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&athophy'io(ogy a)d etio(ogy o* edema +

Burton D Rose, MD
UpToDate performs a continuous review of over 330 journals and other resources. Updates are added as important new information is published. The literature review for version 3.! is current throu"h #pril !00$% this topic was last chan"ed on &ovember 3, !003.

+,T-.DUCT+., ' (dema is defined as a palpable swellin" produced b) e*pansion of the interstitial fluid volume. # variet) of clinical conditions are associated with the development of edema, includin" heart failure, cirrhosis of the liver, and the nephrotic s)ndrome +show table ,. This topic will review the pathoph)siolo") and etiolo") of "enerali-ed edematous states. The clinical manifestations, dia"nosis, and therap) of edema are discussed separatel). +.ee /#pproach to the adult with edema01/,. .ome patients have locali-ed edema. This can be caused b) a variet) of conditions includin" venous obstruction, as occurs with deep vein thrombosis or venous stasis, acute left ventricular failure +which is a form of venous obstruction,, and aller"ic reactions +such as lar)n"eal edema,. &/T0.&012+.3.41 .5 6D67/ 5.-7/T+., 8 There are two basic steps involved in edema formation2 3 #n alteration in capillar) hemod)namics that favors the movement of fluid from the vascular space into the interstitium. 3 The retention of dietar) or intravenousl) administered sodium and water b) the 4idne)s. The importance of the 4idne)s in the development of edema should not be underestimated. (dema +other than locali-ed edema as with an aller"ic reaction, does not become clinicall) apparent until the interstitial volume has increased b) at least !.$ to 3 liters. .ince the normal plasma volume is onl) about 3 liters, it is clear that patients would develop mar4ed hemoconcentration and shoc4 if the edema fluid were derived onl) from the plasma. These complications do not occur because of the followin" se5uence2 3 The initial movement of fluid from the vascular space into the interstitium reduces the plasma volume and conse5uentl) tissue perfusion. 3 1n response to these chan"es, the 4idne) retains sodium and water. 3 .ome of this fluid sta)s in the vascular space, returnin" the plasma volume toward normal. 6owever, the alteration in capillar) hemod)namics results in most of the retained fluid enterin" the interstitium and eventuall) becomin" apparent as edema.

The net effect is a mar4ed e*pansion of the total e*tracellular volume +as edema, with maintenance of the plasma volume at closer to normal levels. This e*ample also illustrates an important point that must be considered when treatin" a patient with edema. Renal sodium and water retention in most edematous states is an appropriate compensation in that it restores tissue perfusion, even thou"h it also au"ments the de"ree of edema. Removin" the edema fluid with diuretic therap) will improve s)mptoms due to edema but ma) diminish tissue perfusion, occasionall) to clinicall) si"nificant levels. +.ee /#pproach to the adult with edema01/, section on Treatment,. The hemod)namic effects are somewhat different when the primar) abnormalit) is i)appropriate renal fluid retention. 1n this settin", both the plasma and interstitial volumes are e*panded and there are no deleterious hemod)namic effects from removal of the e*cess fluid. This is an e*ample of overfillin" of the vascular tree which most often occurs with primar) renal disease Capi((ary hemody)amic' 8 The e*chan"e of fluid between the plasma and the interstitium is determined b) the h)draulic and oncotic pressures in each compartment. The relationship between these parameters can be e*pressed b) .tarlin"7s law 8 ,!92 &et filtration : ;p. : * +delta h)draulic pressure * 8+<cap 0 <if, 0 0 delta oncotic pressure, 0 pi if,9

;p.

s+pi cap

where ;p is the unit permeabilit) +or porosit), of the capillar) wall, . is the surface area available for fluid movement, <cap and <if are the capillar) and interstitial fluid h)draulic pressures, pi cap and pi if are the capillar) and interstitial fluid oncotic pressures, and s represents the reflection coefficient of proteins across the capillar) wall +with values ran"in" from 0 if completel) permeable to if completel) impermeable,. The interstitial oncotic pressure is derived primaril) from filtered plasma proteins and to a lesser de"ree proteo"l)cans in the interstitium. +.ee /=hapter >B2 (*chan"e of water between plasma and interstitial fluid/,. #ppro*imate normal values in the s4eletal muscle capillar) are shown in Table ! +show table !,. #s can be seen, the mean capillar) h)draulic pressure + > mm6",, which pushes fluid out of the capillar), and the plasma oncotic pressure +!? mm6",, which pulls fluid into the vascular space, are 5uantitativel) the most important. There is normall) a small mean "radient of about 0.3 mm6" favorin" filtration out of the vascular space% the fluid that is filtered is then returned to the s)stemic circulation b) the l)mphatics so that fluid accumulation in the interstitium is prevented. .tarlin"7s forces are substantiall) different in some other or"ans, such as the liver 839. The hepatic sinusoids are hi"hl) permeable to proteins% as a result, the capillar) and interstitial oncotic pressures are rou"hl) e5ual and there is little transcapillar) oncotic pressure "radient 8!9. The net effect is that the h)draulic pressure "radient favorin" filtration is essentiall) unopposed. To some de"ree, filtration is minimi-ed b) a lower capillar) h)draulic pressure than in s4eletal muscle, since appro*imatel) two0thirds of hepatic blood flow is derived from the portal vein, a low0pressure s)stem. 6owever, edema does not normall) occur, because the filtered fluid is a"ain removed b) the l)mphatics.

The alveolar capillaries also have a relativel) low capillar) h)draulic pressure +due to perfusion from the low0pressure s)stem in the ri"ht ventricle, and are more permeable than s4eletal muscle to proteins, resultin" in a lesser transcapillar) oncotic pressure "radient 8@9. The clinical si"nificance of this difference will be discussed below. 6dema *ormatio) ' The development of edema re5uires an alteration in one or more of .tarlin"7s forces in a direction that favors an increase in net filtration. This can be produced b) an elevation in capillar) h)draulic pressure, capillar) permeabilit), or interstitial oncotic pressure, or b) a reduction in the plasma oncotic pressure +show table ,. (dema can also be induced b) l)mphatic obstruction, since the fluid that is normall) filtered is not returned to the s)stemic circulation. +)crea'ed capi((ary hydrau(ic pre''ure 8 =apillar) h)draulic pressure, althou"h "enerated b) cardiac contraction, is relativel) insensitive to alterations in arterial pressure. This stabilit) is due to autore"ulator) chan"es in resistance at the precapillar) sphincter, which determine the e*tent to which the arterial pressure is transmitted to the capillar). 1f the arterial pressure is increased, for e*ample, the sphincter constricts, minimi-in" the elevation in capillar) h)draulic pressure and preventin" the development of edema. 1n contrast, the resistance at the venous end of the capillar) is not well re"ulated. =onse5uentl), chan"es in venous pressure result in parallel alterations in capillar) h)draulic pressure. The venous pressure is increased in two settin"s2 + , when the blood volume is e*panded, au"mentin" the volume in the venous s)stem, and +!, when there is venous obstruction. (*amples of edema due to volume e*pansion include heart failure and renal disease% edema due to venous obstruction is commonl) seen with cirrhosis of the liver, in which there is a mar4ed increase in hepatic sinusoidal pressure, and with deep venous thrombosis in the lower e*tremities. (ffective venous obstruction also occurs with acute pulmonar) edema due to diastolic d)sfunction, a settin" in which compliance of the heart is dramaticall) reduced. 0ypoa(9umi)emia 8 6)poalbuminemia due to albumin loss in the urine in the nephrotic s)ndrome or to decreased hepatic albumin s)nthesis is another potential cause of edema. 6owever, chronic h)poalbuminemia alone ma) be insufficient to induce edema +see /.afet) factors/ below,. +)crea'ed capi((ary permea9i(ity ' #n increase in capillar) permeabilit) due to vascular injur) promotes the development of edema both directl) and b) permittin" albumin to move into the interstitium, thereb) diminishin" the oncotic pressure "radient. This problem ma) be operative in the followin" clinical settin"s2 3 Burns, in which both histamine and o*)"en free radicals can induce microvascular injur) 8$9. 3 Therap) with recombinant human interleu4in0! or vascular endothelial "rowth factor, which appear to directl) increase capillar) permeabilit) 8A,>9. 3 (pisodic idiopathic capi((ary (ea: s)ndromes, which ma) be mediated b) increased e*pression of interleu4in0! receptors on circulatin" mononuclear cells or

b) increased "eneration of 4inins 8?0 09. #ffected patients often have an associated monoclonal "ammopath) and, durin" episodes, have a massive lea4 of proteins and fluids out of the vascular space with the hematocrit risin" acutel) to as hi"h as >0 to ?0 percent 8 09. The mortalit) rate is hi"h in this disorder. <reliminar) evidence su""ests that the combination of aminoph)lline +an inhibitor of phosphodiesterase, and terbutaline +a relativel) selective B!0adrener"ic a"onist, ma) prevent episodes 8 0, 9 and therefore improve survival 8?, 9. 1t is not clear, however, wh) these dru"s are effective. <rolon"ed survival ma) provide more time for pro"ression to multiple m)eloma% in one series of patients followed for a mean of A.@ )ears, three died ' one durin" an attac4 and two from multiple m)eloma 8?9. 3 #n) of the conditions associated with the adult respirator) distress s)ndrome. 1n this disorder, ischemia0 or sepsis0induced release of c)to4ines, such as interleu4in0 or tumor necrosis factor, ma) pla) an important role in the increase in pulmonar) capillar) permeabilit), at least in part via the recruitment of neutrophils 8 !, 39. 3 =apillar) permeabilit) is moderatel) increased in patients with diabetes mellitus 8 @, $9. This abnormalit) ma) be mediated in part b) h)per"l)cemia0 induced accumulation of advanced "l)cos)lation end products derived from the combination of "lucose with circulatin" proteins 8 A9. The net effect is to enhance the severit) of edema which, in these patients, is usuall) due to heart failure or the nephrotic s)ndrome. 3 The malnutrition s)ndrome 4washior4or ma) be another e*ample of edema due in part to increased capillar) permeabilit). #lthou"h edema has often been ascribed to h)poalbuminemia +see .afet) factors below,, it has been su""ested that increased "eneration of c)stein)l leu4otrienes ma) be of primar) importance in the edema of 4washior4or b) increasin" capillar) permeabilit) 8 >9. 3ymphatic o9'tructio) or i)crea'ed i)ter'titia( o)cotic pre''ure 8 ;)mphatic obstruction is an unusual cause of edema +called l)mphedema, that is most often seen with nodal enlar"ement due to mali"nanc). +.ee /;)mphedema/,. Cith h)poth)roidism +m)*edema,, on the other hand, there is a mar4ed increase in the interstitial accumulation of albumin and other proteins 8 ?9. #lthou"h this ma) be due in part to an elevation in capillar) permeabilit), the e*cess interstitial protein and fluid would normall) be returned to the s)stemic circulation b) the l)mphatics. 6owever, l)mphatic flow is low or normal in m)*edema 8 ?9, not increased as in other edematous states 8 D9. This ma) be due to bindin" of the filtered proteins to e*cess interstitial mucopol)saccharides, thereb) preventin" their removal b) the l)mphatics 8 ?9. 2a*ety *actor' ' .ince there is normall) a small "radient favorin" filtration, it mi"ht be e*pected that onl) a minor chan"e in these hemod)namic forces would lead to edema. 6owever, e*perimental and clinical observations indicate that there must be at least a %5 mm0g increase in the "radient favorin" filtration before edema can be detected 8 ,!9. Three factors contribute to this protective response. 3 1ncreased l)mphatic flow can initiall) remove the e*cess filtrate. Cith pulmonar) edema due to heart failure, for e*ample, the rate of increase in lun" li5uid accumulation at an) "iven elevation in pulmonar) capillar) pressure is related to the functional capacit) of the l)mphatics which is influenced b) both

individual factors and the acuteness of the hemod)namic chan"e 8!09. Cith acute rises in pulmonar) capillar) pressures, the pulmonar) l)mphatic s)stem does not have an increased capacit) to remove fluid% as a result, pulmonar) edema occurs at pulmonar) arter) capillar) pressures as low as ? mm6". 1n contrast, patients with chronic heart failure have an increased l)mphatic capacit) and do not develop pulmonar) edema until much hi"her pulmonar) capillar) pressures +e", E!$ mm6", are reached. 3 Fluid entr) into the interstitium will eventuall) raise the interstitial h)draulic pressure 8 9. 3 Fluid entr) into the interstitium also lowers the interstitial oncotic pressure, both b) dilution and b) l)mphatic0mediated removal of interstitial proteins. #s an e*ample, interstitial oncotic pressure falls to ver) low levels in heart failure, while the plasma oncotic pressure is relativel) normal 8! 9. The associated increase in the transcapillar) oncotic pressure "radient +pi cap 0 pi if, counterbalances the rise in capillar) h)draulic pressure, thereb) minimi-in" the de"ree of edema formation. The reduction in interstitial oncotic pressure has important implications for the role of h)poalbuminemia in edema formation and for the tendenc) of edema to form at different sites. Recent studies su""est that the normal interstitial oncotic pressure in subcutaneous tissue in humans ma) be as hi"h as ! to $ mm6" 8!!,!39. #s a result, a "radual fall in plasma oncotic pressure in the nephrotic s)ndrome, for e*ample, will be associated with a parallel decline in the interstitial oncotic pressure due to less entr) of albumin into the interstitium. The net effect is that the transcapillar) oncotic pressure "radient is initiall) maintained with little tendenc) to edema formation. Thus, in the absence of severe h)poalbuminemia, edema in the nephrotic s)ndrome and renal disease is primaril) due to renal sodium retention. +.ee /Mechanism and treatment of edema in nephrotic s)ndrome/,. .imilar considerations concernin" h)poalbuminemia0induced edema appl) to the pulmonar) circulation. The alveolar capillaries appear to have a "reater baseline permeabilit) to albumin and therefore a hi"her interstitial oncotic pressure of about ? mm6" 8!,@9. This leads to a lar"er safet) factor a"ainst edema due to h)poalbuminemia than seen in s4eletal muscle, since there can be a "reater parallel decline in the interstitial oncotic pressure. Thus, in the absence of a concurrent rise in left atrial and pulmonar) capillar) pressures, pulmonar) edema is not usuall) seen with h)poalbuminemia, even at a plasma albumin concentration acutel) low enou"h to induce peripheral edema 8!@9. The response is appreciabl) different after the rapid administration of lar"e volumes of saline to patients with mar4ed h)povolemia, a condition in which a low plasma albumin concentration can predictabl) cause edema. 1n this settin", there is acute dilutional h)poalbuminemia without time for the interstitial albumin concentration to fall. #s a result, the transcapillar) oncotic pressure "radient is reduced and peripheral edema can occur before the restoration of normal intracardiac fillin" pressures. -e)a( 'odium rete)tio) 8 #s noted above, the retention of fluid b) the 4idne) in edematous states can represent an appropriate compensator) response to effective arterial or circulatin" volume depletion or an inappropriate manifestation

of renal disease 8!@,!$9. 1n most instances, the effective circulatin" volume is directl) proportional to the cardiac output. Thus, when the cardiac output is reduced because of underl)in" cardiac disease, the 4idne) attempts to restore the effective circulatin" volume b) retainin" sodium and water. 6owever, effective tissue perfusion and the cardiac output are not alwa)s related, since the former can also be reduced b) a decrease in peripheral vascular resistance 8!A9. #s an e*ample, creation of an arteriovenous fistula is associated with no initial chan"e in cardiac output, )et tissue perfusion is reduced since the blood flowin" throu"h the fistula is b)passin" the capillar) circulation. 1n response to this hemod)namic chan"e, the 4idne) retains sodium and water, thereb) increasin" the blood volume and cardiac output 8!>9. The new stead) state is characteri-ed b) a cardiac output that e*ceeds the baseline level b) an amount e5ual to the flow rate throu"h the fistula. # common clinical correlate of this e*periment occurs in patients with cirrhosis and ascites, who fre5uentl) have an elevated cardiac output 8!?9. Despite this, the) behave as if the) are volume depleted, as evidenced b) avid renal sodium retention and a pro"ressive rise in secretion of the three h)povolemic hormone ' renin, norepinephrine, and antidiuretic hormone +#D6, 8!A,!D,309. +.ee /6)ponatremia in cirrhosis/,. The disparit) between the hi"h cardiac output and the renal and neurohumoral responses in cirrhosis is due both to splanchnic vasodilatation and to the presence of multiple arteriovenous fistulas throu"hout the bod), such as spider an"iomata in the s4in. The net effect is a mar4ed fall in s)stemic vascular resistance and a reduction in s)stemic blood pressure 8!A,3 9. Much of the cardiac output is circulatin" ineffectivel) as there is a pro"ressive reduction in renal and eventuall) musculocutaneous perfusion 83!9. The renal sodium and water retention seen in heart failure or cirrhosis results from both a h)povolemia0induced fall in GFR and, more importantl), an increase in tubular reabsorption. The latter is mediated b) increases in the activit) of the renin0an"iotensin0aldosterone and s)mpathetic nervous s)stems 8!A,33,3@9. The compe)'ated 'tate ' #lthou"h the renin0an"iotensin0aldosterone s)stem undoubtedl) contributes to sodium retention in disorders such as heart failure and cirrhosis, the plasma renin activit) is normal in some patients with these disorders 83@,3$9. # partial e*planation for this seemin"l) parado*ical findin" is that the patient has entered a compensated state in which the initial fluid retention has increased venous return to the heart, thereb) allowin" s)stemic hemod)namics to be stabili-ed +at least in the restin" state, and removin" the stimulus for continued renin release 833,3@9. This se5uence is depicted in Fi"ure which shows the chan"es that occur with chronic thoracic inferior vena cava constriction, an e*perimental model that simulates the chan"es seen in heart failure in humans +show fi"ure , 8339. The new stead) state seen after si* to seven da)s is characteri-ed b) plasma volume e*pansion, but normali-ation of the s)stemic blood pressure, urinar) sodium e*cretion, and renin and aldosterone release. 1n man) patients, however, stable heart failure is associated with a persistent reduction in cardiac output and it is not clear wh) renin levels should be normal 8339. Hne possible e*planation is that circulatin" levels ma) not reflect the de"ree

of activation of tissue renin0an"iotensin s)stems. +.ee /#ctions of an"iotensin 11 on the heart/,. The remainder of this topic review is presented separatel). +.ee /<athoph)siolo") and etiolo") of edema011/,. -e*ere)ce' . Gu)ton, #=. Te*tboo4 of Medical <h)siolo"), ?th ed, .aunders, <hiladelphia, DD , chap. A. !. Ta)lor, #(. =apillar) fluid filtration2 .tarlin" forces and l)mph flow. =irc Res D? % @D2$$>. 3. Ren4in, (M. Re"ulation of the microcirculation. Microvasc Res D?$% 302!$ . @. =randall, (D, .taub, &=, Goldber", 6., (ffros, RM. Recent developments in pulmonar) edema. #nn 1ntern Med D?3% DD2?0?. $. Deitch, (#. The mana"ement of burns. & (n"l I Med DD0% 3!32 !@D. A. Bellde"run, #, Cebb, D, #ustin, 6# 111, et al. (ffects of interleu4in0! on renal function in patients receivin" immunotherap) for advanced cancer. #nn 1ntern Med D?>% 0A2? >. >. Baum"artner, 1, Rauh, G, <iec-e4, #, et al. ;ower0e*tremit) edema associated with "ene transfer of na4ed D&# encodin" vascular endothelial "rowth factor. #nn 1ntern Med !000% 3!2??0. ?. #moura, J, <apo, T, &inet, I, et al. .)stemic capillar) lea4 s)ndrome2 Report on 3 patients with special focus on course and treatment. #m I Med DD>% 032$ @. D. =icardi, M, Gardinali, M, Bisiani, G, et al. The s)stemic capillar) lea4 s)ndrome2 #ppearance of interleu4in0!0receptor0positive cells durin" attac4s. #nn 1ntern Med DD0% 32@>$. 0. Droder, RM, K)le, R#, Griepp, <R. =ontrol of s)stemic capillar) lea4 s)ndrome with aminoph)lline and terbutaline. #m I Med DD!% D!2$!3. . Tahir4heli, &K, Greipp, <R. Treatment of the s)stemic capillar) lea4 s)ndrome with terbutaline and theoph)lline. #nn 1ntern Med DDD% 302D0$. !. Hhlsson, K, BjLr4, <, Ber"enfeldt, M, et al. 1nterleu4in0 receptor anta"onist reduces mortalit) from septic shoc4. &ature DD0% 3@?2$$0. 3. =olletti ;M, Remic4 DG, Burtch GD, et al. Role of tumor necrosis factor0alpha in the pathoph)siolo"ic alterations after hepatic ischemiaMreperfusion injur) in the rat. I =lin 1nvest DD0% ?$2 D3A. @. Bollin"er, #, Fre), I, Ia"er, K, et al. <atterns of diffusion throu"h s4in capillaries in patients with lon"0term diabetes. & (n"l I Med D?!% 30>2 30$. $. 6ommel, (, Mathiesen, (R, #u4land K, <arvin" 606. <athoph)siolo"ical aspects of edema formation in diabetic nephropath). Kidne) 1nt DD0% 3?2 ?>. A. Brownlee, M. Gl)cation and diabetic complications. Diabetes DD@% @32?3A. >. Ma)atepe4, (, Bec4er, K, Gana, ;, et al. ;eu4otrienes in the pathoph)siolo") of 4washior4or. ;ancet DD3% 3@!2D$?. ?. <arvin" 66, 6ansen IM, &ielsen .;, et al. Mechanisms of edema formation in m)*edema2 1ncreased protein e*travasation and relativel) slow l)mphatic draina"e. & (n"l I Med D>D% 30 2@A0. D. 6ollander, C, Reill), <, Burrows, B#. ;)mphatic flow in human subjects as indicated b) the disappearance of 1 3 0labeled albumin from the subcutaneous tissue. I =lin 1nvest DA % @02!!!. !0. .-idon, I<. <athoph)siolo") of the con"ested lun". =ardiol =lin D?D% >23D. ! . Kwan T, <intea M, Garcia Morino F, et al. Transcapillar) oncotic pressure in the edema of con"estive heart failure. &ephron DD0% $@2! .

!!. Fauchald, <F. Transcapillar) colloid osmotic pressure "radient and bod) fluid volumes in renal failure. Kidne) 1nt D?A% !D2?D$. !3. Koomans, 6#, Kortlandt, C, Geers, #B, Dorhout Mees, (I. ;owered protein content of tissue fluid in patients with the nephrotic s)ndrome2 Hbservations durin" disease and recover). &ephron D?$% @023D . !@. Jarins, =K, Rice, =;, <eters, RM, Nir"ilio, RC. ;)mph and pulmonar) response to isobaric reduction in plasma oncotic pressure in baboons. =irc Res D>?% @32D!$. !$. .chrier, RC. Bod) fluid volume re"ulation in health and disease2 # unif)in" h)pothesis. #nn 1ntern Med DD0% 32 $$. !A. .chrier, RC. #n od)sse) into the milieu intOriur2 <onderin" the eni"mas. I #m .oc &ephrol DD!% 2 $@D. !>. (pstein, F6, Fer"uson, TB. The effect of the formation of an arteriovenous fistula upon blood volume. I =lin 1nvest D$$% 3@2@3@. !?. Kowals4i, 6I, #belmann, C6. The cardiac output at rest in ;aennec7s cirrhosis. I =lin 1nvest D$3% 3!2 0!$. !D. <ere-0#)uso, RM, #rro)o, N, =ampos, I, et al. (vidence that renal prosta"landins are involved in renal water metabolism in cirrhosis. Kidne) 1nt D?@% !A2>!. 30. 6enri4sen, I6, Bendtsen, F, Gerbes, #;, et al. (stimated central blood volume in cirrhosis2 Relationship to s)mpathetic nervous activit), B0adrener"ic bloc4ade and atrial natriuretic factor. 6epatolo") DD!% A2 A3. 3 . Fernande-0.eara, I, <rieto, I, Puiro"a, I, et al. .)stemic and re"ional hemod)namics in patients with liver cirrhosis and ascites with and without functional renal failure. Gastroenterolo") D?D% D>2 30@. 3!. =ohn, I&. Blood pressure and cardiac performance. #m I Med D>3% $$23$ . 33. Cat4ins, ; Ir, Burton, I#, 6aber, (, et al. The renin0an"iotensin0aldosterone s)stem in con"estive failure in conscious do"s. I =lin 1nvest D>A% $>2 A0A. 3@. D-au, NI, =olucci, C., 6ollenber", &K, Cilliams, G6. Relation of the renin0 an"iotensin0aldosterone s)stem to clinical state in con"estive heart failure. =irculation D? % A32A@$. 3$. =hon4o, #M, Ba), C6, .tein, I6, Ferris, TF. The role of renin and aldosterone in the salt retention of edema. #m I Med D>>% A32?? .