Br Heart (Supplement) 1994; 72: 38-45

Renoprotective role of ACE inhibitors in diabeticnephropathy

Carl Erik Mogensen

Medical DepartmentM, Endocrinology andDiabetes, AarhusKommunehospital,University Hospital ofAarhus, Aarhus,DenmarkC E MogensenCorrespondence to:Dr C E Mogensen,Medical Department M,Endocrinology and Diabetes,Aarhus Kommunehospital,University Hospital ofAarhus, DK-8000 Aarhus C,Denmark.

Patients with diabetes mellitus and overtproteinuria have a poor prognosis.' Recentstudies show that appreciable proteinuria isassociated with a much more rapid progres-

sion of disease than is moderate albuminuria.2Progression is also closely associated withraised blood pressure, but appreciablealbuminuria in itself seems to be an importantprognostic indicator.

Before clinical proteinuria occurs (macro-albuminuria) patients always go through a

stage of microalbuminuria, often lasting 10years. Diabetic renal disease develops in stages,especially in patients with insulin dependentdiabetes.3-5 Classification according to thedegree of albuminuria is important becausepatients with perfectly normal albuminexcretion rates usually have a good long termprognosis, although some (about 4% per year)of them will progress from normoalbuminuriato microalbuminuria.6 On the other hand,patients with persistent microalbuminuria have(without intervention) a much poorer

prognosis, with a much higher risk of pro-

gression to overt renal disease over thefollowing decade.3 According to new morpho-metric studies, this is not surprising becausemicroalbuminuria indicates that patients are ina more advanced stage of glomerular disease.7

In this paper I will review data on inter-vention with ACE inhibitors throughout thecourse of diabetes. Editorials in three majorjournals recently discussed this importantissue.8'0 Table 1 shows an outline of thestages of diabetic renal involvement anddisease in patients with insulin dependentdiabetes from the time of diagnosis of

diabetes. Poor glycaemic control is an

important factor determining transition tomicroalbuminuria and probably progression ofthe microalbuminuric state,6 1" 2 but meta-bolic control is difficult in these patients.

Occurrence of raised blood pressure inrenal diabetic disease

INSULIN DEPENDENT DIABETES MELLITUS

The prevalence of hypertension in patientswith insulin dependent diabetes defined ac-

cording to the World Health Organisation'sclassification, and including patients receivingtreatment, is similar in patients with normo-

albuminuria and the general population.'3 Theprevalence of hypertension increases sharply inpatients with microalbuminuria, and mostpatients with overt proteinuria have classichypertension. Soon after the occurrence ofmicroalbuminuria, blood pressure may increaseby about 4 mm Hg per year.6 Therefore themain group of patients with insulin dependentdiabetes that are given antihypertensive treat-ment are those with microalbuminuria or overtrenal disease. On the other hand, some patientswith insulin dependent diabetes may haveraised blood pressure before microalbumin-uria-that is, coincidental essential hyper-tension. Also, it is important to note thatsome patients with normoalbuminuria willdevelop microalbuminuria. This is part of thenatural course of the disease because during thefirst few years of diabetes most patients aftermetabolic stabilisation will have normo-

albuminuria. Renal damage clearly increasesthe longer the duration of diabetes.

Table 1 Stages of renal disease* in patients with insulin dependent diabetes

Stage Designation Main characteristics Main structural Glomerular Urinary albumin Blood pressure Commentschanges filtration rate excretion

(mllmin)I (at diag- Hyperfunction/ Glomerular Glomerular 150 May be increased Normal Glomerular

nosis) hypertrophyt hyperfiltration hypertrophy volume/pressureincrease (reversible)

II Normoalbuminuria Normal urinary Increasing basal Hyperfiltrationt Normal (high Normal Changes as indicatedalbumin excretion membrane during stress) above but quite

thickness variable

Transition Transition phase High normal urinary Not known Hyperfiltration Increasing Increasing Somewhat poorfrom albumin excretion metabolic controlII - III

III Incipient diabetic Raised urinary Urinary albumin Still high 20 - 200 ,g/min Raised compared Advancing glomerularnephropathy, albumin excretion excretion correlated with stage II lesions;microalbuminuria to structural permeability defect

damage not locatedIV Overt diabetic Clinical proteinuria Advanced structural "Normal" to > 200 ( 10 000 Often frank High rate of

nephropathy or urinary albumin damage advanced ,ug/min) hypertension glomerular closure;excretion > 200 reduction increase by severe mesangial,ug/mm 5% yearly expansion

V End stage renal Uraemia General glomerular Very low Decreasing Often high, Death/uraemiadisease closure albuminuria related to (postponed by ACE

volume inhibition)expansion

*Applied when blood pressure remains untreated. Reducing blood pressure often reduces albuminuria (proteinuria microalbuminuria normoalbuminuria).tChanges present probably in all states when control imperfect.tMarker of future nephropathy.

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NON-INSULIN DEPENDENT DIABETES MELLITUS

The situation in patients with typical non-insulin dependent (type 2) diabetes is some-what different.'4 Many of these patients havehypertension when diabetes is diagnosed, andthey may have renal complications when theyare first seen. According to a recent survey ingeneral practice in Denmark, more than 30%of patients with newly diagnosed diabetes hadmicroalbuminuria and about 6% clinical pro-teinuria, with a male preponderance.'4 Thereis a weak correlation between the degree ofalbuminuria and blood pressure. Also, manypatients are already receiving antihypertensivetreatment. Albuminuria also correlated withdegree of glycaemia and with triglyceride con-centrations. With more advanced renal diseaseblood pressure tended to increase further, andan even larger proportion of patients requireantihypertensive treatment when overt renaldisease is present."

Transition from normoalbuminuria tomicroalbuminuriaINSULIN DEPENDENT DIABETES MELLITUS

New studies measuring ambulatory bloodpressure have clearly indicated that transitionfrom normoalbuminuria to microalbuminuriais associated with a concomitant increase inambulatory blood pressure over 24 hours. Theonset of microalbuminuria is always associatedwith a rise in blood pressure, but the converseis not necessarily true.6 In patients developingmicroalbuminuria the increase in bloodpressure was fourfold compared with that inthose patients who did not do as well ashealthy controls. Therefore, early in the courseof renal complications, raised blood pressure isimportant, although it is difficult to outlineclearly the prime abnormality as patientsdeveloping microalbuminuria already havealbumin excretion rates in the upper part ofthe normal range, around 10 ,ug/min. Theseobservations suggest a radical new preventiveapproach. Maybe patients with normo-albuminuria at risk of renal progression shouldin the future be treated with antihypertensiveagents even if they do not have high bloodpressure. An important recent prospectivestudy also shows that transition from normo-

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albuminuria (defined as < 30 Vig/min: a ratherhigh value) to microalbuminuria (. 30p.g/min) is associated with higher initialalbumin excretion as well as some hyper-tension.'2 In patients with microalbuminuriaeven slight increase in blood pressurepromotes progression.3

NON-INSULIN DEPENDENT DIABETES MELLITUS

Usually there is a gradual increase inalbuminuria with time in patients with non-insulin dependent diabetes. In the normo-albuminuric stage, however, many patientsremain stable despite a long duration ofdiabetes.'6 Albuminuria increases by about20% per year, and this is related to theattained blood pressure (A Schmitz, personalcommunication). This again suggests thedeleterious effect of even a slight increase inblood pressure in type 2 diabetes. Glycaemiccontrol is also likely to be affected, but so farthere are no published long term studies onoptimised diabetes control in patients withtype 2 diabetes, although important work is inprogress."' Many patients with type 2 diabetesare elderly and have confounding risk factors,so it is hazardous to extrapolate the en-couraging data on glycaemic control inpatients with type 1 diabetes to thispopulation. l

Clinical trials in patients withnormoalbuminuriaINSULIN DEPENDENT DIABETES MELLITUS

ACE inhibition in patients with albuminuria isassociated with a significant reduction infiltration fraction and fractional albuminclearance (fig 1).18 Importantly, in this studythere was no significant change in clinic basedblood pressure, although ambulatory bloodpressure over 24 hours was not measured. Thereduction in filtration fraction could, intheory, be associated with a decrease inhydraulic glomerular pressure, which in turncould explain the reduction in albuminuria.Although it is too early to recommend anti-hypertensive treatment in such patients, thisstudy underlines interest in clinical trials inthis area. Patients at risk of developing micro-albuminuria-namely, patients with poormetabolic control (glycated haemoglobin(HbA,c) > 9-10%), some persistent borderlineincrease in albumin excretion already(> 10-12 ,ug/min), and possibly severe hyper-filtration (glomerular filtration rate > 150 ml/min)-should be enrolled in clinical trials tosee whether the development of micro-albuminuria can be prevented.

22- = NON-INSULIN DEPENDENT DIABETES MELLITUS-o92 Recent studies show that ACE inhibitors

reduce blood pressure effectively in patientswith non-insulin dependent diabetes, but toreduce albuminuria within normal excretion

____________________ seems to be difficult. No adverse effect onPlacebo Enalapril concentrations of glucose, lipids, or uric acid

was seen.'9 20 Interestingly, low dose diureticasulin dependent diabetes and treatment is also effective, which may be

because these patients usually retain sodium

0.300c0

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Figure 1 Filtration fraction and fractional albumin clearsplacebo or enalapril 30 mg per day in nine patients with iinormoalbuminuria. 8

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Table 2 Trials resulting in slightly reduced blood pressure in young non-hypertensive patients with insulin dependent diabetes and microalbuminuria orearly nephropathy

Reference (year) Nature of trial Intervention No of patients; Microalbuininuria Conunentsduration oftreatmtient

Christensen and Self controlled, open , blocker + diuretics 6; 5 years Reduced Gradual reversal of albuminuria byMogensen2' (1985) antihypertensive treatment

Marre et al22 (1988) Double blind, randomised ACE inhibition 20; 1 year Reduced by ACE inhibition Untreated patients showed rapidwith parallel controls increase in urinary albumin

excretion (also see figure 2)Brichard et al23 (1989) Open ACE inhibition 7; 1 year Reduced by ACE inhibitionRudberg et al24 (1990) Open ACE inhibition 12; 6 months Reduced by ACE inhibition Young patientsCook et a?2' (1990) Cross over, double blind ACE inhibition 12; 3 months Reduced by ACE inhibition ChildrenMelbourne Diabetic Open, randomised with ACE inhibition v 43; 1 year Reduced by ACE inhibition Effect mostly seen with raisedNephropathy Study parallel controls calcium blocker and by calcium blocker blood pressureGroup26 (1991)

Mathiesen et al27 (1991) Open, randomised with ACE inhibition 44; 4 years Reduced by ACE inhibition First study to indicate preservationparallel controls of glomerular filtration rate;

proteinuria preventedMarre et al28 (1991) Double blind, randomised ACE inhibition 16; 6 weeks Reduced Effect surprisingly not dose

with parallel controls dependentMau Pedersen et al 29 Open, cross over 13, Blocker + thiazide + 8; 3 months Albuminuria reduced Triple treatment may be useful

(1991) ACE inhibition (early nephropathy)Mau Pedersen et al30 Cross over, double blind ,B, Blocker + thiazide + 10; 4 months Albuminuria reduced Triple treatment may be useful

(1992) ACE inhibition (early nephropathy)Hallab et al3' (1993) Randomised with parallel ACE inhibition 21; 1 year Reduced by ACE inhibition ACE inhibition more efficient than

controls thiazideViberti et al32 (1994) Multicentre, double blind, ACE inhibition 92; 2 years Reduced by ACE inhibition First large scale double blind

randomised with parallel study; increase in albuminuriacontrols and proteinuria significantly

prevented

(S Nielsen, personal communication)yet known whether blood pressurein these patients will result in lIcpreservation of renal function.

Clinical trials in patients withmicroalbuminuriaINSULIN DEPENDENT DIABETES MELLI

Over the past decade many clinical tbeen conducted in patients with irminuria, especially patients with insuldent diabetes.2"-32 Firstly, a P1 blo(diuretics were tested, but latterinhibitors have been studied in(table 2). Clearly, a reduction in or staof microalbuminuria is consistentlyand progression to overt proteiprevented by ACE inhibition istudies.22 27 32 This observation is ibecause in the natural course of diabe

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). It is not transition of microalbuminuria to macro-reduction albuminuria there is always a fall in glomerular:ng term filtration rate.33 On the other hand, patients

who remain microalbuminuric usually havewell preserved renal function. Theseobservations suggest that antihypertensiveintervention, particularly ACE inhibition,should be started early in the phase of micro-

[TUS albuminuria. Blood pressure was not raised:rials have according to the WHO criteria, rather it wasiicroalbu- close to normal mean values. This suggestsLin depen- that intervention should be started irrespectivecker plus of blood pressure. However, patients with arly ACE moderate increase in blood pressure usuallyparticular show a more rapid progression in albuminuriaibilisation and a greater risk of progression to overt renalobserved, disease.3 Therefore some increase in bloodinuria is pressure strengthens the indication for anti-in some hypertensive treatment. In clinics patientsimportant should be frequently monitored for micro-tes in the albuminuria, and in the case of increase over

several months or even a year antihypertensivetreatment should be started. At the same time

Enalapril metabolic control and general diabetes careshould be optimised. One long term studyclearly suggests that a drop in glomerularfiltration rate is prevented by ACE inhibitioncombined with diuretics.27 This study has nowreached eight years with consistent results (E RMathiesen, personal communication). Only afew side effects were observed in all the trialsin table 2. The risk of such intervention islimited and the potential benefit enormous.Recent studies clearly show that from a cost-benefit point of view early antihypertensivetreatment in the microalbuminuric state isadvisable.34 It is not yet known if earlyantihypertensive treatment will ameliorate thecourse of the other complications seen at amuch higher prevalence in patients with

dependent microalbuminuria, especially heart disease (leftznge of ventricular hypertrophy) and advanced diabetic*h placebo.22 retinopathy. New studies suggest, however,

Figure 2 Median logarithm of albumin excretion in 10 patients with insulindiabetes treated with placebo and 10 treated with enalapril. Shading shows ravalues. Blood pressure decreased significantly with enalapril and increased wit

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that antihypertensive treatment reduces leftventricular hypertrophy.35

Table 3 Observationsfrom clinical trials ofACEinhibition in patients withinsulin dependent diabetes

Observation

No trials in patients withnewly diagnosed disease

Normoalbuminuria reduced,blood pressure notsignificantly changed,filtration fraction reduced

Blood pressure reduced(diastolic and systolic),microalbuminuriareduced, fall in glomerularfiltration rate prevented(8 year follow up)

Blood pressure reduced(diastolic and systolic),proteinuria reduced, rateof fall in glomerularfiltration rate reduced

End stage renal disease anddeath postponed

NON-INSULIN DEPENDENT DIABETES MELLITUS

Accumulating evidence suggests that ACEinhibition might be indicated in young patientswith type 2 diabetes. Chan et al showed thatACE inhibitors effectively reduced micro-albuminuria, an effect which was superior tothat of the calcium blocker nifedipine, but thiswas a fairly short study.20 The most impressivestudy was conducted by Ravid et al, comparingenalapril with conventional antihypertensivetreatment, to control for changes in bloodpressure (fig 3).36 The group given ACEinhibitors showed an initial reduction in albu-minuria followed by stabilisation for fiveyears.36 A steady increase was observed in thecontrol group. More importantly, an index ofglomerular filtration rate-namely, reciprocalserum creatinine concentration-was stabilisedby enalapril, whereas in the control group thereciprocal steadily declined. (Eight year followup provides similar results (M Ravid, personalcommunication).) The recent study by

Lacourciere et al, shows that microalbuminuriacan be reduced by an ACE inhibitor incontrast to conventional treatment,19 but theydid not find an effect on glomerular filtrationrate in the three years of the study. Also, thedevelopment of macroalbuminuria was pre-vented in the patients with consistent micro-albuminuria. These three studies point to theimportance of early intervention in patientswith diabetes and slight albuminuria. Increasein blood pressure further strengthens thisindication, as recently shown by Lebovitz et al,who found that a fall in glomerular filtrationrate was reduced in microalbuminuric patientsby ACE inhibitors.37

Overt diabetic renal diseaseINSULIN DEPENDENT DIABETES MELLITUS

Antihypertensive treatment not only reducesalbuminuria in patients with overt renal diseasebut also clearly reduces the rate of decline inglomerular filtration rate.8 The initial studiesused a combination of P blockers and diuretics.Recent studies suggest that ACE inhibitorsmay have a more pronounced antiproteinuriceffect. The most extended study on thissubject, by Bjorck et al, finds that in advanceddiabetic nephropathy ACE inhibitors are moreefficient, not only in their antiproteinuric effectbut also in reducing the rate of decline inglomerular filtration rate (fig 4).38 Clearly,much of the effect of antihypertensive agentson the rate of decline in glomerular filtrationrate in diabetic patients with nephropathy isrelated to the effect on blood pressure.3 Thestudy by Bjorck et al suggests that an additionaleffect is obtained using ACE inhibitors, at leastwhen combined with diuretics.38 The superior-ity of ACE inhibitors was, however, notobserved in all studies.39

NON-INSULIN DEPENDENT DIABETES MELLITUS

Bakris et al studied patients with type 2diabetes and clinical proteinuria.40 Lisinopriland certain calcium blockers not only reducedproteinuria but also reduced the rate of fall inglomerular filtration rate.40 4' These studieswere, however, fairly short term, with amaximal follow up of 1-5 years.4' Furtherstudies are needed.

Patients with advanced renal diseaseINSULIN DEPENDENT DIABETES MELLITUS

An interesting end point is the effect on therate of decline in glomerular filtration rate. Inone study captopril delayed the time todoubling of the serum creatinine concen-tration in patients with overt renal disease andinsulin dependent diabetes (fig 5),42 reducingmortality and the need for dialysis or renaltransplantation. ACE inhibitors were highlyeffective in reducing the blood pressure inthese patients, and this may have accountedfor much of the benefit. This is the firstcontrolled study to document a significanteffect on critical end points. Table 3 showsthat ACE inhibition seems to be effectivethroughout the course of renal disease in

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Figure 5 Cumulative incidence of events in patients withdiabetic nephropathy given captopril or placebo. Top:Cumulative percentage of patients with the primary endpoint: a doubling of the baseline serum creatinineconcentration to at least 2-0 mg per 100 ml. Bottom:Cumulative percentage of patients who died or requireddialysis or renal transplantation. The numbers refer to thenumbers of patients in each group at risk for the event atbaseline and after each six month period.42 Reprinted bypermission of the "New England Jtournal of Medicine"(1993;329: 1456-62).

screening patients with type 2 diabetes formicroalbuminuria so that treatment is startedearly.

°O 6I Possible mechanisms of the0 6 12 18 24 30 36 antiproteinuric effect of ACE inhibitorsTime (months) The benefits of ACE inhibition are clear in

4 Decline in glomerularfiltration rate (GFR), animal studies, reducing proteinuria andy albumin excretion, and blood pressure before and structural glomerular damage in the rat modeltreatment with enalapril (0) or metoprolol (0) in of diabetes." The antiproteinuric and renal

~ients with insulin dependent diabetes and diabeticopathy.38 protective effect of ACE inhibitors probably

operate through several mechanisms. Areduction in systemic blood pressure is

in dependent diabetes mellitus. The important, reducing the transmission of theis likely to be a class effect, rather than abnormal systemic pressure to the glomerular

iated with a particular ACE inhibitor. vessels. This may be especially important indiabetic patients, who may have disturbed

INSULIN DEPENDENT DIABETES MELLITUS autoregulation at the afferent arteriole.45neficial effect is also seen in some patients Interestingly, filtration fraction is reduced bytype 2 diabetes, but the most convincing ACE inhibition,'8 which probably reflectsts are obtained in those with efferent arteriolar dilatation associated with a)albuminuria. With more advanced decrease in hydraulic glomerular pressure.se structural vascular damage is probably Some studies suggest that there may be a

advanced,43 and the efficacy of direct effect on the permeability of theypertensive treatment may not be so glomerulus,46 but this may also be explainedounced. This emphasises the need for by decreased pressure induced stretch of the

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Renoprotective role ofACE inhibitors in diabetic nephropathy

glomerular vessels. If the hypothesis is correctthat proteinuria in itself provokes renaldamage by increased mesangial and interstitialflux of protein, a reduction in proteinuriawould clearly be beneficial.47 Inhibition ofgrowth factors may also be operating. Thereare many other reports on the effects of ACEinhibitors on renal function and proteinuria,most of which, but not all, have shown benefitand broadly support one or more of the abovehypotheses.48-90

When to start antihypertensivetreatment in insulin dependent diabetesThe most recent studies suggest that anti-hypertensive treatment should be started inthe microalbuminuric phase. This treatmentshould probably be introduced irrespective ofblood pressure, but of course with low bloodpressure a more conservative attitude shouldapply. Blood pressure usually increaseswithout treatment during follow up. Someevidence suggests that glomerular filtrationrate will remain well preserved if patientsremain microalbuminuric or show reductionto normoalbuminuria. ACE inhibitors, oftencombined with small doses of diuretics, arethen particularly useful with limited or noeffect on glucose and lipid homoeostasis.Triple treatment with diuretics, ACEinhibitors, and 3, blockers also seems to beeffective.29 30

Obviously, careful monitoring for changesin serum potassium concentration as well asglomerular filtration rate (serum creatinineconcentration) is warranted, as well as carefulcontrol of blood pressure and monitoring ofother side effects, especially in more advancedrenal disease. Pregnancy or the desire forpregnancy is a clear contraindication fortreatment.The disease process is to some extent

similar in the microalbuminuric and macro-albuminuric stages. Since preserving glomer-ular filtration rate is clearly beneficial in overtrenal disease, similar benefits may be assumedamong patients with microalbuminuria. Thisconcept is supported by several studies.Importantly, the role of optimising diabetescontrol has recently been emphasised."l A lowprotein diet may also result in a beneficialeffect on renal function.9'

Brief suggestions for young and middleaged patients with type 2 diabetesFrom a theoretical point of view the sameguidelines can be used in patients with non-insulin dependent diabetes as for those withinsulin dependent diabetes. Of course, higherblood pressures should be accepted to allowfor the age dependent rise in pressure. Patientsunder 60 years old may be treated similarly topatients with insulin dependent diabetes afterthe effect of age on blood pressure has beentaken into consideration.So far there are no long term clinical trials

in older patients. Experience indicates thatACE inhibition and conventional antihyper-

tensive treatment reduce blood pressureeffectively in older patients with insulindependent diabetes. Microalbuminuria mayalso be reduced, but there are no long termdata that glomerular filtration rate ispreserved. Generally, the guidelines foryounger patients may be acceptable, but ahigher blood pressure should be tolerated. Ifantihypertensive treatment reduces bloodpressure and albuminuria with stableglomerular filtration rate, this is probablybeneficial. Patients should be carefullymonitored for hypotensive and other sideeffects, which are likely to be more prevalentin older people.

1 Mogensen CE, ed. Definition of diabetic renal disease ininsulin-dependent diabetes mellitus based on renalfunction tests. In: The kidney and hypertension in diabetesmellitus. 2nd ed. Dordrecht: Kluwer AcademicPublishers, 1994:1-14.

2 Rossing P, Hommel E, Smidt UM, Parving H-H. Impactof arterial blood pressure and albuminuria on theprogression of diabetic nephropathy in IDDM patients.Diabetes 1993;42:715-9.

3 Mogensen CE, Damsgaard EM, Froland A, et aL Reducedglomerular filtration rate and cardiovascular damage indiabetes: a key role for abnormal albuminuria. ActaDiabetologica 1992;29:201-13.

4 Mogensen CE. Management of renal disease andhypertension in insulin-dependent diabetes, with anemphasis on early nephropathy. Current Opinion inNephrology and Hypertension 1992; 1: 106-15.

5 Mogensen CE. Microalbuminuria, early blood pressureelevation, and diabetic renal disease. Current Opinion inEndocrinology and Diabetes 1994;1:239-47.

6 Poulsen PL, Hansen KW, Mogensen CE. Ambulatoryblood pressure in the transition from normo- tomicroalbuminuria: a longitudinal study in IDDM.Diabetes (in press).

7 Bangstad H-J, 0sterby R, Dahl-Jorgensen K, Berg KJ,Hartmann A, Hanssen KF. Improvement of bloodglucose control retards the progression of morphologicalchanges in early diabetic nephropathy. Diabetologia1994;37:483-9.

8 Mogensen CE. Angiotensin converting enzyme inhibitorsand diabetic nephropathy: their effects on proteinuriamay be independent of their effects on blood pressure.BMJ 1992;304:327-8.

9 Bakris GL. Angiotensin-converting enzyme inhibitors andprogression of diabetic nephropathy. Ann Intern Med1993;118:643-4.

10 Remuzzi G, Ruggenenti P. Slowing the progression ofdiabetic nephropathy. N Engl J' Med 1993;329: 1496-7.

11 Diabetes Control and Complications Trial ResearchGroup. The effect of intensive treatment of diabetes onthe development and progression of long-termcomplications in insulin-dependent diabetes mellitus. NEnglJ Med 1993;329:977-86.

12 Microalbuminuria Collaborative Study Group, UnitedKingdom. Risk factors for development ofmicroalbuminuria in insulin dependent diabetic patients:a cohort study. BMJ 1993;306:1235-9.

13 Norgaard K, Feldt-Rasmussen B, Borch-Johnsen K, SaelanH, Deckert T. Prevalence of hypertension in type 1(insulin-dependent) diabetes mellitus. Diabetologia1990;33:407-1 0.

14 de F Olivarius N, Andreasen AH, Keiding N, MogensenCE. Epidemiology of renal involvement in newly-diagnosed middle-aged and elderly diabetic patients.Cross sectional data from the population-based study"Diabetes Care in General Practice," Denmark.Diabetologia 1993;36:1007-16.

15 Gall M-A, Rossing P, Sk0tt P, et al. Prevalence of micro- andmacroalbuminuria, arterial hypertension, retinopathy andlarge vessel disease in European type 2 (non-insulin-depen-dent) diabetic patients. Diabetologia 1991;34:655-6 1.

16 Mogensen CE, Schmitz A. Systolic blood pressure relatesto the rate of progression of albuminuria in non-insulin-dependent diabetics [abstract]. Diabetologia (in press).

17 UK Prospective Diabetes Study Group (UKPDS). VIII.Study design, progress and performance. Diabetologia1991 ;34:877-90.

18 Mau Pedersen M, Schmitz A, Pedersen EB, Danielsen H,Christiansen JS. Acute and long-term renal effects ofangiotensin converting enzyme inhibition in normo-tensive, normoalbuminuric insulin-dependent diabeticpatients. Diabetic Med 1988;5:562-9.

19 Lacourciere Y, Nadeau A, Poirier L, Tancrede G.Captopril or conventional therapy in hypertensive type-IIdiabetics: 3-year analysis. Hypertension 1993;21:786-94.

20 Chan JCN, Cockram CS, Nicholls MG, Cheung CK,Swaminathan R. Comparison of enalapril and nifedipinein treating non-insulin dependent diabetes associatedwith hypertension: one year analysis. BMJ 1992;305:981-5.

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21 Christensen CK, Mogensen CE. Effect of antihypertensivetreatment on progression of incipient diabeticnephropathy. Hypertension 1985;7(suppl II):11-109-13.

22 Marre M, Chatellier G, Leblanc H, Guyenne T-T, MenardJ, Passa P. Prevention of diabetic nephropathy withenalapril in normotensive diabetics with micro-albuminuria. BMJ 1988;297:1092-5.

23 Brichard SM, Santoni JP, Thomas JR, van de Voorde K,Ketelslegers JM, Lambert AE. Long term reduction ofmicroalbuminuria after 1 year of angiotensin convertingenzyme inhibition by perindopril in hypertensive insulin-treated diabetic patients. Diabetes Metab Rev 1989;16:30-6.

24 Rudberg S, Aperia A, Freyschuss U, Persson B. Enalaprilreduces microalbuminuria in young normotensive type 1

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