RENAL FUNCTION AND ACE INHIBITORS IN RENAL ARTERY STENOSISA/adbon et al. 651

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2 RENAL FUNCTION AND INHIBITORS IN RENAL ARTERY STENOSISA/adbon et al. 65 Downloaded from by on January, 209 Patents and Methods The dagnoss of renovascular hypertenson was made n patents wth hypertenson that was dffcult to control and n whom a renal arterogram had demonstrated marked renal artery stenoss. The functonal sgnfcance of the stenoss was assessed by renal ven samplng for renn estmaton, the renn response to 2.5 mg of captoprl p.o. (whch produces an exaggerated reactve hyperrennema n patents wth marked stenoss 0 ), the chronc effects of nhbton on blood pressure, and when performed, the response to operaton. Patents were consdered n two groups. An ntal retrospectve analyss dentfed 32 patents treated wth captoprl for 3 or more days. Subsequently, addtonal patents were studed prospectvely. In these patents,renalfuncton was estmated before and to 6 weeks after the ntroducton of an orally admnstered nhbtor (captoprl n 6; enalaprl n 5). Total and splt renal functon was determned by computer analyss of 99 Tc-dethylenetramnepentaacetc acd (DTPA) scntllaton camera renograms. All studes were performed wth the patent sttng uprght wth back aganst the gamma camera (Toshba, 9CA40). A 30 MBq (0 mc) dose of "Tc-DTPA was njected nto the rght cubtal ven wth elevaton of the patent's arm just before cuff release. Acquston of data was n frame mode on a 64 X 64 matrx. Forty - second frames and ten 20-second frames were collected. Regons of nterest were drawn for the kdneys and aorta, and semlunarregonsof nterest for background subtracton were placed around the lower outer renal margns. Dfferental glomerular fltraton rates were computed from the uptake of ""Tc-DTPA by the kdneys between and 3 mnutes after arrval of the bolus n the kdneys, takng nto consderaton background subtracton and correcton for attenuaton caused by depth of the kdneys. The actual counts njected were calculated by subtractng postnjecton counts from prenjecton syrnge counts, and glomerular fltraton rate calculatons were made usng the method of Gates." Serum creatnne estmaton was by autoanalyzer (Techncon SMA260) method usng a modfed Jaffe reacton. Plasma renn concentraton and angotensn II were measured by radommunoassay as prevously descrbed. 2 Blood pressure measurements were made wth a Dynamap (Crtkon, Johnston and Johnston) automatc blood pressurerecorder.statstcal comparsons were by Student's t test, ether pared or unpared; ap level less than 0.05 was requred for sgnfcance. Group results are expressed as mean ± SEM. Results In the retrospectve study, 32 patents wth establshed renovascular hypertenson were treated wth captoprl for 3 or more days (range, 3 days to 56 months). Sx patents experenced acute deteroraton of renal functon (a twofold or greater rse n serum creatnne) that wasreversbleon cessaton of captoprl (Table ). No sgnfcant ncrease n serum creatnne concentraton was noted n the other 26 patents. The 32 patents were grouped accordng to the nature of ther renovascular dsease; 3 patents had unlateral renal artery stenoss; patents had blateral renal artery stenoss; and 8 patents had a sngle kdney (transplant or natve) wth renal artery stenoss. Acute renal falure (ARF) developed n three patents wth blateral renal artery stenoss and n three wth a sngle kdney wth renal artery stenoss. Serum creatnne level remaned stable n all patents wth unlateral renal artery stenoss patents. Patents who experenced ARF had hgher pretreatment serum creatnne levels (25 ± 45 /mol/l) than dd those whose creatnne dd not rse (53 ± 2 /mol/l; p<0.05). After the ntroducton of nhbtor therapy, blood pressure fell to a smlar degree whether or not ARF subsequently developed (n 24 patents wthout ARF mean blood pressure fell from 33 ± 4 to 4 ± 4 mm Hg and n 6 patents wth ARF, from 34 ± 6 to 6 ± 8 mm Hg; p>0.05). No sgnfcant dfference was detectable between plasma angotensn U changes n 8 patents wthout ARF (from 20. ±9.6 to TABLE. Acute Renal Falure n Captoprl-Treated Patents wth Renal Artery Stenoss: Recovery of Renal Functon Followng Wthdrawal of Captoprl Serum creatnne (/nmol/l) Patent 2 3 4* 5 6 Age (yr) Captoprl (mg/day) Treatment (day) Pretreatment Peak durng treatment Postteatment Recovery (day) 6 5 <0 2 In all sx patents n whom acute renaj falure developed, serum creatnne fell rapdly to pretreatment levels followng wthdrawal of captoprl. Rechallenge wth captoprl at successvely lower dosages.

3 652 HYPERTENSION VOL 8, No 8, AUGUST 986 Downloaded from by on January, ±2.9 pg/ml) and 4 patents wth ARF (from 24.6 ±6.4 to.8 ±3. pg/ml; p>0.05). Two patents llustrate aspects of ARF assocated wth nhbton. In one (Patent 4 n Table ), rechallenge wth captoprl on two successve occasons (each at a lower dosage) was assocated wth recurrent rses n plasma creatnne. Followng wthdrawal of captoprl, serum creatnne fell to pretreatment levels each tme. Fgure llustrates the course of a 29-yearold woman wth fbromuscular renal artery dsease. Intally, a marked stenoss was present on the left sde and blood pressure control was acheved wth captoprl and chlorothazde wthout a change n serum creatnne concentraton. Followng operaton, hypertenson was resolved, only to recur wth graft thromboss. Captoprl and chlorothazde controlled blood pressure agan wthout a rse n serum creatnne concentraton. Subsequent nephrectomy cured her hypertenson. Nne months later, she was seen wth severe hypertenson because marked fbromuscular dsease had developed n the remanng renal artery. On ths occason, captoprl produced an acute rse n serum creatnne concentraton. Followng wthdrawal of captoprl, serum creatnne concentraton returned to pretreatment levels. Subsequent reconstructve renovascular surgery cured her hypertenson. In the prospectve study, patents were grouped accordng to renal arterogram results as havng ether unlateral or blateral renal artery stenoss. Sx patents had unlateral renal artery stenoss. Serum creatnne concentraton and total Tc-DTPA clearance were unchanged followng the ntroducton of nhbtor therapy (Table 2). Splt renal functon results are shown n Fgure 2. The Tc-DTPA clearance n the kdneys wth stenoss fell from 25 ± 2 to 4 ± 6 ml/mn. The stenosed kdney was vrtually nonfunctonng n three patents, and no change n clearance was detectable durng nhbtor therapy. In the three patents wth functonng stenosed kdneys, however, sgnfcant falls n clearance occurred. In contrast, "Tc-DTPA clearance n the normal kdneys tended to rse: "Tc-DTPA clearance ncreased from 4 ± to 48 ± ml/mn, wth the most marked rses occurrng n patents n whom clearance n the stenosed kdney decreased. The net effect was to mantan total renal functon, wth the normal kdney compensatng for the functonal mparment of the stenosed kdney. Fve patents had blateral renal artery stenoss. Serum creatnne concentraton rose and total Tc- DPTA clearance fell durng nhbtor therapy n ths group of patents (see Table 2). Splt renal functon studes revealed a fall n "Tc-DTPA clearance n eght of the 0 kdneys studed; average left kdney clearance fell from 8 ± 6 to 5 ± 5 ml/mn, and rght kdney clearance fell from 22 ± 5 to 6 ± 4 ml/mn (Fgure 3). Combnng splt renal functon clearance results from both patent groups showed a fall n Tc-DTPA clearance n 3 of 6 stenosed kdneys after the ntroducton of nhbtor therapy (change n T c- DTPA clearance, -.5 ±2. ml/mn; n = 6; l/l 300- _2OOu f.00- u u OPl - " OP 2 -U.--J OP MONTHS 300 =! 2 FIGURE. Renovascular hypertenson treated wth captoprl on three occasons. Intally, serum creatnne level remaned stable when unlateral stenoss was present; however, acute renal falure developed when the sngle kdney became stenosed. See text for detals. OP. I = revascularzaton of left kdney; 0P.2 = left nephrectomy; OP.3 = revascularzaton of the rght kdney. p<0.0l). In comparson, there was a rse n clearance nfveof the sx nonstenosed kdneys from the unlateralrenalartery stenoss group (change n Tc-DTPA clearance, +8.2 ±4.6 ml/mn; n = 6; 0.>p>0.05). Cessaton of nhbtor therapy was followed by rapd return of serum creatnne concentraton to pretreatment levels n all patents n whom renal falure developed (see Table ). Two patents studed prospectvely wth Tc-DTPA clearance had nhbtor therapy dscontnued after 8 and 6 weeks of treatment, respectvely. In both patents, functon of the stenosed kdneys returned to pretreatment levels (Table 3). Dscusson Ths study shows that renal functon deterorated n a substantal number of patents when nhbtor therapy was used to treat hypertenson assocated wth renal artery stenoss. Sx patents experenced ARF, and n all of these patents the only functonal renal TABLE 2. Effects of Angotensn Convertng Enzyme Inhbton on Renal Functon n Sx Patents wth Unlateral Renal Artery Stenoss and Fve wth Blateral Renal Artery Stenoss Group Unlateral RAS Scrum creatnne ( tmol/l) Tc-DTPA clearance (ml/mn) Blateral RAS Serum creatnne (/tmol/l) Tc-DTPA clearance (ml/mn) Before nhbton 34± ±23 40±9 Durng nhbton 44±32 64±3 8 ±5* 2±5* Values are means ± SEM. = angotensn convertng enzyme; RAS = renal artery stenoss; DTPA = dethylenetramnepentaacetc acd. *p < 0.05, compared wth pretreatment values.

4 RENAL FUNCTION AND INHIBITORS IN RENAL ARTERY STENOSIS/acfcson et al. 653 Downloaded from by on January, 209 I IOO- E UJ STENOSED SPLIT FUNCTION NORMAL 4etr FIGURE 2. Unlateral renal artery stenoss. Splt renal functon studes usng clearance of" m Tc-dethylenetramnepentaacetc acd (DTPA) n the stenosed and normal kdney before and durng angotensn convertng enzyme () nhbtor therapy LEFT \»te g^ SPLIT ms FUNCTION RIOHT ttt* o.n^ 6 +4 ACC FIGURE 3. Blateral renal artery stenoss. Splt renal functon studes usng clearance of" m Tc-dethylenetramnepentaacetc acd (DTPA) before and durng angotensn convertng enzyme () nhbtor therapy. tssue was perfused through a stenosed renal artery. In contrast, patents wth unlateral renal artery stenoss dd not show a rse n plasma creatnne concentraton. The pathogeness of functonal renal mparment durng nhbton remans unclear. Our fndngs do not support acute hypotenson as a major contrbutng factor, as there was no dfference n the blood pressure fall between groups wth or wthout ARF. Interference wth glomerular dynamcs caused by reducton of ntrarenal angotensn II followng nhbton has been proposed as a mechansm of acute renal nsuffcency n these patents. 6 In our patents, smlar degrees of depresson of plasma angotensn II concentraton occurred n patents n whom renal falure developed and n those wth stable renal functon. Ths observaton does not exclude partcpaton of angotensn II n the pathogeness of the renal falure, as crculatng angotensn II levels may not be an accurate reflecton of the ntrarenal level. Experments by Anderson et al. 3M n dogs wth renal artery stenoss TABLE 3. Splt Renal Functon Before, Durng, and After Treatment wth Enalaprl or Captoprl "Tc-DTPA clearance (ml/mn) Treatment Enalaprl Arterogram results Before Durng After Kdney nhb- nhb- nhbsde tor tor tor Atheromatous blateral RAS Left Rght Captoprl Fbromuscular RAS Left The reducton n functon observed durng nhbton recovered to pretreatment levels followng nhbtor wthdrawal. See Table 2 for key to abbrevatons. support the role of angotensn II n mantanng renal hemodynamcs. In those experments, nhbton abolshed the renal autoregulaton that normally occurred after renal artery stenoss. Ths effect was largely corrected by an nfuson of angotensn II nto the stenosed renal artery. Smlar changes of renal functon have been shown n the two-kdney, one clp Goldblatt model of hypertenson n the rat. In ths model, glomerular fltraton was compromsed n the stenosed kdney followng nhbton, whereas the contralateral normal kdney showed a marked ncrease n glomerular fltraton rate. 5 ' 6 The present prospectve study usng "Tc-DTPA clearance as an ndex of glomerular fltraton has confrmed that ths stuaton also prevals n humans. In patents wth unlateral renal artery dsease, ""Tc- DTPA clearance was suppressed n the kdney wth renal artery stenoss followng nhbtor therapy and ncreased n the normal kdney. The net effect n these patents was a preservaton of total renal functon; serum creatnne concentraton remaned unchanged despte marked reducton n functon of the stenosed kdney. In contrast, patents wth blateral renal arteral dsease showed a reducton n total renal functon, reflected by a fall n ""Tc-DTPA clearance and arsen serum creatnne concentraton. Followng the ntroducton of nhbtor therapy n these patents, serum creatnne concentraton rose to a hgher level and subsequently remaned stable. That all patents wth blateral renal artery stenoss dd not experence ARF may have been due to the varable degree of stenoss of the renal vessel. In patents wth more severe renal artery stenoss, angotensn II-nduced efferent arterolar vasoconstrcton may be the only mechansm for mantanng glomerular fltraton, whereas wth lesser degrees of arteral stenoss, addtonal mechansms may compensate for the reduced angotensn II durng nhbton and result n preservaton of fltraton, albet at a reduced level. The nhbton n the patents studed prospectvely was nduced wth ether captoprl or enalaprl. Although t s possble that these agents have dfferng renal toxcology, we attrbute the effects on renal func-

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