ace inhibitors in renal disease · proteinuria was achieved with ace inhibitors,22 23 although...

Br Heart J (Supplement) 1994; 72: 46-51

ACE inhibitors in non-diabetic renal disease

Richard J Fluck, Anthony E G Raine

The advent of angiotensin converting enzyme(ACE) inhibitors has provided not only a newtreatment for hypertension but also a specifictreatment for hypertension in renal disease,which carries the promise of lessening theprogression of renal disease and the risk ofadditional side effects. In this review we aim tocover the evidence for a role for ACEinhibition in the slowing or halting ofprogression of chronic renal disease, togetherwith the possible consequences of the use ofthese drugs in patients with renovascular hyper-tension and other forms of renal disease.

Progression of renal diseaseDespite the advent of effective renal replace-ment therapy, mortality and morbidity remainhigh in patients undergoing dialysis. Effectivetreatment to slow or halt the progression ofrenal failure in patients with mild to moderatechronic uraemia is of prime importance. Suchtreatment would delay the onset of renalreplacement therapy, thereby reducing theincidence of associated complications and thelimitations it places on the quality of life.Currently, apart from specific treatments forparticular renal diseases, efforts to slow theprogression of renal failure have focused ontwo factors: the control of hypertension anddietary protein restriction. Recent data havesuggested that progression of renal disease inhumans is not significantly improved byprotein restriction, hence, the control ofhypertension remains the mainstay of con-servative measures.' Evidence is now accumu-lating that there may be a specific additionalrole for ACE inhibitors in the treatment ofrenal disease.

Department ofNephrology, StBartholomew'sHospital, LondonR J FluckA E G RaineCorrespondence to:Professor A E G Raine,Department of Nephrology,St Bartholomew's Hospital,London EClA 7BE.

Hypertension in renal diseaseAll forms of renal disease are associated withhypertension.2 The prevalence of hypertensionrises as renal disease progresses, and most(90%) patients are hypertensive at the time ofend stage renal failure. This high rate ofdevelopment of high blood pressure partlycontributes to the excess mortality in thisgroup of patients,3 in particular cardiovasculardisease, which accounts for 50% of deaths inpatients with end stage renal failure.4Not only is the incidence of hypertension

increased by chronic renal failure buthypertension itself may worsen uraemia andaccelerate the progression of the disease. It isthe breaking of this reciprocal relation byeffective antihypertensive treatment that mayslow or halt progression towards end stagerenal failure.

Theories of progression of renal diseaseWidely held theories to account for themechanism of progression of renal diseasehave emphasised the importance of glom-erular capillary hypertension.5 In essentialhypertension effective autoregulation of theafferent arteriolar resistance seems to protectthe glomerulus from the effects of systemichypertension, but in chronic renal disease thisautoregulatory mechanism fails. As a con-sequence, progressive glomerular injury isaggravated by increased glomerular capillarypressure, culminating in glomerular sclerosis.6Other theories explaining progressive hyper-tensive glomerular injury have focused onglomerular hypertrophy. These are based onexperiments in animals showing a significantcorrelation between glomerular size and thedegree of glomerular sclerosis.7 Thesefindings suggest that glomerular hypertrophyis an adaptive response, compensating for thereduction in renal mass, but which itself insome way predisposes to progressive glomer-ular injury-that is, the process becomesmaladaptive.These other mechanisms provide at least

two possible targets that may be used inattempts to slow the progression of renaldisease. Firstly, as the intrarenal vasocon-strictor action of angiotensin II is primarily onthe efferent arteriole, ACE may reduceglomerular hypertension by preferential vaso-dilatation of the efferent arteriole, therebyreducing glomerular pressure. Secondly,angiotensin II may act as a growth factorwithin the glomerulus, and successful use ofACE inhibition may thereby reduce glomer-ular hypertrophy.As hypertension itself is a major promoter of

declining renal function, however, it is logicalin the first place to attempt to reduce or haltthis progression by effective control of bloodpressure.

Evidence for role of hypertension in theprogression of renal diseaseA retrospective study of 198 patients startinglong term dialysis suggested that poor controlof diastolic blood pressure was associated withan increased rate of decline in renal function.8A controlled study of 79 Afro-Caribbeanpatients with moderate to severe chronic renalimpairment who were not yet receiving dialysisshowed that tight control of diastolic bloodpressure could halt the progression of renaldisease. In this three year study glomerularfiltration rate increased slightly in response totreatment.9 A more detailed small scale studyof 18 patients suggested that controlling the

S 46

on July 21, 2021 by guest. Protected by copyright.

http://heart.bmj.com

/B

r Heart J: first published as 10.1136/hrt.72.3_S

uppl.S46 on 1 S

eptember 1994. D

ownloaded from

http://heart.bmj.com/


diastolic blood pressure at less than 84 mm Hgwas beneficial in slowing the progression ofrenal disease, but further lowering bloodpressure below 80 mm Hg did not confer anyadditional benefit.'0These and many other studies provide good

evidence that control of blood pressure is notonly beneficial but mandatory in the treatmentof chronic renal impairment. Do ACEinhibitors confer additional benefit aboveantihypertensive treatments?

Specific role for ACE inhibitors inchronic renal failure?ROLE OF ANGIOTENSIN IIIn addition to the efferent arteriolar vaso-constriction caused by angiotensin II, there isevidence that it acts as a growth factor in bothglomerular and tubulointerstitial tissue, assummarised in table 1." Given these cellulareffects of angiotensin II and their possibledetrimental consequences for progressive renalimpairment, ACE inhibitors might provideadditional benefit over and above theirantihypertensive action. In studies using the5/6 nephrectomy experimental model ofchronic renal failure, ACE inhibitors loweredglomerular pressure and decreased glomerularsclerosis to a greater degree than comparableantihypertensive treatment with reserpine,hydralazine, and hydrochlorthiazide.'2 Aretrospective uncontrolled study in humanshas suggested that ACE inhibition also slowedthe progression of clinical renal failure.'3Few studies, however, have compared

different antihypertensive treatments directlyin human renal disease. Glomerular haemo-dynamics have been studied in normotensivesubjects subjected to treatment with eithernifedipine or captopril.1' The ACE inhibitorreduced the extent of amino acid inducedglomerular hyperfiltration, in contrast tonifedipine, which induced hyperfiltration atrest and allowed maximal hyperfiltration tooccur when the amino acid infusion wasadministered. This is interesting as calciumchannel blockers have a preferential vaso-dilator action on the afferent arteriole. Thismay lead to glomerular hypertension, despitelowering of systemic blood pressure, byimpairing glomerular autoregulation. Inkeeping with these hypotheses, studies inwhich treatment was started some weeks aftersubtotal nephrectomy in rats showed thattreatment with calcium antagonists wasassociated with reduced nephron survival andprogressive glomerular sclerosis-in contrastto ACE inhibition, which was protective.'5

Table 1 In vitro effects of angiotensin II on mesangial and proximal tubular cells"

Phenotype Mesangial cells Tubular cells

Growth effect Proliferation HypertrophyAngiotensin II receptor type AT, AT, and AT2Signal transduction pathway IP3/DAG/Ca'+ Intracellular cyclic AMPOncogene activation Yes YesCollagen synthesis Preferentially type I Preferentially type IVExistence of genes inducedby angiotensin II Unknown Yes

IP3, inositol 1,4,5-triphosphate; DAG, diacylglycerol; Ca2', intracellular calcium.

PROTEINURIA-SURROGATE MARKER FOR

PROGRESSION?

Proteinuria may be a marker for bothglomerular hypertension and hyperfiltrationand, as a consequence, treatments that reduceproteinuria may be beneficial in renal failure.'6Long term administration of angiotensin IImay increase proteinuria in normal rats."' Alarge study in animals compared the calciumchannel blocker verapamil with enalapril'5; itshowed that proteinuria increased in responseto calcium antagonism, and this was associatedwith a high percentage of glomerular sclerosis.This occurred despite equivalent bloodpressure control with verapamil and enalapril;in the group given enalapril proteinuria andglomerulosclerosis were reduced.

Protein excretion is also increased in reno-vascular disease, a high renin state.'8 Morerecently, ACE inhibitors have reducedproteinuria in rats with induced chronicuraemia,'9 and there have been comparablestudies in patients with moderate uraemia dueto a variety of renal diseases.20 Fractionalurinary albumin excretion was significantlyreduced in patients with mild, moderate, andsevere albuminuria, but without a significantchange in serum creatinine concentrations.Both enalapril and captopril are effective inreducing proteinuria in hypertensive patientswith renal disease.2' 22 In some studiescomparing ACE inhibitors with calciumchannel blockers a greater reduction inproteinuria was achieved with ACEinhibitors,22 23 although recent prospectivestudies have failed to confirm this.24 Inaddition, in none of these studies was adifference in rate of progression detected inthe different treatment groups.

In summary, there is no doubt that ACEinhibitors are effective in reducing proteinuria.However, it remains unproved whetherreduction in proteinuria and the impliedbeneficial effect on glomerular haemo-dynamics will lead to a more favourable renaloutcome in the long term.

BLOOD PRESSURE INDEPENDENT EFFECTS OF

ACE INHIBITORS

It remains a matter of controversy whether thebeneficial actions of ACE inhibitors relatesolely to their antihypertensive properties orwhether additional mechanisms independentof blood pressure control also contribute.Ikeda et al and Bianchi et al found that bloodpressure control in the different treatmentgroups was equivalent.22 23 However, smalldifferences, or an unmeasured change in theprofile of blood pressure control over 24 hours,may well result in significant changes in renaloutcome. The possibility that ACE inhibitorsmay have an additional beneficial effectthrough reducing the effect of angiotensin II asa growth factor is of current interest. Actionsof ACE inhibitors independent of those onblood pressure may potentially be investigatedthrough their use in normotensive patientswith renal disease, with subsequent assess-ment of their effects on progression of renaldisease and on proteinuria. Such studies will

S 47



/B


uppl.S46 on 1 S

eptember 1994. D

ownloaded from


Fluck, Raine

require long follow up times and largenumbers of patients; no data are yetavailable.A small study of ACE inhibition in 14

patients with chronic renal failure and pro-teinuria greater than 1 g/day included fivenormotensive subjects.25 Overall, creatinineclearance and urine protein excretion bothimproved during a 30 month follow up period,though no comparisons were made betweennormotensive and hypertensive subjects. In acrossover study subjects given conventionaltriple drug treatment were given captopril for12 months.26 This small study of 10 patientssuggested that the ACE inhibitor halted thedecline of renal failure with no change incontrol of blood pressure. Of interest in thisstudy was the fact that blood pressure controlwas identical and urinary protein excretion didnot improve during the 12 months of captopriltreatment. Despite this, the progression ofrenal disease, as assessed by reciprocal plots ofcreatinine concentration, was retarded. A criti-cism of this study, as of many others, is thatrenal function was poorly assessed, with failureto use definitive methods such as isotopicassessment of glomerular filtration rate.

SummaryIn non-diabetic chronic renal failure there is atpresent incomplete evidence that ACEinhibitors have an additional benefit in theslowing of progressive renal disease over andabove their antihypertensive properties. Intheory, their beneficial action might resultboth from decreased glomerular hypertension,through selective dilatation of the afferentarteriole, and from blocking the actions ofangiotensin II as a growth factor in both theglomerulus and the interstitium. The evidenceis, however, flawed, incomplete, and in manycases circumstantial. Long term placebocontrolled crossover studies are still requiredto answer these questions.

ACE inhibition in renovascular diseaseThe widespread use of ACE inhibitors inclinical practice requires an awareness of theirside effects, particularly those related tounderlying renal disease. The main area ofconcern is the use of these drugs in occult orovert renovascular disorders. This awarenessmust encompass not only renal physicians butall physicians who prescribe ACE inhibitors.The dilemma arises because ACE inhibitorsare very effective in reducing blood pressure inpatients with renovascular hypertension, mostof whom have an activated renin-angiotensinsystem. However, the possible long termadverse effects of ACE inhibitors on renalfunction in unilateral stenosis of the kidney areworrying; they may precipitate severe renalimpairment in bilateral renovascular disease.

Incidence of renovascular diseaseThe incidence of renovascular disease isdifficult to ascertain as the condition is largely

painless and asymptomatic. If only one kidneyis stenosed, there will be no warning change inthe indicators of renal function measuredroutinely. For these reasons, a high index ofsuspicion must be maintained in patients atrisk.The proportion of patients with end stage

renal failure who have renovascular disease asthe primary diagnosis ranges from 8% to140/o.27 28 This incidence increases with age attime of presentation. Renovascular diseasemay be a relevant factor in up to 16% ofpatients with acute presentation of renalfailure.29 Mailloux et al reported that the prog-nosis in patients with end stage renal failuredue to renovascular disease was worse thanthat in patients with diabetic nephropathy.30The comparatively high rate of renovascular

disease in patients with known renal diseasegives no information about its incidence in thegeneral population. Nevertheless, data fromgeneral angiography indicate that renovasculardisease is common. Patients investigated forperipheral vascular disease with angiographyhad significant renal artery stenosis in 42% ofcases,3' and 19% of 1303 patients undergoingcardiac catheterisation had renal arterystenosis.32 The predictors for renal arterystenosis included increased age, the presenceof peripheral vascular disease, raised serumcreatinine concentrations, smoking, andfemale sex (table 2). Another study found thathalf of the 450 patients undergoingangiography for peripheral vascular diseasehad an occlusion of a renal artery."3 It is ofnote that a fifth of these were in factnormotensive at the time of study.ACE inhibitors may acutely impair renal

function in patients with renal artery stenosis,and this was first described in a renaltransplant recipient over 10 years ago.34 Inpatients with hypertension due to renovasculardisease plasma renin concentration is usuallyhigh. Treatment with an ACE inhibitorgenerally produces a gratifying fall in bloodpressure, but this may be accompanied by therisk of an appreciable deterioration in renalfunction. This risk arises particularly inpatients with a single functioning kidney orwith bilateral renal artery stenosis.

MECHANISM

The mechanism of acute renal failureaccompanying the use of ACE inhibitors inrenovascular disease is still imperfectly under-stood. The generally accepted explanation isthat arterial stenosis results in impairedperfusion of the afferent arteriolar circulation.The increased renin secretion this inducescauses a compensatory efferent arteriolarvasoconstriction, which maintains glomerularhydraulic pressure and thus maintains anormal glomerular filtration rate.36 When anACE inhibitor is administered the renin-angio-tensin cascade is inhibited, with a decrease inangiotensin II concentration and therefore aloss of the efferent arteriolar compensatoryvasoconstriction. This leads to a reduction inglomerular capillary pressure, and glomerularfiltration and acute renal failure may result.

Table 2 Risk factors forrenal artery stenosis32

Risk factor

Old agePeripheral vascular diseaseCongestive cardiac failureRaised serum creatinineHistory of smokingFemale sex

S 48



/B


uppl.S46 on 1 S

eptember 1994. D

ownloaded from



Cases of acute renal failure are oftenmultifactorial, and renal failure associatedwith ACE inhibitors in renovascular disease isno exception. Cases may be exacerbated inpatients who are given non-steroidal anti-inflammatory drugs at the same time,37 whoare salt depleted, particularly when receivingloop diuretics,38 or who have other underlyingrenal parenchymal disease. Hence a con-

tinuing awareness of patients at risk, especiallythose with volume depletion, diabetesmellitus, or underlying chronic renal disease,is required.

CLINICAL COURSE

In general, acute renal failure secondary to theuse of ACE inhibitors in renovascular diseaseshould be reversible, but this is not always thecase. Firstly, the condition must be recognisedearly enough to allow the treatment to bewithdrawn in time. Secondly, blood pressure

and circulatory volume should be restored tominimise the risk of long term renal ischaemicdamage or thrombosis.Acute renal failure due to ACE inhibitors in

renovascular disease is symptomless, clinicalsequelae often becoming apparent only whenthe patient has established acute renal failure.Therefore it is recommended that patients atrisk have their renal function assessed beforetreatment is started and within 2-5 days afterthe first dose. In addition, the starting doseshould be at the lower end of therecommended range for any given ACEinhibitor.

Acute renal failure in non-renovascularconditionsIn addition to concern over ACE inhibitors inrenovascular disease, acute renal failureassociated with their use in other renaldisorders is not unknown. The use of enalaprilhas been associated with reversible renalfailure in hypertensive nephrosclerosis inwhich the main additional risk factor was a

local heat wave, perhaps associated withvolume depletion.39 All cases were reversibleand were successfully managed by dosereduction or withdrawal of the ACE inhibitor.A series of five patients with autosomal domi-nant polycystic kidney disease were reportedto have suffered acute renal failure associatedwith the use of ACE inhibitors.40 Again, therewere other precipitating factors, includingintravascular volume depletion secondary todiuretic treatment in at least two cases. In twoof the patients studied acute renal failureoccurred again after rechallenge with the ACEinhibitor. These patients were extensivelyinvestigated and no evidence of renal arterystenosis was found.

Use ofACE inhibitors in renaltransplantationHypertension is a common accompaniment ofcadaveric renal transplantation, and its inci-dence and prevalence have increased with theintroduction of cyclosporin.4' Consequently,

patients receiving renal transplants areincreasingly exposed to the use of ACEinhibitors for the treatment of hypertension. Insuch patients who have one functioning kidneythe incidence of renal artery stenosis issignificant.42 There is no doubt that the use ofACE inhibitors should be discouraged in theearly stages of renal transplantation, whilerenal function is being established. Treatmentwith ACE inhibitors for resistant hypertensionfollowing transplantation should be precededby investigation for occult renal arterystenosis, particularly as this may be the causeof the hypertension.

In view of the potential benefit of ACEinhibitors in progressive renal disease, it isnatural to speculate whether these drugs mayhave a beneficial action in slowing or prevent-ing the decline in renal function that resultsfrom long term graft rejection. As yet there areno long term placebo controlled trials avail-able to assess this question, but several studieshave assessed proteinuria in renal transplantrecipients. Use of lisinopril in a group of12 hypertensive recipients with proteinuriabut no evidence of renal artery stenosis re-sulted in a decrease in proteinuria from2-98 (SD 2.06) g/24 h to 2.06 (2.9) g/24 h.43A control group of patients with comparableblood pressure control but who were nottaking ACE inhibitors did not show anychanges in the degree of proteinuria. Thestudy lasted only three months and glomerularfiltration rate remained unchanged, but theshort term nature of the study allows no con-clusions about the progression of renal dys-function.

ACE inhibitors in end stage renal failureThe pharmacokinetics of ACE inhibitors inrenal failure have been extensively reviewed.44The absorption of ACE inhibitors is generallyunchanged in renal disease, but after meta-bolism in the liver most active compounds areexcreted by the kidney. As a consequence,recommended maximal doses of these drugsare reduced in patients with renal failure, withthe exception of fosinopril, whose clearance isprimarily hepatic. In maintenance haemo-dialysis most ACE inhibitors, includingcaptopril, enalapril, and lisinopril, have highclearances. By contrast, quinapril, which hashigh plasma protein binding, has an extremelylow clearance of 0-6 ml/min.A recent problem reported with ACE

inhibitor treatment in patients receivinghaemodialysis is the development of ana-phylactic reactions associated with the use ofAN69 polyacrylnitrile high flux dialysers. Themechanism is largely unknown, but it may bea result of an increase in bradykinin synthesisinduced by an interaction of blood and bloodcompounds with the polymer and a con-comitant blockade of bradykinin metabolismbecause of inhibition of kininase by the ACEinhibitor.45 The current recommendation isthat ACE inhibitors should not be used inassociation with these particular high fluxdialysers.

S 49



/B


uppl.S46 on 1 S

eptember 1994. D

ownloaded from


Fluck, Raine

In patients receiving continuous ambulatoryperitoneal dialysis the pharmacokinetic dataon ACE inhibitors are few. Quinaprilexcretion in the peritoneal dialysate seems tobe negligible compared with that of captopril,where a single dose led to the detection ofcaptopril in the dialysate.44

ACE inhibitors as a diagnostic toolThe use of captopril renography has enjoyedrecent popularity. In essence, the techniqueentails isotopic renal scanning before and aftera single dose of captopril (25 mg orally).46 47

After the administration of captopril theexpectation is a delay in tracer handling on theside of the renal artery stenosis. Other datasuggest that the specificity and sensitivity ofthis test for the absolute diagnosis ofrenovascular disease are poor, but that theresults are a better predictor of successfuloutcome of revascularisation or angioplasty.48

SummaryIn non-diabetic renal disease ACE inhibitorshave brought both benefit and problems. Onthe one hand, they are undoubtedly effectiveantihypertensive agents and data suggest thatthey may have a beneficial role in theprevention of progression of renal disease,although further placebo controlled doubleblind trials of adequate duration are required.On the other hand, their widespread use inelderly patients and those with generalisedatherosclerosis has increased the risk of acuterenal failure when occult renovascular diseaseis present. Awareness among physicians of thehigh rate of renovascular disease in popula-tions at risk is to be encouraged.

1 Levey AS, Bosch JP, Coggins CH, et al. Effects of diet andblood pressure on creatinine clearance (CCR) and serumcreatinine (PCR) in the MDRD study (abstract). J7ournalof the American Society of Nephrology 1993;4:253.

2 Brown MA, Whitworth JA. Hypertension in human renaldisease. 7 Hypertens 1992;10:701-12.

3 Ma KW, Greene EL, Raij L. Cardiovascular risk factors inchronic renal failure and hemodialysis populations. AmKidney Dis 1992;6:505-13.

4 Raine AEG, Margreiter R, Brunner FP, et al. Report on themanagement of renal failure in Europe. XXII 1991.Nephrol Dial Transplant 1992;7(suppl 2):7-35.

5 Brenner BM, Meyer TW, Hostetter TH. Dietary proteinintake and the progressive nature of kidney disease: therole of hemodynamically mediated glomerular injury inthe pathogenesis of progressive glomerular sclerosis inaging, renal ablation, and intrinsic renal disease. N EnglMed 1982;307:652-9.

6 Tolins JP, Raij. Antihypertensive therapy and the pro-gression of chronic renal disease. Are there reno-

protective drugs? Semin Nephrol 1991;11:538-48.7 Yoshida Y, Fogo A, Sharaga H, et al. Serial micropuncture

analysis of single nephron function in the rat model ofsubtotal renal ablation. Kidney Int 1988;33:855-67.

8 Brazy PC, Stead W, Fitzwilliam JF. Progression of renalinsufficiency: role of blood pressure. Kidney Int1989;35:670-4.

9 Pettinger WA, Lee HC, Reisch J, Mitchell HC. Long-termimprovement in renal function after short-term bloodpressure control in hypertensive nephrosclerosis.Hypertension 1989;13:766-72.

10 Wight JP, Brown CB, El Nahas AM. Effect of control of

hypertension on progressive renal failure. Clin Nephrol1993;39:305-1 1.

11 Wolf G, Neilson EG. Angiotensin II as a renal growthfactor. J7ournal of the American Society of Nephrology1993;3: 1531-40.

12 Anderson S, Rennke HG, Brenner BM. Therapeuticadvantages of converting enzyme inhibitors in arrestingprogressive renal disease associated with hypertension.Clin Invest 1986;77:1993-2000.

13 Mann JFE, Reisch C, Ritz E. Use of angiotensin-convertingenzyme inhibitors for the preservation of kidney function.A retrospective study. Nephron 1990;55(suppl 1):38-42.

14 Bohler J, Woitas R, Keller E, Reetze-Bonorden P,Schollmeyer PJ. Effect of nifedipine and captopril onglomerular hyperfiltration in normotensive man. Am JKidney 1992;20: 132-9.

15 Brunner FP, Thiel G, Hermle M, Bock A, Mihatsch MJ.Long-term enalapril and verapamil in rats with reducedrenal mass. Kidney Int 1989;36:969-77.

16 Glassock RJ. Focus on proteinuria. Am J Nephrol1990;10(suppl 1):88-93.

17 Bohrer MP, Deen WM, Robertson CR, et al. Mechanismof angiotensin II induced proteinuria in the rat. Am JPhysiol 1977;233:F13-21.

18 Pasternack A, Eklund J, Krohn K. Renal artery stenosis andthe nephrotic syndrome. Acta Med Scand 1967;181:265-8.

19 Anderson S, Meyer TW, Rennke HG, Brenner BM.Control of glomerular hypertension limits glomerularinjury in rats with reduced renal mass. J Clin Invest1985;76:612-9.

20 Kurkus J, Thysell H. Reduction of albuminuria afterangiotensin converting enzyme inhibition of various renaldisorders. Scandj Urol Nephrol 1990;24:63-8.

21 Grazi G, Cirami C, Panichi V, et al. Renal effects ofenalapril in hypertensive patients with glomerulone-phritis. Nephrol Dial Transplant 1989;4:396-8.

22 Ikeda T, Nakayama D, Gomi T, Sakurai T, Yamazaki T,Yuhara M. Captopril, an angiotensin I-convertingenzyme inhibitor, decreases proteinuria in hypertensivepatients with renal diseases. Nephron 1989;52:72-5.

23 Bianchi S, Bigazzi R, Baldari G, Campese VM. Long-termeffects of enalapril and nicardipine on urinary albuminexcretion in patients with chronic renal insufficiency: a 1year follow-up. AmJ Nephrol 1991;11:131-7.

24 Zucchelli P, Zuccala A, Borghi M, et al. Long termcomparison between captopril and nifedipine in theprogression of renal insufficiency. Kidney Int 1992;42:452-8.

25 Ferder LF, Inserra F, Daccordi H, Romano L, FernandezA, Tessler J. Effects of enalapril on renal parameters inpatients with primary glomerulopathies associated withchronic renal failure. Drugs 1990;30(suppl 2):40-6.

26 Ruilope LM, Miranda B, Morales JM, Rodico JL, RomeraJC, Raij L. Converting enzyme inhibition in chronic renalfailure. AmJ Kidney Dis 1989;13:120-6.

27 Broyer M, Donckerwolcke RA, Brunner FP, et al.Combined report on regular dialysis and transplantationin Europe. Proceedings of the European Dialysis andTransplant Association 1983;20:2-75.

28 Scoble JE, Maher ER, Hamilton G, Dick R, Sweny P,Moorhead JF. Atherosclerotic renovascular diseasecausing renal impairment-a case for treatment. ClinNephrol 1989;31:119-22.

29 Kalra PA, Mamtora H, Holmes AM, Waldek S.Renovascular disease and complications of angiotensinconverting enzyme inhibitor therapy. Q J Med1990;77:1013-8.

30 Mailloux LU, Belluci AG, Mossey RT, et al. Predictors ofsurvival in patients undergoing dialysis. Am J Med1988;84:855-62.

31 Choudri AH, Cleland JGF, Rowlands PC, Tran TL,McCarthy M, Al-Kutoubi MA. Unsuspected renal arterystenosis in peripheral vascular disease. BMJ1990;301:1197-8.

32 Harding MB, Smith LR, Himmelstein SI, et al. Renalartery stenosis: prevalence and associated risk factors inpatients undergoing routine cardiac catheterization.3rournal of the American Society of Nephrology 1992;2:1608-16.

33 Swartbol P, Thorvinger BO, Parsson H, Norgen L. Renalartery stenosis in patients with peripheral vascular diseaseand its correlation with hypertension. A retrospectivestudy. IntAngiology 1992;11:195-9.

34 Farrow PR, Wilkinson R. Reversible renal failure duringtreatment with captopril. BM3 1979;i:1680.

35 Miyamori J, Yasuhara S, Takeda Y, et al. Effects ofconverting enzyme inhibition on split renal function inrenovascular hypertension. Hypertension 1986;8:415-21.

36 Hricik DE, Brown PJ, Kopelman R, Goomo WE, MadiasNE, Dzau VJ. Captopril induced functional renalinsufficiency in patients with bilateral renal arterystenoses or renal artery stenosis in a single kidney. N EnglJ Med 1983;308:373-6.

37 Seelig CB, Maloley PA, Campbell JR. Nephrotoxicityassociated with concomitant ACE inhibitor and NSAIDtherapy. South MedJ 1990;83:1144-8.

38 Lee H-C, Pettinger WA. Diuretics potentiate theangiotensin converting enzyme inhibitor associated acuterenal dysfunction. Clin Nephrol 1992;38:236-7.

39 Toto RD, Mitchell HC, Lee H-C, Milam C, Pettinger WA.Reversible renal insufficiency due to angiotensin con-verting enzyme inhibitors in hypertensive nephro-sclerosis. Ann Intern Med1991M115.513-9.

40 Chapman AB, Gabow PA, Schrier RW. Reversible renalfailure associated with angiotensin converting enzymeinhibitors in polycystic kidney disease. Ann Intern Med1991;115:769-73.

41 Luke RG. Hypertension in renal transplant recipients.Kidney Int 1987;31:1024-37.

42 Curtis JJ, Luke RG, Whelchel JD, Diethelm AG, Jones P,Dustan HP. Inhibition of angiotensin converting enzymein renal transplant recipients with hypertension. N Engl_r Med 1983;308:377-81.

S 50



/B


uppl.S46 on 1 S

eptember 1994. D

ownloaded from



43 Traindl 0, Falger 8, Reading 8, et aL. The effects of

lisinopril on renal function in proteinuric renal transplantrecipients. Transplantation 1993;55: 1309-13.

44 Hoyer J, Schulte K-L, Lenz T. Clinical pharmacokinetics of

angiotensin converting enzyme (ACE) inhibitors in renalfailure. Clin Pharmacokinet 1993;24:230-54.

45 Tielemans C, Madhoun P, L-enaers M, et aL. Anaphylactoidreactions during hemodialysis on AN69 membranes inpatients receiving ACE inhibitors. Kidney Int 1990;38:982-4.

46 Nally JV Jr. Renal physiology of renal artery stenosis.Implications for captopril stimulated renography. AmHypertens 1991 ;4:669-74S.

47 de Zeeuv WD, Jonker GJ, Hovinga TK, et al. Themechanism and diagnostic value of angiotensin Iconverting enzyme inhibition renography. Ain Jf Hypertens1991;4:741-4S.

48 Fommei E, Mezzasalma L, Ghione S, et al. Europeancaptopril radionuclide test multicenter study. Preliminaryresults. Am Hypertens 199 1;4:690-7S.

S 51



/B


uppl.S46 on 1 S

eptember 1994. D

ownloaded from


ace inhibitors in renal disease · proteinuria was achieved with ace inhibitors,22 23 although...

Documents