb. Is highly )ermeable to %a. %a reabsor)tion is limited by )assi8e ba 9 flu7. In S1 segment3 %a entry into ell is fa ilitated by S0$PORT )ro ess trans)orting %a 5 6lu ose together = A Co(trans)ort system dri8en by ele tro hemi al gradient for %a a ross luminal memb reated by %a = J = ATPase )um) at baso( lateral memb. Amino(a ids also share similar Co(trans)ort ?Sym)ort@ system. GL1COSE REA/SORPTION .reely filtered Almost all reabsorbed in Pro7. Tubule ACTIHE TRA%SPORT S0STE$ #IT/ T.ma7. in8ol8ing Co(Trans)ort with %a at the luminal side and arrier mediated at basement memb. ;u7ta($edullary %e)hron 55 6lu ose Reabsor)tion. L'$I%AL S'R.ACE S)e ifi %a 5 d ( 6lu ose $a7imal in S1 segment L'$E% %a CELL 6 PERIT'"'LAR .L'I> 6 Cl 6 %a J ATPase ACTIHE
-. 4.
Tm 1 -O2mgBmin W
-++ mgBmin X
Energy lin9ed to %a = J = ATPase system at baso(lateral memb. 6lu ose 5 %a lin9ed as Co trans)ort system Reabsorbed at luminal surfa eI ACTIHE REA"SORPTIO% se ondary to %a = J = ATPase system at "aso(lateral $emb.S0$PORT. PHOSPHATE Tm ACTI7E TRANSPORT Tm 1 +.1mmolBmin %a = Cou)led PO4 Co trans)ort system. Tm C C Hit.> /!O Parathyroid /ormone Cal itonium Cortisone AMINO3ACI4S Sym)ort System Cou)led with %a5 L forms reabsorbed better 4 different arrier systems lin9ed with a@ %E'TRAL A$I%O ACI>S b@ >I"ASIC A$I%O ACI>S @ >ICAR"O<0LIC ACI>S d@ I$I%O ACI>S : 6L0CI%E $aYority absor)tion in S1 Segment. /ICAR/ONATE REA/SORPTION L1MEN NaG Na
G G G G
CELL NaG
ISF
/! CO/!O 5 CO!
1.
Com)le7 Pro ess in8ol8ing /5 se retion /5 Se retion balan ed by %a5 Entry ( A%TIPOR S0STE$ >RIHE% %a ELECTROC/E$ICAL 6RA>.
!. Lumen M /5 ion ombined with /CO-( /!O 5 CO! 5 5 Cell / )romotes CO! 5 /!O /!CO/ 5 /CO-( C.A. ( /CO- formed trans)orted by Trans)ort $EC/. A ross
"asolat. $emb. %ET RES'LT M >isa))earan e of Tubular /CO-( is ou)led with /CO-( Reabsor)tion at ".$. At S1 ( initial fra tional rate of /CO- reabsor)tion is more ra)id than /!O reabsor)tion. So thatI i@ /CO- ?Tubular fluid@ falls ii@ /5 ion ?Tubular fluid@ rises leading to ba 9 flu7 : redu ed /5 se retion. CHLORI4E TRANSPORT CZ( reabsor)tion dri8en )rimarily by ele tro hemi al gradient established by %a5 reabs. S1 %egati8e lumen small transe)ithelial P.>. may )ro8ide ele tro hemi al gradient in )ara ellular s)a e. Initially CZ( reabsor)tion is slower than /!O reabsor)tion so that CZ( on . Rises in tubular fluid fa8ouring CZ( reabsor)tion.
S0$PORT CZ( CZ( PARA CELL'LAR L1MINAL MEM/. Sym)ort system ? %aCZ@ mo8ing %a 5 CZ into ell. CZ( CZ(
nA CZ( CZ(
Trans)ort )ro ess dri8en by the %a ele tro hemi al gradient established by %a = J ATPase system.
%a
J
/P
b /!O
/!O
+.P !(- mmosm higher 1. Labyrinth of inter ellular hannels formed interdigitating lamellae3 o)ening onto the )ermeable ".$.I losed off by Tonula o ludens. !. %a53 CZ(3 /CO-( are trans)orted into )ara ellular s)a e ma9ing fluid hy)erosmoti . -. This indu es /!O flow from ell : then e from lumen into hannels. 4. /ydrostati P. in PARACELL'LAR SPACE rises ausing "'LJ flow of /!O 5 ele trolytes a ross "$. 2. Para ellular fluid Osmoti P A !(- mosm B9g /!O higher to P.T.C. )lasma ? A -G(2E@ *. On oti P. of Peritubular Ca)illary )lasma is higher with low Peritubular a)illaries hydrostati P aids reabsor)tion of fluid. POTASSI1M A/SORPTION L SECRETION G+D J. .iltered reabsorbed in )ro7 T. : loo) of /. 1. !. -. O+(E+D is absorbed in )ro7. Tubule. J. also diffuses in des . Limb of loo) of /enle and e7tensi8ely absorbed in as . Limb. >istal Tubule. J is se reted in distal [ >.T. and Corti al se retions of olle ting Tubules. At medullary Se tion of C.T.3 there is some J reabsor)tion.
*++ 1++
2+
G+
TJJB
PJ 1.+
Pro7 T S'$$AR0 M !@
Loo) of /E%LE
>istal T'"'LE
1@ G+D reabsorbed )ro7imally Hariation in E7 retion C 8ariation e7 retion of distal segments. -@ $ost of hanges due to rate of se retion $EC/A%IS$ O. J TRA%SPORT 1. Cellular J5 /igh internal J5 against ele tro = h. 6radient %a = J = ATPase system at basolateral memb. $aintains high intra ellular J. TRA%SEPIT/ELIAL TRA%SPORT ?i@ Pro7. Tubule M A ti8e J reabsor)tion at luminal memb. ?gradient = limited me h.@. /igh a)a itylow gradient system : rate is de)endent on /!O reabsor)tion. ?ii@ >es . Lim. Loo) of /enle Jenters 8ia )assi8e )ro ess due to gradient between $E>'LLAR0 IS. : T... ?iii@ As ending limb A ti8e reabsor)tion of J ?e7a t natureN@ against ele tro( hemi al gradient. ?i8@ ?a@ A ti8e J5 se retion a ross basolat. $emb. ?b@ N A ti8e J se retion at a)i al memb. ACTIHE SECRETIO% ( 6radient limited.
!.
J5 J5 %a J
5
/0>RO6E% IO% SECRETIO% A ti8e Se retion of /5 SITE Pro7imal >istal Colle ting A$O'%T E2D total 1+D 2D )/ T'"'LAR .L'I> O.+ *.+ 4.2
%a SECO%>AR0 A%TIPORT PROCESS PRI$AR0 TRA%SPORT %a /5 /!O /5 CO! CO! /!O O/( 5 / 5 /CO/CO-(
$EC/A%IS$ a@ Primary Trans)ort System b@ A%TIPORT System Cou)led with %a5 with energy deri8ed from %a(J(ATPase. %et Result M E7 hange of %a with /5 $e hanism is 6RA>IE%T limited. ! .ACTORS a@ Tubular .luid "uffers whi h remo8e /5 in tubular fluid reating a /5 Con . 6radient a ross PTC to lumen. PCO! and amount of CO! in ell regulating O!. Su))ly of /5 ions ?es). hroni A id "ase L'A%TITATIHE ASPECTS Se retion 2+++ mmol B day -.2mmol /5 B min -.4 mmol B min 5 /CO-( +.+2 mmol B min with non /CO-( ?/PO4(@ ?TITRA"LE ACI>IT0@ or %/%/4 @
b@
OR6A%IC IO%S A ti8e Se retion Pro ess eg. PA/. Amount filtered and amount %OT bound to Protein PTC L'$E% >I..'SIO% P'$P
.ree Anion "inds to Trans)ort System at "asolateral memb. To raise yto)lasmi on . And Anion diffuses )assi8ely to lumen ?Con . 6rad.@ S! Segment is )redominant Se retory site OR6A%IC $OLEC'LES ACTIHEL0 SCRETE> EN4OGENO1S ;EAC ACI4 4R1GS "ile Salt A etoTolamide Cy li A$P Ce)halothin .atty A ids Peni illin O7alate Probebe id 'rate Sali ylate Prostaglandin .rusemide ChlorthiaTide A etyl Choline Choline Creatinine >o)amine E)ine)hrine /istamine 2/T Atro)ine $or)hine Trimeta)han Pro aine %eostigmine Luinine /e7amethonium TolaToline
A%IO%
CATIO%
A$O%IA SECRETIO% 1. PRO>'CTIO% 6lutamine 6lutaminase 6lutami A id %/a5 >EA$ 6L03 ALA
%/ - 5 /5
/- 5 /5 %/45 ?1++@ Ph . *+
%/- 5 /5
%/4?1+++@
%/4 5 )rodu tion C )/ urine ? )/ %/45@ Rate %/- )rodu tion ?rate = limiting fa tor@ Rate %/- )rodu tion de)ends on I 1@ rate of /5 Se retion !@ rate of )rodu tion of enTymes Chroni a idosis %/4 )rodu tion due to )rodu tion A1+ 7 st in 1 !(- days. 1+! 'rine %/4 C/RO%IC 1+1 Theoreti al ACI>OSIS % 1 2 P/ #ATER REA"SORPTIO% 1. >es ending ?thin@ limb %o 9nown a ti8e trans)ort )ro ess /ighly )ermeable to /!O a@ Corti al ne)hron ( little /!O absorbed IS. 1 T. O6P. OS.P b@ ;u7ta = $ed. %e)hron ( /!O absorbed. As ending ?thi 9@ limb. %ot?low@ )ermeable to /!O A ti8e solute trans)ort system Trans e)ithelial P> A 4 = 1+ mH lumen 58e Theories M a@ A ti8e Cl( )um) at luminal memb. : %a ( follows Cl * O E
!.
b@ Sym)ort Cl 5 %a at Luminal $emb. #ith ele tro h. 6radient established by %a = J = ATPase system at "asement $. low %a 5 Cl ondu tan e of e)ithelium redu e ba 9 flu7. L'A%TITATIHE 12(!+D filtrate reabsorbed !+(-+D )assed on to distal tubule %aCl reabsorbed F /!O fra tion absorbed. 'REA E<CRETIO% Plasma urea A 4.2 mmolBl E7 retion 1 amt. filtered = amt. absorbed. 2+D filtered load is reabsorbed. Of whi h 2+D is reabsorbed in )ro7imal tubule. \ PER$EA"ILIT0 of $emb. To 'rea. Pro7imal tubule and medullary olle ting du ts are )ermeable to urea. REST I$PER$EA"LE . Pro7imal Tubule 1@ Reabsor)tion /!O 5 %a rate C tubular fluid raises urea on . In tubular fluid establishing on . 6radient a ross lumen to PTC. !@ Rate of Tubular fluid flow rate 6.R A. .ra tion %a urea on . In Tubular fluid A. .r. 'rea. 6.R a8bsorb)tion .r. of %a Absor)tion. .ra tion of 'rea L'$E% K 'REA ] C %a /!O A"SOR"E> %a3 /!O CELL 'rea E7 retion P.T.C. K'REA] 6radient %a .RACTIO% /!O
$E>'LLAR0 COLLECTI%6 >'CT 'rea )assi8ely enters interstitium : Hasa re ta Toni ity of $ed. Interstitium. This )romotes /!O reabsor)tion at des . Limb of /enle&s loo) : at as ending limb %aCl diffuses out more ra)idly than urea entry as it is only slightly )ermeable to urea. >ISTAL T'"'LE Initial SE6$E%T ( E7tention of as ending limb Low /!O ). and a ti8e salt Trans). >istal SE6$E%T negati8e. a@ A"SE%CE of A>/ ( Transe)ithelial P> 1 4+ = 2+ mH Lumen
( >iluting Segment with Low )ermeability to /!O 5 A ti8e salt absor)tion ?E+ ( 1++ mos B 9g /!O@ b@ PRESE%CE of A>/ )ermeability to /!O 12+ osmoti 2 = ED filtrate reabsorbed. %a reabsor)tion ( with $ineralo orti oids Cl reabsor)tion ( against ele tro h. 6radient Co ( trans)ort = system. /CO- reabsor)tion C /5 Se retion Amts3 reabsorbed mu h less in distal tubule than in )ro7. Tubule. 'nder influen e of A>/ ( $ineralo orti oids. >ISTAL T'"'LE .'%CTIO% Ele tri al 6radient M Peritubular .luid is 58e to lumen by =1+ to = 1++ mH %E6ATIHE P.>. ACTIHE REA"SORPTIO% PASSIHE REA"SORPTIO% ACTIHE SECRETIO%
%a 1+D C Aldos. Cl /@ Cation Ca55 /COJ@ e7 h. !5 $g /!O C A>/ %/'rate Se retion \#ater im)ermeable C A>/I LI$ITE> reabsor)ti8e CAP. /!O Reabsor)tion Pro7. Tubule O2D Loo) of /enle 2D >istal Tubule 12D@ @ C A>/ Colle ting >u t 2D@ %a REA"SORPTIO% $a7imal GGD with A>/ EED without A>/
Pro7. Tubule O+D As. /enle loo) !!D >istal Tubule 4(2D@ @ C Aldosterone Colle ting > !(-D@ Cations in general3 8ia ACTIHE $e hanisms. Anions 8ia )assi8e me hanism along ele tri al gradient generated by ation 2+D urea reabsorbed /CO- reabsorbed 1 /5 se retion 1 %a absor)tion %/- )rodu ed in )ro7. and distal %a ou)ling with 6L'COSE 5 A$I%O ACI>S. COLLECTI%6 >'CT
Chara teristi s M 1@
PTightQ e)ithelium Im)ermeable to Ele trolytes3 ele . Resistan e and /!O in absen e of A>/. !@ In )resen e of A>/3 Luminal membranes be ome highly )ermeable to /!O. A. /!O Reabsor)tion ( Corti al Segments 12D filtered fr. $edullary Segment 2D Affe ted A>/ ". Ele tri al Resistan e ( )ara ellular )athway. /igh ele tri al Resistan e of
C. Ele trolytes %a ( A ti8e reabsor)tion but at lower rate only small ba 9 flu7 due to high resistan e. %a Con . Tubular fluid 1m$I C $ineralo orti oids Cl ( reabsorbed against ele tro( h. 6radient. /5 Se retion /CO-( on . Hery low ? ^ +.1m$@. The 8ariable )ermeability to /!O : low ). to ele trolytes and 8ariable rates of trans)ort of salt )ermit reabsor)tion of salt and /!O in 8arying )ro)ortions so that the ele trolyte and osmoti on . As well as the 8olume of urine an flu tuate o8er wide range. CO%CE%TRATIO% PROCESS ( CO'%TER C'RRE%T $EC/A%IS$ Osmoti on entration by the 9idney in8ol8es all the tubular stru tures 5 a)illaries in the $edullaI intera ting with ea h other and the medullary interstitial fluid to ?1@ )rodu e and ?!@ onser8e hy)erosmoti medium within the medulla. "asi ally3 an osmoti gradient is reated a ross the e)ithelium of the thi 9 as ending limb and this is onser8ed and multi)lied by the ounter urrent flow of urine in the loo) of /enle and 8asa re ta a)illary blood. The ounter urrent me hanism enables on entrated urine to be )rodu ed with minimum energy reUuirements. a@ b@ Counter urrent flows seem inI ;u7ta medullary %e)hron&s loo)s of /enle whi h a t as ounter( urrent myulti)lier ?Counter urrent flow of urine@ /air)in onstru tion of Hasa(re ta of Yu7ta(medullary ne)hrons whi h fun tion as ounter = urrent E<C/A%6ER?with ounter = urrent flow of blood@.
CO'%TER = C'RRE%T $'LTIPLIER - )rereUuisites for ounter = urrent multi)lier ?Juha 1G4!@ M i@ Counter( urrent flow of urine )ro8ided by loo) of /enle of the Yu7ta(medullary ne)hrons.
ii@ iii@
>es ending limb of loo) of /enle is $ORE )ermeable to /!O than as ending limb. ACTIHE reabsor)tion of %aCl in the as ending limb of loo) of /enle remo8ing Solute in tubular fluid and de)ositing it to the $edullary I.S... This )ro8ides the PRI$AR0 6E%ERATI%6 for e for the ounter( urrent multi)lier system. The im)ermeability of the as ending limb of the loo) slows the rate at whi h /!O follows solute out. /en e3 the osmoti on . Of the tubular fluid is redu ed whilst the on entration of the medullary interstitial fluid is raised. The ounter urrent flow P$ulti)liesQ this initial small horiTontal osmoti gradient a ross the tubular wall 8erti ally along the loo) by ounter urrent flow.
A%ATO$ICAL C/ARACTERISTICS 1. Counter Current flow of tubular fluid in the loo)s of /enle of ;u7ta($edullary %e)hrons !. Permeability Chara teristi s M a@ >es ending limb of loo) of /enle. /ighly )ermeable to /!O Low )ermeability to %aCl 5 urea %o A ti8e Trans)ort $e hanisms b@ @ Thin As ending limb of loo) N Slightly )ermeable to /!O 5 urea Thi 9 As ending limb of loo) %OT )ermeable to /!O 5 urea ACTIHE transe)ithelial TRA%SPORT of %aCl.
d@ >istal 5 Colle ting >u ts_ Im)ermeable to %aCl Permeability to /!O A A>/ Corti al Segment of Colle ting >u t is not )ermeable to urea Inner $edullary C.>. 8ery )ermeable to urea. -. $E>'LLAR0 I%TERSTITIAL .L'I> %ot well mi7ed >iffusion %OT ra)id
$'LTIPLIER S0STE$ 1. Primary generating for e 1 A ti8e Trans)ort me hanism in T/ICJ ASCE%>I%6 limb of loo) f /enle lo ated in O'TER $E>'LLA. Chloride ion is a ti8ely reabsorbed reating transtubular )otential differen e with lumen )ositi8e. %a )assi8ely absorbed as a result of ele tri al P.>. Result M
!.
i@ $edullary IS. /0PERTO%IC ii@ Tubular .luid in ASC. Limb /0POTO%IC as Thi 9 As . Limb is im)ermeable. -.
of
loo)
of
/enle
At Thin >es ending limbI a@ /!O diffuses out from des . Limb ?as it is highly )ermeable@ to medullary IS. : Hasa Re ta as . Limb. b@ Some %a 5 Cl may diffuse in Result M Tubular .luid be omes /0PEROS$OTIC and on . As it )asses down >es . Limb ?+.P 1 1!++@. After fluid flows around the bend3 to the as ending limb3 %a 5 Cl are remo8ed3 %ot /!O as as . Limb is im)ermeable to /!O. Result M Tubular fluid be omes more dilute as it a))roa hes distal tubule. CO'%TER(C'RRE%T L'LTIPLIER S0STE$ >istal Tubule 'REA CORTE< 5 H"O urea %aCl %a5 Cl( %a5 'REA $ "
4.
Cl(
INNER ME41LLA
%aCl 5 H"O
COLLECTING T1/1LE
5:
T'i.% A,.e! i!* Lim< A.ti8e Cl3 a<,or(tio! =. Na: re! eri!* tu<ular flui ilute L me ullar& ISF '&(erto!i.
":
4i,tal Tu<ule G .olle.ti!* 4u.t i! Outer Me ulla a! Corte) H"O A<,or<e 1rea .o!.. 1rea A<,or(tio! at i!!er me ulla To!i.it& me ullar& ISF. Colle.ti!* Tu<ule Some urea e!ter, loo( Ait' me ullar& re.&.li!* of urea ma%e, me ullar& ISF e)tra.t H"O from e,.e! i!* lim<. 4e,.e! i!* Lim< Lo,, of H"O .o!.e!trate, NaCl i! e,.e! i!* lim<.
$:
>: 5:
T'i! A,.e! i!* Lim< Permea<le to NaCl <ut !ot Aater H NaCl mo8e, out.
OSMOTIC CONCENTRAITON CHANGES ALONG T1/1LAR FL1I4 a@ Tubular .luid at initial Segment of >es ending limb 1 !E2mosmB9g /!O Ti) of loo) 1 14++mosmB9g /!O At the end of As .limb A 1++ mosmB9g. .ra tionally more solute is remo8ed from tubular fluid : de)osited in the medullary IS.. Osmoti on . Of medulla does not rise at infinitum as some of reabsorbed solute is arried away by blood in 8asa re ta. A steady state is rea hed until the amt. of solute lea8ing tubular fluid eUuals amt. arried away by Hasa Re ta. ROLE OF 4ISTAL T1/1LE L COLLECTING 41CT .luid from loo) is hy)o = osmoti and >T : C> reabsorbed solute 5 /!O. The /!O reabsorbed in the orti al IS. : hen e is returned to systemi ir ulation. #ith A>/3 the orti al segments lose more /!O to orti al IS.. As fluid re(enters medulla3 /!O flows out to $edullary IS.3 on entrating the tubular fluid3 and tending to dilute $edullary IS.. "ut amt. of Solute entering $edullary IS. from as ending limb F /!O re(entering medullary IS. at olle ting du t. ROLE OF 1REA IN THE INNER RENAL ME41LLA.
?i.e. >ilute@ 'rea )ermeability is low : urea in T... remains. At distal Tubule3 /!O is reabsorbed with a tion of A>/ at late distal tubule3 olle ting tubule in orte7 : outer medulla. 'rea on . Rises in T... : at inner medulla3 both /!O 5 urea are reabsorbed. As e)ithelium C.> in inner $edulla is highly )ermeable3 urea is tra))ed and a umulates in $edullary IS.. $e hanism is me hanism. alled PPASSIHE 'RI%AR0 CO%CE%TRATI%6Q
"ut energy is reUuired to reate initial differen e of urea 5 %aCl in loo) 5 $edullary IS. and is deri8ed from a ti8e Cl( reabsor)tion by thi 9 as ending limb of /enle&s Loo).
Co3Tra!,it Na 6 C 6 "Cl at T'i.% A,.e! i!* lim< of He!le T1/1LAR L1MEN /ASOLAT MEM/RANE NaG I!ter,titial Flui
Na 3 C ATPa,e ACTI7E
(a,,i8e
CO1NTER C1RRENT E2CHANGER H 7ASA RECTA 1@ /air)in arrangement )ro8ided by 8asa re ta = ?)eritubular Ca)illaries of ;u7ta($edullary ne)hrons@ !@ "lood .low rate is Slower than in the Corte73 allowing blood flow this the medullary tissue without ausing osmoti gradient disturban es. -@ Hasa re ta endothelium is 8ery )ermeable to /!O3 %aCl3 urea but %OT to )lasma )rotein. As blood enters medulla down des ending Hasa Re ta3 %a5 Cl5 diffuse in : /!O flows out . A lag is )resent as a)illary hydrostati P o8erride osmoti P to fa8our /!O loss from des ending 8asa re taI o))osing osmoti for es. 4@ As ending Hasa Re taM As blood flows u) as . Hasa Re ta3 on . Of Solutes in reases leading to osmoti P. Osmoti 5 Osmoti Pressure fa8ours u)ta9e at as ending a)illaries. .L'I> E%TERI%6 ASCE%>I%6 limb e7 eeds fluid lost from des ending Hasa Re ta. E7 ess .luid re)resents %et fluid remo8al from $edulla : 1 Hol. reabsorbed in olle ting tubule : des . /enle Lim. TRAPPI%6 SOL'TE PRESERHE E<C/A%6ER /0PEROS$OLARIT0 RE$OHE /!O
CO1NTER 6 C1RRENT E2CHANGE /Y 7ASA RECTA CORTE< Pr Pr O'TER /! O /!O 'rea /!O On oti P /!O Abs. u)ta9e Osmoti P = fa8our ')ta9e $E>'LLA %aCl On oti P( fa8our
SOL'TE /A%>LI%6 Ca)illaries )ermeable to %aCl 5 'rea %aCl 5 urea enter >es . Hasa Re ta 5 lea8e as ending Hasa Re ta /!O /A%>LI%6 a@ >es ending Hasa Re ta $edullary IS. Osmoti P F trans a) osmoti P 11 /!O loss Trans a) /ydrostati P fa8our /!O loss Trans a) on oti o))oses loss %ET RES'LT 1 /!O loss from a)illary blood. b@ As ending Hasa Re ta Osmoti 5 On oti for es in same dire tion fa8ouring AS"SORPTIO% TOTAL RES'LT 1 .L'I> E%TR0 .L'I> LOSS .RO$ I% ASCE%>I%6 F >ESCE%>I%6 HASA HASA RECTA RECTA /O4Y FL1I4 HOMEOSTASIS EC. maintained within narrow limits Plasma 8olume also tends to remain onstant : is determined by the total EC. 8olume. The 8olume Control me hanisms o)erate by ontrolling the amount of the )rin i)al osmoti onstituant in EC. i.e. %aCl. Alterations aused by the e7 retion of %aCl by 8arious me hanism would tend to ause M a@ >ire tly retaining or e7 reting an osmoti eUui8alent of /!O through the effe t of salt reabsor)tion on water reabsor)tion. b@ Or Indire tly3 through hanges in %aCl on . Affe ting EC. on osmoti on entration and A>/ se retion. INTRA THORACIC STRETCH OS$ORECEPTORS < I<
Transduration of fluid ARTERIAL HOL. SE%SORS Carotid sinus barore e)tor stimulation
?%o
RE%AL HOL SE%SORS Renal Perfusion Pressure ;6A Renin ( Angiotensin Aldosterone SENSORS OF FL1I4 HOMEOSTASIS Intra thora i Holume Re e)tor Cardia atria RH Pulm. Ca)illaries Arterial Holume Re e)tors Renal Holume Re e)tors C%S Hol. re e)tors /e)ati Hol. Re )tor. Intra throra i Hol. Re e)tor Ty)e A ( Atrial Systole PaQ wa8e Ty)e " ( Atrial .illing P8Q wa8e Right Atrial >istention Left Atrial >istention Renin a ti8ity %a A>/ A>/ le8els Renin no
urinary %a e7 retion.
Pulmonary interstitial re e)tor ?; re e)tors@ dete t )ulm. Interstitial oedema.& C%S 5 /e)ati Holume Sensors 1. C%S CS. 5 Carotid arterial )lasma %a Renal %a e7 retion !. /e)ati %a in Portal 8ein %a e7 retion .
$A;OR E.ECTOR $EC/A%IS$S 6.R PERIT'"'LAR 5 L'$I%AL .ACTORS Peritubular a). Starling .or es Luminal Com)osition $edullary IS. Com)osition Transtubular Ioni gradients /'$ORAL E..ECTORS Renin = Angiotensin = Aldosterone Prostaglandin Jalli9rein = Jinin %atriureti /ormone. I%TRA( RE%AL >ISTRI"'TIO% O. "LOO> .LO# FL1I4 COMPARTMENTS TOTAL "O>0 #ATER A))ro7. *+D "ody weight 1B- EC. !B- IC. !+D body weight 4+D "ody weight
.ACTORS AGE Premature "irth 1 month 1 year T/; E+ O2 O+ *2 D T.". #eight ECF ICF ( ( 4! --! -E !* -G
**+ 21 24E 24 44
!* !O !!4 !!* !!
-* -!E !G !2 !E !!
SE< .emales ( /igher )ro)ortion of .AT /!O ontent of .AT !2(-+D $us le O4(OED /en e3 /!O Content less !. -. >AIL0 HARIATIO% A))ro7imately +.!D ".#. $EAS'RE$E%T "ased on ISOTOPE >IL'TIO% Hd 1 C1 7 Hi Cd #here Hd 1 Hol of distribution Hi 1 .luid Com)artment Hol Ci 1 Initial Con . Cd 1 .in al Con . MEAS1REMENT OF TOTAL /O4Y H"O I 4E1TERI1M O2I4E Small mole ules EUuilibration Time - = 4 hrs. 1D E7 hange with /5 in )rotein -D Renal E7 retion 1+D hea8ier than body /!O S)e trometer II TRITI1M O2I4E #ea9 for emitter +.2 mC T [ 1 1+ days EUuilibration Time 4 = * hrs. 5 !D Error ANTIPYRINE E2TRACELL1LAR FL1I4 7OL1ME MEAS1REMENT a@ CR0STALLOI>S Inulin3 Su rose3 $annitol
measured
using
$ass
III
Problem M Large mole ule. >o %OT )enetrate entire EC. '%>ER( ESTI$ATE. b@ IO%IC S'"STA%CES Isoto)es of Cl3 "r3 %a SO4. ! )ools i@ RAPI> EL'ILI"RATIO% POOL ?!+ minutes@ in dynami EU. with Plasma. A !+D total body water ?E.4L@ easily mobilised. SLO# EL'ILI"RATIO% POOL onne ti8e tissue 5 bone. MEAS1REMENT I ii@ ?F!4hrs@ mainly in
PLASMA 7OL ?1@ >yes bound to Albumin E8an&s "lue ?T1E!4@ ?!@ R.I.S.A Radio = iodinated Serum Albumin ?-@ Labelled $a roglobulin RISA o8erestimated due to O(1+D interstitial fluid. RE4 CELL 7OL. ?1@ Rb labelled with Chromium2B ?!@ Cal ulated from )lasma Hol. and PCH True body PCH 1 E2(G!D Henous PCH. E2TRACELL1LAR FL1I4 % <o & ;ei*'t 4.2 1!.+ 4.2 4.2 1.2 !O !.-*+ % T./ H"O O.2 !+.+ O.2 O.2 !.2 42 -.E 22 1++ -.! E.4 -.! -.! 1.+ 1G 1.* !4! 7ol.
es a)e
into
II
5 PHASES COMPARTMENT ml#%* /; PLAS$A I%TERSTITIAL CO%%ECTIHE TISS'E "O%E TRA%SCELL'LAR TOTAL EC. RE> CELL TOTAL IC. TOTAL "O>0 #ATER
INTERSTITIAL ;ATER ECF 3 PLASMA 7OL. INTRACELL1LAR ;ATER ICF K T/; 3 ECF F $$% TOTAL /O4Y ;EIGHT 55% TOTAL /O4Y H"O IONIC COMPOSITION ION PLASMA INTERSTITIAL INTRACELL1LA R 5? 55E $.? 5? 3 55.? $5.? 55
POTASSI1M 5. ". Pri!.i(al I!tra.ellular Catio! Fu!.tio! H a@ b@ @ $. Total <o & C mus le. $embrane )olarisation .un tion of %er8e and $us le Tissue ( )ro)agation of im)ulses. Influen es ell fun tion in8ol8ing arbohydrate3 gly ogen 5 )rotein syn. 42 = 2+ mmolB9g most of whi h in
>.
G+(G2D E7 hangeable : GED intra ellular !D e7tra ellular 4ail& I!ta%e 4+ = 1!+ mmolBday 1ri!e e).retio! -+ = *+ mmolBday Tolera!.e to a.ute C loa , lea , to 9 a@ In reased Renal e7 retion 8ia in reased aldosterone %a = J ATPase a ti8ity. b@ Insulin 5 6lu ogen release leading to intra( ellular redistribution of J5ions.
ate holamines whi h in reases J5 entry into the ells mediated by "! re e)tors. RENAL HAN4LING OF POTASSI1M
1.
Pro7imal Con8oluted Tubule E2(G+D J reabsorbed >oes not show any 8ariation in different states of J balan e. >istal Tubules $aYor site of regulation of )lasma le8els. 4 determinants M a@ $inerals Corti oids ( AL>OSTERO%E Stimulus i@ )lasma %a5 ii@ )lasma J5 F +.2 mmolBl Aldosterone leads to i@ )assi8e luminal )ermeability for J ii@ A ti8e J at basolateral membrane iii@ A ti8e %a5 reabsor)tion b@ Sodium Potassium ATPase a ti8ity with J load In reased J e7 retion @ >istal Tubular .low .low e7 retion d@ A id1(base "alan e Al9alosis J5 loss Hia intra ellular in distal tubular ells : J 5 e7 hange is in reased.
!.