Renal Adaptation to Dietary Sodium Restriction in Moderate Renal Failure Resulting from Chronic Glomerular Disease1 2

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1 Renl Adpttion to Dietry Sodium Restriction in Moderte Renl Filure Resulting from hronic Glomerulr Disese1 2 Bruno inciruso, Vincenzo Bellizzi, Roberto Minutolo, Giuseppe olucci, Vincenzo Bisesti, Domenico Russo, Giuseppe onte, nd Luc De Nicol3 B. inciruso. V. Bellizzi. P. Minutolo. G. olucci. V. Bisesti, D. Russo, L. De Nicol, Division of Nephrology. School of Medicine. First University. Nples. Itly G. onte, Division of Nephrology. School of Medicine. Second University, Nples, Itly (J. Am. Soc. Nephrol. 199#{243}; 7:3#{243}-313) ABSTRAT The renl response to sodium restriction ws evluted, nd the concurrent chnges of the plsm levels of ldosterone (ALDO) nd tril ntriuretic peptide (ANP), in helthy ptients (NOR), in normtensive ptients with non-nephrotic chronic glomerulonephritis nd norml renl function (GN), nd in ptients with glomerulonephritis nd moderte renl filure (GFR, 41 ± 4 ml/min; RF). The three groups were studied for 1 wk fter chnging from normlsodium diet (NSD, 235 mq NI/dy) to lowsodium diet (LSD, 35 mq NI/dy). All ptients reched stedy sodium blnce within the 4th nd 5th dy of LSD with n nlogous cumultive loss of sodium. After slt restriction, the frctionl urinry sodium excretion diminished by the sme extent in the three groups, wheres the frctionl free-wter genertion, mesured during wter diuresis, did not vry in NOR nd mrkedly decresed in GN nd RF. Plsm levels of ALDO were similr in ll groups t NSD nd similrly incresed during LSD. In GN nd RF, s compred to NOR, ANP levels were higher t NSD nd decresed by minor extent during LSD. Notbly, in GN nd RF, but not in NOR, the ltinment of the new sodium blnce fter sodium restriction ws preceded by significnt prllel reduction of blood pressure nd GFR; the GFR decline ws secondry to mjor decrement of RPF so tht filtrtion frction (FF) incresed. It ws concluded tht in NOR, distl tubulr effects of ANP nd ALDO c- 1 Received June 13, Accepted September 25, Portion ofihis pper ws presented t the 27th Annul Meeting ofthe Americn Society of Nephrology nd published In bstrct form on the J Am Soc Nephrol, 5:326, correspondence to Dr. L De Nicol, Division of Nephrology, School of Med Icine, University of Nples Federico II, Vi Belvedere 52, 8127 Nples, Itly /72-36$3./ Journl of the Americn Society of Nephrology copyright c 1996 by the Americn Society of Nephrology count for the ttinment of sodium blnce during LSD. As difference, both GN nd RF ptients chieve the new sodium blnce primrily through hemodynmic chnges: the renl hypoperfusion secondry to decrese in blood pressure tht diminishes the filtered lod of sodium, nd the increse of FF tht enhnces the proximl tubulr sodium rebsorption. This bnorml response seems relted to both the minor suppression of ANP nd the incresed slt-sensitivity of blood pressure tht re likely the result of the presence of volume expnsion. Key Words: Humns, renl hemodynmics, sodium blnce, ANP, ldosterone S lt-intke restriction represents the cornerstone in the mngement of hypertension secondry to chronic renl filure (RY). Such dietry modifiction is prescribed erly in the course of the renl disese becuse RY-relted hypertension often occurs fter only mild impirment ofrenl function, with greter prevlence in chronic glomerulonephnitis compred with other nephnopthies ( 1 ). Surprisingly, the renl dpttion to low-sodium diet (LSD) in the initil stges of RY still remins ill-defined. This criticl issue hs been investigted only in ptients with dvnced RY who undergo slt-free diet (2-7). Under these conditions, the renl dpttion to sodium deprivtion is inefficient, with significnt dely in the chievement of new sodium blnce. Moreover, in these ptients, further OFR decline could be observed when sodium blnce becme mrkedly negtive. In ddition, the interprettion of these studies ws complicted by the presence of ptients with slt-wsting diseses tht result from primry tububointenstitil lesion. In moderte renl insufficiency. tht is, the stge t which clinicl dignosis of renl filure is more often mde, the dy-by-dy renl response to n LSD tht contins 2 to 5 g Nb/dy hs never been object of investigtion. It is importnt to note tht potentil influence of slt Intke on the GFR outcome my be present in these ptients, s in SRD: OFR decrement, in fct, hs been reported in the initil period of protein restriction in lrge number of ptients with moderte RF (8). This phenomenon, which is ssodted with prllel reduction ofbbood pressure, hs been ttributed to hemodynmic chnges subsequent to the lower protein intke. However, becuse bowprotein diet in RF ptients is generlly ssocited with prllel reduction of slt intke, it is possible 36 Volume 7. Number

2 inciruso et l tht the decrese of dietry sodium my hve contnibuted to the GFR decline observed in tht study. Indeed, we hve recently demonstrted tht in moderte RF, low-protein diet does not decrese GFR if the norml slt intke is mintined (9). To nlyze the mechnisms of the renl dpttion to pure dietry sodium restriction, ptients with moderte RF secondry to biopsy-verified glomenubr disese were studied dily while they were mintmed on norml-sodium diet (NSD; 235 mq Nl/ dy) nd fter strting n LSD (35 mq Nb/dy) while the protein intke ws kept constnt ( 1. g/kg body \vi per dy). We lso compred the dily chnges of urinry sodium excretion with the djustments of the plsm levels of tnil ntriuretic peptide (ANP) nd ldostenone (ALDO) tht re the most importnt volume sensing hormones In helth ( 1). No uthor hs previously evluted the dily vrition of these hormones fter sodium restriction in RY ptients; on the contrry, for the best ssessment of the sensitivity of ANP nd ALDO response to LSD, it is crucil to exmine the first dy s results, tht is, before the chievement of neutrl sodium blnce ( 1 1 ). Two control groups were included in the nlysis: group of helthy ptients nd group of ptients with biopsy-proven chronic gbomenubonephnitis nd norml renl function. This ltter group ws the determinnt to better evlute whether the potentil bnormlities in the renl response to LSD In RF were the result of the gbomenubr disese per Se, or, lterntively, of the functionl nd structurl ltertions tht chrcterize the boss of functioning nephrons. MTHODS Ptients Seven helthy mle volunteers of our medicl stff nd 14 mle ptients were studied for 15 dys fter their informed consent ws obtined. The clinicl chrcteristics of the ptients studied re depicted in Tble 1. Helthy ptients (NOR group) hd negtive history for renl disese, nd norml urinlysis nd cretinine clernce (cr) vlues. All ptients hd primry glomerulr disese; the histologicl dignosis re reported in Tble 1. Seven ptients showed moderte reduction of renl function (RF group). nd seven ptients did not hve ny reduction in renl function (GN group). xclusion criteri for ptients consisted of men rteril pressure higher thn 15 mm Hg during ntihypertensive tretment, neopbstic disese, protein urinry excretion 1.5 g/dy. hert filure, cirrhosis, edem of ny cuse, dibetes mellitus, or presence of significnt tubulointerstitil lesions. Ptients were periodiclly seen by the sme physicin in dy-hospitl setting for period of t lest 6 months before the study. Systemic hypertension. defined s blood pressure 14/9 mm Hg in three different mesurements from the sme dy throughout the period of observtion. ws present in six ptients with RF, nd ws bsent in GN. Antihypertensive therpy consisted only of clonidine (.75 mg twice dily or three times dily); ech ptient mintined the sme constnt dosge throughout the study. Study Protocol For 7 dys. helthy volunteers nd ptients received diet contining 35 mq of sodium, 7 mq of potssium, 1. g/kg body wt per dy ofproteins, 35 kcl/kg body wt per dy, nd supplement of2 mq ofsodium s orl cpsules. On the 4th dy of this diet (norml-sodium diet, NSD). helthy volunteers nd ptients were dmitted to our unit. The constncy of 24-h urinry ure nitrogen nd sodium excretion vlues, showing complince to the prescribed diet, ws proved by stedy levels for t best 3 dys. Ptients underwent renl clernce studies of inubin nd p-minohippuric cid (PAll) on the 3rd dy t 8. m. Therefter, the sodium supplement of2 mq/dy ws withdrwn while the clorie nd protein content of the diet (low-sodium diet, LSD) ws kept constnt. The renl clernce studies were repeted when new stedy sodium blnce could be documented in the lst 3 dys of LSD. In ech subject. t both dietry regimens. the externl sodium blnce ws considered chieved if the dily urinry output of sodium corresponded to the prescribed intke ± 1%. very morning t 8. m., during the entire period of observtion in our unit, blood pressure nd pulse rte were registered nd blood smples were drwn from ll of the ptients in the study. All ptients hd fsted from the previous evening while still lying In bed. The ptients were then llowed to stnd nd void: body weight (with underwer clothing) ws then recorded. Twenty-four-hour urinry coblection ws obtined dily. TABL 1. linicl chrcteristics of helthy ptients (NOR), nd ptients with chronic glomerulonephritis with (RF) nd without (GN) renl filure hrcteristic NOR GN RF Ptients (N) Age (yr) 35.4 ± ± ± 5.9 Body Weight (kg) 8. 1 ± ± ± 2. 1 b cr (ml/min) ± ± ± 44 Serum Bicrbonte (mq/l) 24.9 ± ± ± 9b Uprot (g/24 h).8 ±.35.7 ±.28 Glomerulr Disese 2 MSP, 2 M, 2 ga, 1 FS 2 MSP, 2 M, 2 IgA, 1 FS The vlues re men ± S. Ocr. cretinine clernce; Uprot. urinry protein excretion; MSP, diffuse mesngil prolifertive; M, membrnous; IgA. Berger disese; FS, focl sclerosis; M, mesngil cpillry. b p <.5 versus NOR. p <.5 versus other groups. Journl of the Americn Sociely of Nephrology 37

3 Renl Adpttion to Sodium Restriction in Moderte Renl Filure Blood pressure ws mesured with mercury sphygmomnometer s men ofthree consecutive mesurements on the sme rm. The levels of ANP, ALDO, nd totl protein were mesured from plsm smples. Sodium, potssium. ure. nd cretinine vlues were ssessed from blood nd 24-h urinry smples. GFR nd RPF Mesurements Renl function determintion ws performed t the sme time of the dy, (8..m). According to our previous studies (9. 1 2). renl clernce vlues were mesured during stedy stte of mximl wter diuresis to gin insights into the tubulr function of the proximl nephron. On the morning of the test, fsting ptients drnk 1 ml/kg body wt of tp wter; therefter, to mintin wter blnce, ptients drnk n mount of wter equl to the urinry volume collected minus the mount dministered with the infusion solution tht ws given orlly. To perform iv infusions nd blood smpling. smll Teflon cnnule (Abbott Lbs, Illinois) were inserted into n ntecubitl vein of ech rm; bobus Injection of priming dose of inulin (5 mg/kg body wt; Jcopo Monico, Venezi/Mestre, Itly) nd PAH ( 1 mg/kg body wt; Jcopo Monico) in 5 ml of sline solution ws performed; therefter, continuous infusion (1 ml/mln) of inulin (125 mg/r per 5 ml 5% D-solution) nd PM! ( 12.5 mg/ estimted RPF per 5 ml 5% D-solution) ws strted nd continued throughout the experiment to mintin constnt plsm concentrtion of the two mrkers. After 6 mm of stbiliztion, three clernce periods of 3 mm ech were obtined. Blood ws withdrwn t the beginning nd t the end ofech period through ctheter kept open by flushing of heprinized solution. In ll of the ptients studied, urine collection ws obtined by spontneous voiding. A postvoiding residul urinry volume in bldder ws previously excluded by ultrsound evlution. Blood pressure ws mesured every 1 min during ech clernce period. Anlyticl Determintions Plsm nd urinry concentrtions of proteins. nitrogen. sodium. potssium, osmoles, inubin, nd PM!, s well s plsm ANP nd ALDO levels, were nlyzed by using stndrd techniques described in our previous ppers ( ). Blood smples (7 ml) for ANP rdioimmunossy were coblected in chilled polystyrene tubes contining.3 ml of 1% DTA, nd immeditely centrifuged t 4#{176}. Plsm ws seprted nd stored t -2#{176}.ANP from plsm ws extrcted by following the extrction protocol suggested by Amershm, using Amershm s Amprep 1 mg 8 columns (Amershm Interntionl plc. United Kingdom). The ssy ws performed by following the rdioimmunossy procedure s indicted in the commercil kit from Amershm (Humn ANPI 1251] rdiolmmunossy system, code RPA Amershm). Plsm ALDO ws mesured by rdioimmunossy with commercil kits from Sorin (Sorin, Sluggi. Itly). lcultion GFR nd RPF were corrected for body surfce re. RPF ws clculted by division of the corresponding PM! clernce by n estimte of the renl extrction rtio of PM!. According to other uthors tht hve exmined ptients with GFR vlues similr to those recorded in our study, the renl PM! extrction rtio ws ssumed to be.85 in helthy ptients, nd.7 in ptients with RY (15). Sttisticl Anlysis All vlues re reported s men ± S. We used one-wy nlysis ofvrince for comprisons mong different groups, nd for repeted mesurements to nlyze differences in the sme group. Liner regression nlysis ws lso performed. The level of sttisticl significnce ws defined s P <.5. RSULTS Dily vlution of the ffects of Low-Sodium Diet Sodium Blnce. No difference ws noted mong groups in the dily sodium blnce fter sodium restriction (Figure 1 ). On the first dy of LSD, ptients developed negtive sodium blnce of 7 to 1 mq; the difference between slt intke nd output progressively decresed in the following dys. We considered the externl sodium blnce to hve been chieved if the 24-h urinry output of sodium mtched the prescribed intke with mximl vri- LU -2 ).5-4 e..2-6.d, -8 e ci LU -5 ) e. - U) -15 > TIM, dys Figure 1. Dily (top) nd cumultive (bottom) sodium blnce during the 7 dys of low-sodium diet in glomerulonephritic ptients with norml (digonl br) or modertely reduced GFR (doffed br), nd In helthy ptients (solid br). 38 Volume 7 - Number

4 inciruso et l tion of 1 % ; ccordingly, stedy blnce ws reched t the 4th dy in R1 ptients nd t the 5th dy in GN nd NOR. At the end of the LSD period, the men cumultive sodium blnce result ws lso similr in the three groups (- 134 ± 2 mq in control ptients, ± 66 mq in GN, nd - 16 ± 28 mq in RY, Figure 1), indicting net decrese of bout 1 L of extrcelbulr volume in ll of the ptients studied. This finding is in greement with the significnt men decrement of body weight observed t the end of LSD versus NSD (NOR, from 8. 1 ± 1.9 to 78.9 ± 1. kg; GN, from 73.6 ± 3.3 to 72.2 ± 3.3 kg; RF, 66.4 ± 2.1 to 65.3 ± 2.1 kg). Plsm protein concentrtion (TP) ws slightly but significntly higher t NSD in NOR thn In GN nd R1 (Tble 2); t the end of LSD, this vlue hd incresed in ll groups: from 7.3 ±. 1 to 7.6 ±.1 g/dl, from 6.5 ±.3 to 6.8 ±.1, nd from 6.4 ±.2 to 6.8 ±.2 in NOR, GN, nd RF, respectively (P <.5 versus NSD). The sme difference ws mintmed t LSD. Notbly, the reduction of dietry slt ws ssocited with constnt protein intke. Indeed, on the bsis of the dily mesurements of urinry ure nitrogen excretion, the protein intke clculted pen kg of body weight rnged from.95 to 1. 1 g in the three groups. These vlues remined constnt throughout the study. Blood Pressure nd Renl Prmeters. After slt restriction, progressive reduction of blood pressure ws recorded in the two groups of ptients but not in helthy individuls (Figure 2). In GN nd RF, MAP ws significntly lower t the 4th nd the 3rd dy of LSD, respectively; this phenomenon therefore preceded the ttinment of sodium blnce in both groups of ptients. The dy-by-dy study evidenced significnt decrese of GFR tht ws simultneous with the reduction of blood pressure in ptients. Indeed, cr vlues (Figure 2) diminished t the 4th dy in the GN group (17.1 ± 4.7 versus ± 3. ml/min, P <.5) nd t the 3rd dy of LSD In RY (36.9 ± 4. 1 versus ± 4.4 ml/min, P <.5). The renl function remined constnfly depressed in the subsequent dys (cn on the lst dy oflsd: 18.4 ± 6. ml/min in GN nd 34.2 ± 4.8 ml/min in RF). On the contrry, cr did not vry throughout the period of observtion in helthy ptients (Figure 2). The bsl frctionl urinry excretion of sodium (FN) ws greter in RF ptients with respect to the two groups with norml GFR mintined on both dietry regimens (Figure 3). After slt restriction, FN progressively decresed by the sme extent in the three groups, reching stedy level once sodium blnce ws chieved: by the lst dy of LSD, FN ws reduced by 82 ± 4%, 79 ± 7%, nd 74 ± 5% In NOR, GN, nd RF, respectively. Plsm Levels of ANP nd ALDO. With both NSD nd LSD, plsm ANP levels were significntly higher in GN nd RF ptients thn in helthy ptients (Figure 4). In contrst, no difference ws detected mong groups with regrd to the ALDO levels. In ll of the ptients under study, LSD ws ssocited with decrese ofanp nd concurrent increse ofaldo. A significnt chnge in the ANP levels ws noted s erly s the first dy fter dietry sodium restriction ws begun. wheres ALDO chnged by the 2nd dy of LSD. When the finl vrition ofanp bevels from NSD to the end of LSD ws exmined, greten decrese ws observed in NOR (-83.4 ± 4%) thn In GN nd RF (-43. ± 9% nd ± 7%, respectively. P <.5 versus NOR). ALDO incresed by the sme extent in the two groups. The liner regression nlysis, clculted by plotting the dily ANP concentrtion with the corresponding vlue of FN from ech subject, showed significnt direct correltion only in the NOR group (N = 56, TABL 2. Renl function t the lst dy of norml-sodium diet (NSD) nd low-sodium diet (LSD) in helthy ptients (NOR), nd in ptients with chronic glomerulonephritis with (RF) nd without (GN) renl filure#{176} Test NOR GN RF NSD LSD NSD LSD NSD LSD MAP (mm Hg) 96.3 ± ± ± ± 1,1b 97.6 ± ± 33b GFR (ml/min) 18.3 ± 5.9 W8.7 ± ± ± 67b 4.9 ± 2.9c 34.9 ± 39bc RPF (ml/min) 435 ± ± ± 4 39 ± 23b,c 222 ± ± 2b.c FF (%) 27. ± ± ± ± 1b 18.2 ± 7d 24.1 ± 18b RVR (mm Hg/mi per mm).1 14 ± ± ±.1.15 ±.Olb.263 ±.4c.396 ± 6b.c Hct (%) 44.6 ± ± ± ± ± ± 23b TP (g/dl) 7.3 ± o.v 7.6 ± 1b,c 6.5 ± ±.lb 6.4 ± ± 2b V (ml/min) 13.6 ±.7w 1 1. ± ± ± 1 5b 8. ±.8w 49 ± 8b.c H2O/ln ( #{176}) 7.5 ± ± ± ± 1#{149}8b 16.2 ± 1.3c 8.43 ± 199b The vlues re men ± S. GFR. glomerulr filtrtion rte; RPF, renl plsm flow; FF, filtrtion frction; RVR, renl vsculr resistnce; Hct, hemtocrit; TP. serum totl protein; V. urinry volume; 2O/. frctionl free-wter genertion. b p <.5 versus NSD. p <.5 versus other groups. d p <.5 versus NOR. Journl of the Americn Society of Nephrology 39

5 Renl Adpttion to Sodium Restriction in Moderte Renl Filure , I...i (U (U j 1.5 U-... * ) TIM, dys 45 ) e ) Figure 3. Dily chnges of the frctionl urinry excretion of sodium during the seven dys of low-sodium diet In gbmerubonephritic ptients with norml (dshed line) or modertely reduced GFR (doffed line), nd in helthy ptients (solid line). Dy is the lst dy of the norml-sodium diet. op <.5 versus other groups; P <.5 versus other dys; p <.5 versus helthy ptients. r =.693, P <. 1 ). No correltion ws found between plsm ALDO bevels nd the respective FN vlues in ny of the groups studied. 13.c 125 I12o 115 ) 11 e ( TIM, dys Figure 2. DIly chnges of cr (column) nd men rteril pressure (dshed line) during the 7 dys of low-sodium diet in glomerulonephritlc ptients with norml (top) or modertely reduced GFR (middle), nd in helthy ptients (bottom). Dy is the lst dy of the norml-sodium diet. <.5 versus Dy. Renl Function Before nd After Low-Sodium Diet The renl clernce dt from the lst dy of NSD nd LSD (Tble 2) confirmed the results of the dy-by- 15 dy evlution. At NSD, GFR. nd RPF, mesured by inulin nd PM! renl clernce, ws comprble in ) NOR nd GN groups. At the end of the LSD period. 1 : significnt renl hypopenfusion ws detected only in GN nd RF. In the GN group. LSD ws ssocited with 1 2% decrese of GFR tht ws secondry to prllel 24% reduction of RPF; this resulted in.. significnt increse in the filtrtion frction (FF). Sim-. ilrly, in the RF group, sodium restriction deter- mined GFR decline of bout 15% tht ws depen- 85 dent on 33% decrese of RPF with consequent elevtion of FF. The observed renl hypoperfusion in GN nd RF t LSD ws coupled with significnt 8 increse of the renl vsculr resistnces. After slt restriction, the frctionl free-wter genertion strikingly decresed in both GN nd RY groups, nd did not chnge in NOR. These dt, ttined in condition of mximl wter diuresis, re comptible with increment of tubulr sodium rebsorption t the level of the proximl nephron (9,12). DISUSSION The dherence to the prescribed LSD llowed the correct nlysis of the renl response to the pure slt restriction, tht is, independently of influences deter- 31 Volume 7 - Number

6 inciruso et l 5. : z i * *# * I * TiM, dys I I I Figure 4. DIly chnges of plsm ANP (top) nd ALDO (boffom) levels during the 7 dys of low-sodium diet in gbomerulonephritic ptients with norml (dshed line) or modertely reduced GFR (doffed line), nd In helthy ptients (solid line). Dy is the lst dy of the norml-sodium diet.* P <.5 versus Dy ; #{176}P <.5 versus other groups; P <.5 versus gbomerubonephrltic ptients with norml GFR. mined by potentil vrition of protein Intke. RY ptients, s well s those with chronic glomerulonephritis nd norml GFR, reched the new slt blnce s quickly s the control ptients did. Thus, s opposed to SRD (2-7), in moderte renl filure tht results from chronic glomerulr disese, the cpbility to efficciously conserve sodium fter sudden slt restriction is preserved. Nevertheless, the underlying mechnisms re different in helthy individuls nd renl ptients. ANP nd ALDO re considered to be the min humorl meditors of the volemi-induced chnges of ntniuresis in helthy ptients ( 1). The study presented here shows evidence of the higher sensitivity of ANP versus ALDO to the volume chnges in chronic gbomerulr disese. In fct, the dy-by-dy evlution showed tht negtive blnce of pproximtely 8 mq of sodium developed in the three groups 24 h fter sodium restriction; the corresponding extrcellulr volume depletion of pproximtely.5 L (bout -5%) ws ssocited with simultneous mrked decrese of ANP levels in the bsence of significnt chnges of plsm ALDO. Therefore, the relese of ANP ws suppressed by very smll reductions of the extrcellulr volume in ll groups. It is probble tht the high sensitivity ofanp relese ws criticl to the finl chnge ofanp levels in helthy ptients nd renl ptients fter slt restriction. A significnt minor ANP suppression ws evident in GN (-43%) nd RY (-47%) with respect to NOR (-83%). Such diverse response my hve been dependent on the presence of mild volume expnsion in both GN nd RY groups. Indeed, ANP levels were higher in RY thn In helthy ptients t both levels of sodium Intke. The sme finding hs been reported by other uthors nd interpreted s consequence of enhnced ANP relese secondry to volume expnsion nd/or determined by decresed renl clernce of this hormone ( 16-18). In the study presented here, the significntly lower vlues of plsm protein concentrtion, s well s the presence of high ANP bevels in the ON group with norml GFR, re consistent with the former hypothesis. We cn therefore hypothesize tht in both groups ofptients, the inhibitory effects of LSD on ANP relese my hve been smller becuse of volemi tht ws constntly ugmented. Notbly, the presence of incresed extrcellulr volume in ON nd RY ptients cnnot be excluded on the bsis of ALDO levels similr to the control vlue becuse the ALDO concentrtions hve been found to be norml or even elevted in moderte to dvnced RY (19-21). In the NOR group, the frctionl urinry sodium excretion significntly correlted with ANP bevels but not with ALDO. This finding, s well s the mximl suppression of ANP relese In the sme group. confirm tht ANP is the min determinnt of the tubulr response to sodium restriction In helth ( 1 1 ). In helthy ptients, sodium rebsorption likely Incresed t the distl tubule level s indicted by the decrement of FeN ssocited with constnt frctionl free-wter genertion. On the contrry, no reltionship ws detected between FeN nd either ANP or ALDO in GN nd RY ptients, suggesting tht in gbomerulr disese, the two hormones do not ply mjor role In downregubting ntniuresis fter slt restriction. Indeed, In GN nd RY but not in NOR, the dily mesurements of blood pressure nd cr showed simultneous decrese of both prmeters tht took plce before the ttinment of the new sodium blnce. These results show tht reduction of GFR secondry to the decrement of blood pressure represents primry mechnism dopted by these ptients to conserve sodium t LSD. The inulin nd PAH clernces performed on the lst dy of ech dietry regimen not only confirmed the significnt GFR decline In ON nd RY fter Journl of the Americn Society of Nephrology 311

7 Renl Adpttion to Sodium Restriction in Moderte Renl Filure sodium restriction, but lso demonstrted tht this ws secondry to greter reduction of renl plsm flow coupled with n elevtion of the FF. In ddition, the cute study showed mrked decrese of the frctionl free-wter genertion in the sme two groups, mesured during mximl wter diuresis. It is therefore resonble to hypothesize tht in ON nd RY ptients, proximl tubulr rebsorption of sodium incresed in response to LSD nd, moreover, tht this phenomenon ws primrily ttributble to the renl hypoperfusion nd the consequent increment of the oncotic pressure t the level of the proximl penitubulr cpillry (22). We cnnot exclude, however, tht fctors other thn the hemodynmic chnges my hve been involved in the tubulr dpttion to LSD In the renl ptients. The functionl impirment of renl perfusion fter sodium restriction in RY ws dependent on the simultneous decrese of the systemic rteril pressure. At the end of the LSD period, the depletion of the extrcellulr volume ws comprble in the three groups; however, blood pressure diminished in renl ptients but not in helthy ptients. These dt re therefore comptible with n incresed slt-sensitivity of blood pressure tht hs been previously described in ptients with mild to dvnced RY (21,23-26). Importntly, the fmdings in the ON group indicte tht in ptients with primry gbomerulr disese, this peculir response to slt restriction develops even before hypertension nd/or GFR decline become mnifest. The ugmented volemi my hve plyed centrl role in the pthophysiology of this phenomenon. This ltertion, in fct, is crucil to the enhncement of the slt-sensitivity of blood pressure in renl ptients (2 1, 23-26). In conclusion, in glomerubonephnitic ptients with or without moderte RF, the renl dpttion to LSD is chieved s promptly s it is in helthy ptients, however, the underlying mechnisms pper to be different. In helthy ptients, sodium excretion is efficciously redjusted by hormonl chnges with ANP plying predominnt role. On the other hnd, renl ptients chieve the new sodium blnce pnimnly through hemodynmic chnges: the renl hypoperfusion secondry to reduction of blood pressure tht diminishes GFR nd the filtered lod of sodium, nd the increse of filtrtion frction tht enhnces the proximl tubulr sodium rebsorption. In these ptients, the bnorml mechnism of dpttion is likely to be ttributble to the presence of volume expnsion tht is ssocited with minor suppression of ANP relese nd incresed slt-sensitivity ofblood pressure. These phenomen precede the development of systemic hypertension nd GFR dedine. Interestingly, these findings imply tht creful nlysis of the possible chnges in slt Intke is mndtory when exmining the impct of low-protein diet, s with ny other therpeutic intervention, on the progressive GFR decline in estblished renl disese. Indeed, we hve recently demonstrted tht protein restriction does not decrese GFR in ptients with moderte RY if the usul sodium intke is kept constnt (9). Therefore, the results ttined in both the previous study nd this study strongly suggest tht the reduced slt intke, usully ssocited with protein restriction, is the primry determinnt of the GFR decline observed fter strting low-protein diet in ptients with renl insufficiency (8). AKNOWLDGMNTS This study ws prtilly supported by onsiglio Nzionle delle Ricerche (tb. # ctO4). Dr inciruso ws recipient of grnt from MURST 6%, RFRNS 1. Smith M, Dunn MJ. Hypertension due to renl prenchyml disese. In: Brermer BM, Rector F, ds. The Kidney. 4th d. Phildelphi: W Sunders; 1991: Nickel JF, Lwrence PB, Leifer, Brdley S: Renl function, electrolyte excretion nd body fluids in ptients with chronic renl insufficiency before nd fter sodium deprivtion. J hin Invest 1953;32: Levin DM, de R: Influence of dietry sodium on renl function in ptients with chronic renl disese. Ann Intern Med 1965;62: olemn AJ, Aris M, rter NW, Rector P, Seldin DW: The mechnism of slt wstge in chronic renl disese. J hin Invest 1966;45: Gonick H, Mxwell MH, Rubini M, Kleemn R: Functionl Impirment in chronic renl disese. I. Studies of sodium-conserving bility. Nephron 1966;3: Blumberg A, Nelp WB, Hegstrom RM, Scribner BH: xtrcellubr volume in ptients with chronic renl disese treted for hypertension by sodium restriction. Lncet l967;2: Dnovltch GM, Bourgoignie J. Bricker NS: Reversibifity of the slt-losing tendency of chronic renl filure. N ngl J Med 1977;296: Klhr 5, Levey AS, Beck GJ, et t. (for the MDRD Study group): The effects of dietry protein restriction nd blood-pressure control on the progression of chronic renl disese. N ngl J Med 1994;33: inciruso B, Bellizzi V. puno A, et t.: Short-term effects of low protein-norml sodium diet on renl function in chronic renl filure. Kidney Int 1994;45: Lrgh JH: Atril ntriuretic hormone, the reninldosterone xis, nd blood pressure-electrolyte homeostsis. N ngl J Med 1985;313: onte G, Romno G, Sepe V. et!.: Role of inhibition of tril ntriuretic fctor relese in the down-regultion of slt excretion. Kidney Int 1992;42: onte G, Dl nton A, Sbbtini M, et t.: Acute cyclosporine renl dysfunction reversed by dopmine infusion in helthy subjects. Kidney mt 1989;36: Dc Nicol L, Romno G, Memoli B, et l.: xtrntniuretic effects oftril peptide in humns. Kidney Tnt 1993;43: Dl nton A, Romno G, onte G, et t.: Role of tnil ntniuretic fctor in renl dpttion to vrition of slt intke in humns. Am J Physiob 199;258:F1579- F hn AYM, heng MLL, Keil L, Myers BD: Functionl response of helthy nd disesed glomeruli to lrge. protein-rich mel. 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