Iiadic

onmassIctrc

A

Intensive Versus Conventional Therapy to Slow the Progression ofIdiopathic Glomerular Diseases

Stefano Bianchi, MD,1 Roberto Bigazzi, MD,1 and Vito M. Campese, MD2

Background: Chronic kidney disease (CKD) caused by idiopathic glomerular diseases usually isprogressive. Inhibition of the renin-angiotensin system (RAS) retards, but does not abrogate, CKDprogression. Statins and spironolactone may decrease the rate of CKD progression independently or inaddition to RAS inhibition.

Study Design: Randomized open-label study.Setting & Participants: We recruited 128 patients (82 men and 46 women) with a clinical diagnosis

of idiopathic chronic glomerulonephritis and estimated glomerular filtration rate (eGFR) �30 mL/min/1.73 m2 (range, 36-102 mL/min/1.73 m2), and urine protein-creatinine ratio ranging from 1.1-5.2 g/g.

Intervention: Intensive therapy (a combination of RAS inhibitors [angiotensin-converting enzyme[ACE] inhibitors plus angiotensin receptor blockers [ARBs] plus a high-dose statin and spironolactone)versus conventional therapy (a regimen based on ACE inhibitors with a low-dose statin).

Outcomes: Changes in eGFR, proteinuria, and adverse events after 3 years of therapy.Results: With intensive therapy, urine protein-creatinine ratio decreased from 2.65 (range, 1.1-5.2) to

0.45 (0.14-1.51) g/g (P � 0.001) and eGFR did not significantly change over time (64.6 � 2.1 vs 62.9 �2.9 mL/min/1.73 m2). With conventional therapy, urine protein-creatinine ratio decreased from 2.60(range, 1.32-5.4) to 1.23 (0.36-3.42) g/g (P � 0.001) and eGFR decreased from 62.5 � 1.7 to 55.8 � 1.9mL/min/1.73 m2 (P � 0.001). Comparison of the decreases in proteinuria and GFR between intensiveversus conventional therapy was significantly different starting in the 1st and 12th months, respectively.Systolic blood pressure was lower with intensive than conventional therapy (113.5 � 1.4 vs 122.7 � 1.2mm Hg; P � 0.01). We found an inverse relationship between percentage of decrease in proteinuria andchange in eGFR (P � 0.001). Patients on intensive therapy were more likely to develop adverse events,such as hyperkalemia (9 vs 3 patients in the conventional therapy group) and discontinue therapy (15 vs8 patients in the conventional therapy group).

Limitations: Open-label design.Conclusions: A more intensive therapy that includes a combination of ACE inhibitors and ARBs plus

high-dose statins and spironolactone may retard CKD progression more effectively than conventionaltherapy based on ACE inhibitors plus low-dose statin, but may lead to more adverse effects anddiscontinuation of therapy.Am J Kidney Dis 55:671-681. © 2010 by the National Kidney Foundation, Inc.

INDEX WORDS: Idiopathic glomerular diseases; chronic kidney disease; proteinuria; angiotensin-converting enzyme (ACE) inhibitors; angiotensin II receptor blockers; statins; aldosterone antagonists.

ltait

LS

Nj

A

S9

t is a commonly held view that the incidenceand prevalence of end-stage renal disease are

ncreasing alarmingly in developed countries1

nd that this burden may increase even moreuring the next decade, particularly in develop-ng countries. However, this view has been criti-ized by others.2

Several factors contribute to the progressionf chronic kidney disease (CKD), including re-al hemodynamic derangements, vasoactive hor-ones, cytokines, growth factors, oxidative stress,

nd inflammation.3,4 Numerous studies havehown the important role of the renin-angioten-in system (RAS) in the progression of CKD.5,6

nhibitors of the RAS, such as angiotensin-onverting enzyme (ACE) inhibitors and angio-ensin type 1 receptor antagonists (angiotensineceptor blockers [ARBs]) have been used suc-

essfully to retard CKD progression,7-11 particu-

merican Journal of Kidney Diseases, Vol 55, No 4 (April), 2010: p

arly in patients with diabetic nephropathy. Dualherapy with ACE inhibitors and ARBs may havedditive renal protective effects.12 However, ACEnhibitors and ARBs retard, but do not abrogate,he progression of kidney disease in most pa-

From the 1Unità Operativa Nefrologia Spedali Riuniti diivorno, Livorno, Italy; and 2Division of Nephrology, Keckchool of Medicine, USC, Los Angeles, CA.Received March 4, 2009. Accepted in revised form

ovember3,2009.Originallypublishedonlineasdoi:10.1053/.ajkd.2009.11.006 on January 25, 2010.

Trial registration: www.anzctr.org.au; study number:CTRN12610000034033.Address correspondence to Vito M. Campese, MD, Keck

chool of Medicine, USC, 1200 N State St, Los Angeles, CA0033. E-mail: campese@usc.edu© 2010 by the National Kidney Foundation, Inc.0272-6386/10/5504-0010$36.00/0

doi:10.1053/j.ajkd.2009.11.006

p 671-681 671

tRaAnnlr

rhAuo

cHkprpstcs

atmis

seiRsl�ot

S

DNRacf

spsmoticf

hdpt1Adw

T

swo

rmtBcea

itioTsssdt

csutdptwcr

ps3p

Bianchi, Bigazzi, and Campese672

ients, suggesting that mechanisms other than theAS are important in CKD progression andlternative or adjunctive therapies are needed.CE inhibitors and ARBs are unable to perma-ently decrease plasma aldosterone levels, a phe-omenon known as “aldosterone escape,” thuseaving potentially detrimental effects of aldoste-one unabated.13

Several studies have suggested that aldoste-one may participate in CKD progression throughemodynamic and direct cellular actions.14,15

ldosterone antagonists may decrease protein-ria and retard CKD progression independentlyf effects on blood pressure (BP).16-20

Evidence also suggests that dyslipidemia mayontribute to the progression of kidney disease.ypercholesterolemia is a predictor of loss ofidney function in diabetic21,22 and nondiabeticatients with CKD,23 and treatment with statinsetards the progression of kidney disease in ex-erimental animals24 and humans.25,26 In a pro-pective controlled open-label study, we showedhat treatment with atorvastatin for 1 year de-reased proteinuria and the rate of CKD progres-ion in nondiabetic patients.27

In summary, evidence indicates that the man-gement of patients with CKD may require mul-iple drugs addressing different pathogenicechanisms and not only the RAS. Approaches

n this direction have already been attempted ino-called CKD remission clinics.28

In this prospective randomized open-labeltudy, we compared effects on proteinuria andstimated glomerular filtration rate (eGFR) ofntensive therapy comprising a combination ofAS inhibitors (ACE inhibitors plus ARBs),

pironolactone, and a dose of statin to achieve aow-density lipoprotein (LDL) cholesterol target

100 mg/dL versus conventional therapy basedn ACE inhibitors with a low-dose statin toarget an LDL cholesterol level �130 mg/dL.

METHODS

etting andParticipants

Patients were recruited in the Center for the Prevention,iagnosis, and Treatment of CKD of the Unità Operativa diefrologia, Spedali Riuniti of Livorno, Italy. The Humanesearch Committee of the Spedali Riuniti of Livornopproved the study, and all participants gave their informedonsent. No sample-size determination was performed be-

ore the study. (

In this study, we included patients with a clinical diagno-is of idiopathic chronic glomerulonephritis (GN) and urinerotein-creatinine ratio �1 g/g, confirmed on at least 2eparate occasions. Patients with membranous GN and mini-al change disease were excluded because of the possibility

f spontaneous remission and the unpredictable response toreatment. We excluded participants with secondary GN,ncluding diabetes mellitus, because the pathophysiologicharacteristics and clinical course of these diseases differrom those of idiopathic GN.

We excluded patients with renovascular or malignantypertension, rapidly progressive GN, malignancies, myocar-ial infarction, or cerebrovascular accident within 6 monthsreceding the study; congestive heart failure; hepatic dysfunc-ion; serum potassium level �5 mEq/L; eGFR �30 mL/min/.73 m2; and a history of intolerance to ACE inhibitors orRBs. We excluded patients treated with steroids, nonsteroi-al anti-inflammatory drugs, or immunosuppressive agentsithin 6 months preceding the study.

reatment Procedures

Patients were randomly assigned to conventional or inten-ive therapy using a numerical sequence. Randomizationas performed by Drs Bianchi and Bigazzi, who were awaref group assignment.Patients treated with conventional therapy received

amipril, 10 mg/d, and atorvastatin, 10 mg/d. During the firstonth of therapy, all participants were followed up weekly

o monitor serum potassium and creatinine levels and achieveP �130/80 mm Hg with the addition of diuretics (hydro-hlorothiazide or furosemide), calcium antagonists, �-block-rs, or �1-receptor antagonists. The dose of atorvastatin wasdjusted to achieve LDL cholesterol levels �130 mg/dL.

Patients on intensive therapy received ramipril, 10 mg/d;rbesartan, 300 mg/d; atorvastatin, 20 mg/d; and spironolac-one, 25 mg/d. During the first month of therapy, patients onntensive therapy were followed up weekly to adjust dosagesf antihypertensive drugs to achieve the lowest tolerated BP.he dosage of spironolactone was increased to 50 mg/d iferum potassium levels were �4.5 mEq/L. In contrast, iferum potassium reached levels �5.5 mEq/L, the dosage ofpironolactone was decreased to 25 mg 3 times weekly. Theosage of atorvastatin was adjusted to achieve LDL choles-erol levels �100 mg/dL.

Thereafter, all patients were evaluated in the outpatientlinic 3, 6, 9, 12, 24, 30, and 36 months after initiation of thetudy. During follow-up clinic visits, BP was measuredsing a mercury sphygmomanometer at least 3 times, andhe average of these measurements was recorded. Blood wasrawn to measure serum creatinine, sodium, potassium, lipidrofile, creatine kinase, alanine aminotransferase, and aspar-ate aminotransferase. In addition, 2 random urine samplesere obtained during 2 consecutive days for measurement of

reatinine and protein, and the 2 values were averaged andecorded.

Patients were withdrawn from the study if: (1) serumotassium level remained �5.5 mEq/L despite dietary potas-ium restriction, decreasing spironolactone dosage to 25 mgtimes weekly, increasing the dosage of diuretics, and use ofotassium-binding resins; (2) kidney function decreased

defined as a decrease in eGFR �30% compared with

pq

A

BdctgeDwn

uaesmowtnlwAdtp

P

i

aoultwess3c

22F

ifgwt9t(c1p

ct

s

Intensive Therapy in Idiopathic Glomerular Diseases 673

revious values); and (3) adverse events occurred that re-uired discontinuation of the drugs used in the study.

nalytic Procedures

BP was measured using a mercury sphygmomanometer.ody mass index was calculated as weight (kilograms)ivided by height (meters) squared. Urinary protein, serumreatinine, sodium, potassium total cholesterol, LDL choles-erol, high-density lipoprotein (HDL) cholesterol, and tri-lycerides were measured using standard methods. GFR wasstimated using the 4-variable Modification of Diet in Renalisease (MDRD) Study equation.29 For statistical analysis,e used the Kolmogorov-Smirnov test for comparison ofonparametric parameters.The primary end points were changes over time in protein-

ria and eGFR. Secondary outcomes were adverse eventsnd drop outs. Random-effects mixed models were fitted forach outcome variable with an autoregressive covariancetructure, covariate adjustment for baseline values, and treat-ent-by-time interaction to compare the pattern of change

ver time between treatment groups. A quadratic time factoras included in each model. Before analysis, transforma-

ions of the time and outcome variables were applied aseeded to improve model fit. For random-effects models, theog of urine protein values was regressed on log time,hereas eGFR values were regressed on square root of time.pattern-mixture approach was used to test the effect of

rop outs.30 When a significant dropout effect was detected,reatment-specific averaging was used to estimate modelarameters.

RESULTS

atients

We screened 324 patients. Of those, 151 met thenclusion and exclusion criteria and 128 (82 men

Figure 1. Flow diagram for thetudy.

nd 46 women) agreed to participate (Fig 1). In 48f these patients, the diagnosis was confirmedsing renal biopsy: 28 patients had immunoglobu-in A nephropathy and 20 had focal and segmen-al glomerulosclerosis. In the remaining patients,e cannot exclude the possibility of renal dis-

ases other than GN. All patients had hyperten-ion (BP �140/90 mm Hg or using antihyperten-ive drugs), eGFR �30 mL/min/1.73 m2 (range,6-102 mL/min/1.73 m2), and urine protein ex-retion ranging from 1.1-5.2 g/g creatinine.

The screening process started on January 2,003; the last patient was enrolled on February 1,005; and the last follow-up was concluded onebruary 15, 2008.Baseline clinical characteristics of all patients

ncluded in the study are listed in Table 1. Sixty-our patients with CKD were assigned to eachroup and followed up for 3 years. Baseline BPas 156.6 � 1.9/94.1 � 1 mm Hg in patients

reated with intensive therapy and 155.7 � 1.6/3.3 � 1.0 mm Hg in patients on conventionalherapy. eGFR was 62.5 � 1.7 mL/min/1.73 m2

range, 40-92 mL/min/1.73 m2) in patients ononventional therapy and 64.6 � 2.1 mL/min/.73 m2 (range, 36-102 mL/min/1.73 m2) inatients on intensive therapy.Baseline urine protein excretion was 2.60 g/g

reatinine (range, 1.32-5.4 g/g creatinine) in pa-ients on conventional therapy and 2.65 g/g creat-

io

w

C

i1tmta

C

d0p

cuctp

C

c2ttDsitct

N

A

B

S

K

S

D

L

H

M

S

S

S

e

U

rtf

Bianchi, Bigazzi, and Campese674

nine (range, 1.10-5.2 g/g creatinine) in patientsn intensive therapy.Table 2 lists types of medications patients

ere using at the time of randomization.

hanges inBP

Systolic BP decreased more (P � 0.01) in thentensive-therapy group (from 156.6 � 1.9 to13.5 � 1.4 mm Hg) than in the conventional-herapy group (from 155.7 � 1.6 to 122.7 � 1.2m Hg; Table S1; provided as online supplemen-

ary material available with this article at www.jkd.org).

hanges in Proteinuria

With intensive therapy, urine protein excretionecreased from 2.65 to 0.45 g/g creatinine (P �.001; Fig 2). With conventional therapy, urine

Table 1. Baseline

All P

o. of patients (M/F) 128

ge (y) 53.2

ody mass index (kg/m2) 25.1

mokers (no/yes) 9

idney diseaseChronic kidney diseaseFocal segmental glomerulosclerosisImmunoglobulin A

ystolic blood pressure (mm Hg) 156.

iastolic blood pressure (mm Hg) 93.7

ow-density lipoprotein cholesterol (mg/dL) 160.

igh-density lipoprotein cholesterol (mg/dL) 45.5

ean blood pressure (mm Hg) 114.

erum triglycerides (mg/dL) 169.

erum sodium (mEq/L) 139.

erum potassium (mEq/L) 4.3

GFR (mL/min/1.73 m2) 63.5

rine protein (g/g creatinine) 2.610 (1

Note: Data are expressed as mean � standard error oange). Conversion factors for units: low- and high-densitriglycerides in mg/dL to mmol/L, �0.01129; eGFR in mL/mor sodium and potassium in mEq/L and mmol/L.

Abbreviation: eGFR, estimated glomerular filtration rate.

rotein excretion decreased from 2.60 to 1.23 g/g o

reatinine (P � 0.001). The decrease in protein-ria in patients on intensive therapy was signifi-antly greater than in patients on conventionalherapy after only 1 month of treatment and itersisted for the entire duration of the study.

hanges in eGFR

With intensive therapy, eGFR did not signifi-antly change over time (64.6 � 2.1 vs 62.9 �.9 mL/min/1.73 m2). In contrast, with conven-ional therapy, eGFR decreased from 62.5 � 1.7o 55.8 � 1.9 mL/min/1.73 m2 (P � 0.01; Fig 3).uring the first 3 months of the study, we ob-

erved a greater decrease in eGFR in patients onntensive therapy than those on conventionalherapy (Fig 3; Table S1). Thereafter, eGFRontinued to deteriorate in patients on conven-ional therapy, but stabilized and then improved

al Characteristics

Conventional Therapy Intensive Therapy

64 (39/25) 64 (43/21)

53.1 � 1.1 53.1 � 1.1

25.3 � 0.3 24.9 � 0.3

44/20 47/17

41 3912 811 17

155.7 � 1.6 156.6 � 1.9

93.3 � 1.0 94.1 � 1.0

161.6 � 1.7 160.4 � 2.2

45.5 � 1 45.6 � 1.1

114.0 � 1.1 114.9 � 1.1

174.9 � 6.4 164.3 � 6.8

139.4 � 0.3 139.9 � 0.3

4.3 � 0.04 4.3 � 0.03

62.5 � 1.7 64.6 � 2.1

400) 2.597 (1.320-5.400) 2.645 (1.100-5.200)

ean. Urine protein is expressed as median (interquartilerotein cholesterol in mg/dL to mmol/L, �0.02586; serumm2 to mL/s/1.73 m2, �0.01667. No conversion necessary

Clinic

atients

(82/46)

� 0.9

� 0.3

1/37

802028

1 � 1.3

� 0.7

9 � 4.7

� 0.7

5 � 0.8

6 � 4.7

7 � 0.2

� 0.03

� 1.4

.100-5.

f the my lipopin/1.73

ver time in patients on intensive therapy. By the

e0wwic�wtspig

ie1

rafst0bsosdistp

gm0tst

E

eiibipset(tgdcdh

T

osfw

R

I

S

A

A

D

O

Intensive Therapy in Idiopathic Glomerular Diseases 675

nd of the study, we observed a greater (P �.01) rate of decrease in eGFR in patients treatedith conventional therapy than in those treatedith intensive therapy (Fig 4). We found an

nverse relationship between percentage of de-rease in proteinuria and change in GFR (r �0.415; P � 0.001) in patients in both groupsho completed the study (Fig 5). We observed

hat the rate of decrease in eGFR at the end of thetudy was lower in patients who achieved a urinerotein-creatinine excretion ratio �0.5 g/g thann those with urine protein-creatinine ratio �2/g (Fig 6).LDL cholesterol levels decreased more in the

ntensive- than conventional-therapy group. At thend of the study, levels were 79.5 � 1.3 and 116.7 �

Table 2. Baseline Medical Treatments

AllPatients(n�128)

ConventionalTherapy(n�64)

IntensiveTherapy(n�64)

amipril (mg/d)5 10 7 310 118 57 61

rbesartan (mg/d)150 6 0 6300 58 0 58

pironolactone(mg/wk)

75 1 0 1100 10 0 10175 50 0 50350 3 0 3

torvastatin (mg)10 35 35 020 65 27 3840 28 2 26

ntiplatelet agents(yes/no)

77/51 17/47 60/4

iureticsNone 21 9 12Furosemide 80 44 36Hydrochlorothiazide 27 11 16

ther antihypertensivedrugs

0 56 19 371 35 16 192 31 23 83 6 6 0

.2 mg/dL, respectively (P � 0.01; Fig 7). s

Multiple regression analyses using monthlyate of change in eGFR as the dependent variablend 6 independent variables, including changesrom baseline in proteinuria, systolic and dia-tolic BP, LDL cholesterol, HDL cholesterol, andriglyceride levels showed proteinuria (P �.001) and LDL cholesterol level (P � 0.001) toe significant predictors, whereas changes inystolic BP (P � 0.09) were no longer predictivef changes in eGFR. Multiple regression analy-es using monthly rate of change in eGFR as theependent variable and 6 independent variables,ncluding baseline proteinuria, systolic and dia-tolic BP, LDL cholesterol, HDL cholesterol, andriglyceride levels showed that only systolic BPredicted changes in eGFR (P � 0.02).Serum potassium levels increased in both

roups of patients, from 4.3 � 0.04 to 5.0 � 0.04Eq/L in patients on intensive therapy and 4.3 �

.0 3 to 4.8 � 0.04 mEq/L in patients on conven-ional therapy. The difference in serum potas-ium levels between these 2 groups at the end ofhe study was statistically significant (P � 0.01).

ffect ofDropOuts

Twenty-three participants did not complete thentire 36 months of the study: 8 (12.5%) receiv-ng conventional therapy and 15 (23.4%) receiv-ng intensive therapy. Because of the small num-er of dropouts, the pattern-mixture modelnvestigated only 1 missing data pattern (com-leters vs dropouts). Failure to complete thetudy had no significant impact on the treatmentffect for urine protein excretion, but was relatedo the treatment difference over time for eGFRP � 0.06 and P � 0.001 for linear and quadraticerms, respectively). Individual time curves sug-est that patients on conventional therapy whoropped out had a steeper decrease in eGFR thanompleters and did not recover, whereas bothropouts and completers on intensive therapyad similar time courses.

reatment EffectsOver Time

Although urine protein excretion decreasedver time for both the conventional- and inten-ive-therapy groups, there was a significant dif-erence between groups in the rate of change,ith those on intensive therapy experiencing a

teeper decrease (P � 0.001 for treatment-by-

toitsman

D

d

b�rdmm1dm(a

m(cc(tt

Bianchi, Bigazzi, and Campese676

ime interaction). Significant differences also werebserved between groups in the pattern of changen eGFR over time (P � 0.001 for treatment-by-ime2 interaction). Those on conventional therapyhowed a steady decrease from baseline to 36onths, whereas those on intensive therapy hadgreater initial decrease followed by a return toear-baseline levels.

ropOuts andAdverse Events

In the conventional-therapy group, 8 patientsiscontinued the study: 3 during the first 3 months

Figure 3. Changes in esti-ated glomerular filtration rate

eGFR) over time in patients ononventional (C) therapy (openircles) and intensive (I) treatmentclosed circles). Numbers of par-

icipants in each group at eachime are shown below the graph.

ecause of hyperkalemia (serum potassium5.5 mEq/L), 2 because of cough, 1 because of

apid deterioration in kidney function (eGFRecrease �30% vs baseline value) after 24onths, and 2 were lost to follow-up after 6onths (Table 3). In the intensive-therapy group,

5 dropped out: 9 because of hyperkalemia (3uring the first 3 months, 3 at 6 months, 1 at 18onths, and 2 at 24 months), 1 because of cough

after 3 months), 3 because of hypotension (2fter 3 months and 1 after 6 months), and 2 were

Figure 2. Urine protein excre-tion at baseline and for the entireduration of the study in patientstreated with conventional (C)therapy (open circles) and inten-sive (I) therapy (closed circles).Numbers of participants in eachgroup at each time are shown be-low the graph.

l2sntasBd

kp

ipsmwgoa

adCGetc

Aacp

ttipas

dwbOcc

ttpt

dp

Intensive Therapy in Idiopathic Glomerular Diseases 677

ost to follow-up (1 after 12 months and 1 after4 months; Table 3). Nine patients in the inten-ive-therapy group developed gynecomastia, butone of them dropped out of the study because ofhis side effect. Twelve patients on conventionalnd 31 on intensive therapy had to interrupt thetudy temporarily (not �10 days) because of lowP in coincidence with episodes of diarrhea,ehydration, fever, etc.No patient developed an increase in creatine

inase, alanine aminotransferase, and alkalinehosphatase levels during the study.

Figure 4. Rate of estimated glomerular filtration rateecrease (�eGFR; mL/min/1.73 m2/mo) in patients treatedith conventional (closed bars) or intensive therapy (openars) during the first, second, or third year of treatment.nly the 49 patients on intensive therapy and the 56 ononventional therapy who completed the study are in-luded in this analysis.

Figure 5. Relationship between decrease in urine pro-ein excretion and changes in estimated glomerular filtra-ion rate decrease (�eGFR; mL/min/1.73 m2/mo) in the 49

atients on intensive therapy and the 56 on conventionalherapy who completed the study.

(a

DISCUSSION

This study supports our hypothesis that a morentensive therapy consisting of ACE inhibitorslus ARBs, tighter BP control, higher doses oftatins to achieve LDL cholesterol levels �100g/dL, and administration of spironolactoneould decrease proteinuria and retard CKD pro-ression more effectively than a regimen basedn ACE inhibitors and a small dose of statins tochieve LDL cholesterol levels �130 mg/dL.

In patients with CKD, intensive therapy causedsubstantial and statistically significant greater

ecrease in urine protein excretion and rate ofKD progression than conventional therapy.iven the study design, the individual role of

ach drug cannot be ascertained and it is likelyhat all may have contributed to the better out-ome.

Dual RAS blockade with ACE inhibitors andRBs decreases proteinuria more effectively than

ny single drug given alone and is used widely inlinical practice, although data for long-termreservation of kidney function are lacking.31,32

In a previous study, we showed that spironolac-one can substantially decrease urine protein excre-ion and the rate of CKD progression20 when givenn addition to ACE inhibitors and/or ARBs. Inatients treated with spironolactone, we observedn initial rapid decrease in eGFR followed bytabilization. However, by the end of 1 year of

Figure 6. Rate of estimated glomerular filtration rateecrease (�eGFR; mL/min/1.73 m2/mo) based on levels ofroteinuria achieved at the end of the study in all patients

conventional and intensive treatment). Values expresseds mean � standard error.

tptsfip

tlgsGa

Bianchi, Bigazzi, and Campese678

reatment, the decrease in eGFR was greater inatients treated with conventional therapy than inhose treated with spironolactone. In the presenttudy, we observed a similar pattern. During therst 3 months, the decrease in eGFR was moreronounced in patients on intensive than conven-

Table 3

Patient No. Therapy Sex Age (y)

1 Conventional F 612 Conventional M 593 Conventional M 524 Conventional M 475 Conventional F 366 Conventional M 517 Intensive F 668 Intensive M 579 Intensive M 61

10 Intensive M 5311 Intensive F 4912 Intensive M 5813 Intensive F 5914 Intensive M 5215 Intensive M 6016 Intensive F 7217 Intensive M 5818 Intensive M 6619 Intensive F 5120 Conventional M 5621 Conventional F 6122 Intensive M 49

23 Intensive F 42

ional therapy. However, with time, eGFR stabi-ized and finally improved in the intensive-therapyroup. In contrast, eGFR continued to progres-ively decrease in patients on conventional therapy.iven the nature of the protocol, it is impossible to

ttribute the initial decrease in eGFR exclusively to

Figure 7. Serum levels of lowdensity lipoprotein (LDL) choles-terol at baseline and for the en-tire duration of the study in pa-tients treated with conventional(C) therapy (open circles) andintensive (I) therapy (closedcircles). Numbers of participantsin each group at each time areshown below the graph.

Outs

eGFR (mL/min/1.73 m2)Adverse Events and

Drop Outeline End of Study

42 38 Potassium �5.5 mEq/L44 39 Potassium �5.5 mEq/L56 46 Potassium �5.5 mEq/L62 60 Cough56 56 Cough48 24 Worsening renal function48 36 Potassium �5.5 mEq/L78 70 Symptomatic hypotension63 62 Potassium �5.5 mEq/L70 56 Symptomatic hypotension48 45 Potassium �5.5 mEq/L74 70 Potassium �5.5 mEq/L71 70 Cough66 58 Potassium �5.5 mEq/L70 71 Potassium �5.5 mEq/L60 52 Potassium �5.5 mEq/L44 41 Potassium �5.5 mEq/L48 40 Potassium �5.5 mEq/L62 70 Symptomatic hypotension72 42 Lost to follow-up62 58 Lost to follow-up74 64 Lost to follow-up

. Drop

Bas

58 53 Lost to follow-up

stAt

cifamtm

itc�wtadpiaaEret

tiemip

lta

mdidet1td

gi

ppittsaS

Atsccp

lBiaHecsnpomvrpsyipdnScsayo

tra

Intensive Therapy in Idiopathic Glomerular Diseases 679

pironolactone therapy and rule out the possibilityhat other factors, such as ACE inhibitors andRBs or lower BP levels, might have contributed

o the decrease.This initial rapid decrease in eGFR could be

aused by the known effects of aldosterone onntraglomerular hemodynamic33 and endothelialunction.34 The beneficial role of aldosteronentagonists is consistent with the wealth of experi-ental evidence that aldosterone may contribute

o renal injury and antagonists of aldosteroneay result in renal protection.35

Aldosterone may damage nonepithelial tissues,ncluding the kidneys.36 Aldosterone stimulatesype IV collagen accumulation in rat mesangialells,37 transforming growth factor �1 (TGF-1),38 and plasminogen activator inhibitor 1,39

hich are involved in fibrinolysis and contributeo glomerulosclerosis and tubulointerstitial dam-ge. In uninephrectomized rats fed a high-saltiet, continuous infusion of aldosterone causesodocyte injury and proteinuria, along with anncrease in oxidative stress and expression ofldosterone effector kinase Sgkl. These effectsre reversed by aldosterone-antagonists.40

plerenone inhibits oxidized LDL (lectin-like)eceptor 1 (LOX-1)-mediated adhesion mol-cules and results in improved endothelial func-ion.41

Despite the wealth of experimental data, an-agonists of aldosterone have been used sparselyn clinical practice because of their weak diureticfficacy, poor tolerability, and fear of hyperkale-ia, particularly in patients treated with RAS

nhibitors. In recent years, use of these agents inatients with CKD has increased.42-44

Larger prospective randomized studies ofonger duration are needed to conclusively showhe beneficial effects and safety of aldosteronentagonists on CKD progression.

Increasing evidence suggests that dyslipide-ia may contribute to the progression of kidney

isease45,46 and treatment with statins may retardts course.47 The renal benefit of statins mayepend on the presence of intrinsic kidney dis-ase and the degree of proteinuria. In a prospec-ive controlled open-label study, we showed that

year of treatment with atorvastatin in additiono a regimen with ACE inhibitors and/or ARBs

ecreases proteinuria and the rate of CKD pro- w

ression more than a regimen based on ACEnhibitors and ARBs alone.20

The mechanisms through which lipids andarticularly oxidized LDL48,49 can accelerate therogression of renal disease are complex andnvolve mesangial cells hypertrophy50; activa-ion of cytokines, such as monocyte chemoattrac-ant protein 151; formation of vasoactive sub-tances, such as endothelin, thromboxane, andngiotensin II52; and endothelial dysfunction.tatins appear to inhibit these effects.A potential synergism between statins and

CE inhibitors has been postulated; however,his requires further studies.53,54 In the presenttudy, it is impossible to ascertain the relativeontribution of higher doses of statins and LDLholesterol levels �100 mg/dL to the rate ofrogression of CKD.Finally, it is possible that the difference in BP

evels (9 mm Hg systolic and 3 mm Hg diastolicP) between the 2 groups could account, at least

n part, for the difference in proteinuria decreasend CKD progression between the 2 treatments.owever, this difference in BP is unlikely to

xplain entirely the observed difference in out-ome. First, we have already shown that atorva-tatin28 and spironolactone20 may decrease uri-ary protein excretion and the rate of CKDrogression independently of BP control. Sec-nd, the MDRD Study55 examined the effect ofore strict (mean arterial pressure �92 mm Hg)

ersus more conventional BP control (mean arte-ial pressure �107 mm Hg) on the rate of CKDrogression. A low target BP did not produce alower projected mean decrease in GFR at 3ears compared with the usual BP target exceptn participants with proteinuria �1 g/d. Theresent study showed that intensive therapy pro-uced a benefit in eGFR after only 18 months andot after several years, as observed in the MDRDtudy, suggesting that although lower BP may haveontributed to the improved outcome in the inten-ive-therapy group, this is not likely to be the onlynd major factor. Finally, multiple regression anal-ses showed that changes in BP were not predictivef changes in eGFR.

Patients on intensive therapy did not alwaysolerate this regimen. They manifested increasedisks of hyperkalemia, hypotension, and discontinu-tion of treatment. This regimen should be used

ith caution, particularly in patients with eGFR

�admmwde

opctnfins

lnAbtns

r

ft

aa

UA

k2

nlt

t2

agi

rn

HaK

Svn

ttN

rn2

tw

aJ

chVt

i1

rh1

ot

eonr4

rt

iI

fp

Bianchi, Bigazzi, and Campese680

60 mL/min/1.73 m2. Close clinical observationnd adjustment of dietary potassium intake andose of diuretics are indispensable if this regi-en must be used in patients with CKD. Treat-ent with spironolactone has to be discontinuedhen the serum potassium level becomes tooifficult to control and the initial decrease inGFR is �30%.

Our study has several limitations. The study waspen label and not placebo controlled; therefore,otential bias in the evaluation of data cannot beompletely excluded. In addition, exclusion of pa-ients with other kidney diseases, such as diabeticephropathy, does not allow generalization of thesendings to all patients with CKD. Finally, we didot measure true GFR, and the use of eGFR haseveral limitations.

In summary, an intensive therapy composed ofower BP and LDL cholesterol targets, a combi-ation of RAS inhibitors (ACE inhibitors plusRBs), and spironolactone seems to be moreeneficial than conventional therapy in retardinghe progression of CKD. However, these patientseed to be followed up more closely to preventerious adverse events.

ACKNOWLEDGEMENTSSupport: None.Financial Disclosure: The authors report they have no

elevant financial interests.

SUPPLEMENTARY MATERIALTable S1: Clinical characteristics at baseline and during

ollow-up in patients treated with conventional or intensiveherapy.

Note: The supplementary material accompanying thisrticle (doi:10.1053/j.ajkd.2009.11.006) is available at www.jkd.org.

REFERENCES1. Collins AJ, Foley R, Herzog C, et al. Excerpts from the

nited States Renal Data System 2007 Annual Data Report.m J Kidney Dis. 2008;51(1 suppl 1):S1-320.2. Glassock RJ, Winearls C. An epidemic of chronic

idney disease: fact or fiction? Nephrol Dial Transplant.008;23:1117-1121.3. Myers BD, Deen WM, Brenner BM. Effects of norepi-

ephrine and angiotensin II on the determinants of glomeru-ar ultrafiltration and proximal tubule fluid reabsorption inhe rat. Circ Res. 1975;37:101-110.

4. Remuzzi G, Ruggenenti P, Benigni A. Understandinghe nature of renal disease progression. Kidney Int. 1997;51:

-15. 2

5. Anderson S, Rennke HG, Brenner BM. Therapeuticdvantage of converting enzyme inhibitors in arresting pro-ressive renal disease associated with systemic hypertensionn the rat. J Clin Invest. 1986;77:1003-2000.

6. Ibrahim HN, Rosenberg ME, Hostetter TH. Role of theenin-angiotensin-aldosterone system in the progression of re-al disease: a critical review. Semin Nephrol. 1997;17:431-440.

7. Andersen S, Tarnow L, Rossing P, Hansen BV, ParvingH. Renoprotective effects of angiotensin II receptor block-

de in type 1 diabetic patients with diabetic nephropathy.idney Int. 2000;57:601-606.8. Brenner BM, Cooper ME, De Zeeuw D, et al; RENAAL

tudy Investigators. Effects of losartan on renal and cardio-ascular outcomes in patients with type 2 diabetes andephropathy. N Engl J Med. 2001;345:861-869.9. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renopro-

ective effect of the angiotensin-receptor antagonist irbesar-an in patients with nephropathy due to type 2 diabetes.

Engl J Med. 2001;345:851-860.10. Agodoa LY, Appel L, Bakris GL, et al. Effect of

amipril vs amlodipine on renal outcomes in hypertensiveephrosclerosis: a randomized controlled trial. JAMA. 2001;85:2719-2728.11. Ruggenenti P, Perna A, Gherardi G, et al. Renoprotec-

ive properties of ACE-inhibition in non-diabetic nephropathiesith non-nephrotic proteinuria. Lancet. 1999;354;359-364.12. Cohen DL, Townsend RR. Is there added value to

dding ARB to ACE inhibitors in the management of CKD?Am Soc Nephrol. 2009;20:1666-1668.13. McElvie RS, Yusuf S, Pericak D, et al. Comparison of

andesartan, enalapril, and their combination in congestiveeart failure: Randomized Evaluation of Strategies for Leftentricular Dysfunction (RESOLVD) pilot study. Circula-

ion. 1999;10:1056-1064.14. Greene E, Kren S, Hostetter TH. Role of aldosterone

n the remnant kidney model in the rat. J Clin Invest.996;98:1063-1068.15. Rocha R, Rudolph AE, Frierdich GE, et al. Aldoste-

one induces a vascular inflammatory phenotype in the rateart. Am J Physiol Heart Circ Physiol. 2002;283:H1802-810.16. Rocha R, Chander PN, Zuckerman A, Stier CT. Role

f aldosterone in renal vascular injury in stroke-prone hyper-ensive rats. Hypertension. 1999;33:232-237.

17. Rachmani R, Slavachevsky I, Amit M, et al. Theffects of spironolactone, cilazapril and their combinationn albuminuria in patients with hypertension and diabeticephropathy is independent of blood pressure reduction: aandomized controlled study. Diabet Med. 2004;21:471-75.18. Sato A, Hayashi K, Saruta T. Effectiveness of aldoste-

one blockade in patients with diabetic nephropathy. Hyper-ension. 2003;41:64-68.

19. Schjoedt KJ, Rossing K, Juhl TR, et al. Beneficialmpact of spironolactone in diabetic nephropathy. Kidneynt. 2005;68:2829-2836.

20. Bianchi S, Bigazzi R, Campese VM. Long-term ef-ects of spironolactone on proteinuria and kidney function inatients with chronic kidney disease. Kidney Int. 2006;70:

116-2123.

fpc

li1

St

k

YpN

ht

cpD

rS

tc3

en

s

dA

vl

ap

p

ctk

IiI

afi

oo

Ts

sap

DawtoN

iI

et2

t

yR

ir

Sm

Oa

WJ

Ord2

LD

trt

cr1

dpR

Intensive Therapy in Idiopathic Glomerular Diseases 681

21. Ravid M, Broshd D, Ravid-Safran D, et al. Main riskactors for nephropathy in type 2 diabetes mellitus arelasma cholesterol levels, mean blood pressure and hypergly-emia. Arch Intern Med. 1998;158:998-1004.

22. Krolewsky AS, Warram JH, Christlieb AR. Hypercho-esterolemia a determinant of renal function loss and deathsn IDDM patients with nephropathy. Kidney Int Suppl.991;45:S125-131.23. Maschio G, Oldrizzi L, Rugiu C, Lo Schiavo C.

erum lipids in patients with chronic renal failure on longerm protein restricted diets. Am J Med. 1989;87:51N-54N.

24. Oda H, Keane WF. Recent advances in statins and theidney. Kidney Int Suppl. 1999;71:S2-5.25. Chan PCK, Robinson JD, Yeung WC, Cheng IKP,

eung HWD, Tsang MTST. Lovastatin in glomerulone-hritic patients with hyperlipidemia and heavy proteinuria.ephrol Dial Transplant. 1992;7:93-99.26. Fuiano G, Esposito C, Sepe V, et al. Effects of

ypercholesterolemia on renal hemodynamics: study in pa-ients with nephrotic syndrome. Nephron. 1996;73:430-435.

27. Bianchi S, Bigazzi R, Caiazza A, Campese VM. Aontrolled, prospective study of the effects of atorvastatin onroteinuria and progression of kidney disease. Am J Kidneyis. 2003;41:565-570.28. Ruggenenti P, Perticucci E, Cravedi P, et al. Role of

emission clinics in the longitudinal treatment of CKD. J Amoc Nephrol. 2008;19(6):1213-1224.29. National Kidney Foundation. K/DOQI Clinical Prac-

ice Guidelines for Chronic Kidney Disease: evaluation,lassification, and stratification. Am J Kidney Dis. 2002;9(suppl 2, February):S1-266.30. Hedeker D, Gibbons RD. Application of random-

ffects pattern-mixture models for missing data in longitudi-al studies. Psychol Methods. 1997;2(1):64-78.

31. Ruggenenti P, Remuzzi G. Is the ONTARGET renalubstudy actually off target? Nat Rev Nephrol. 2009;5:1-2.

32. Ku E, Park J, Vidhun J, Campese VM. The hazards ofual renin-angiotensin blockade in chronic kidney disease.rch Intern Med. 2009;169:1015-1018.33. Arima S, Kohagura K, Xu HL, et al. Non genomic

ascular action of aldosterone in the glomerular microcircu-ation. J Am Soc Nephrol. 2003;14:2255-2263.

34. Chun TY, Pratt JH. Non genomic renal effects ofldosterone. Dependency on NO and genomic actions. Hy-ertension. 2006;47:636-637.35. Hollenberg NK. Aldosterone in the development and

rogression of renal injury. Kidney Int. 2004;66:1-9.36. Roland BL, Krozowski ZS, Funder JW. Glucocorti-

oid receptor, mineralocorticoid receptors, 11 beta-hydroxis-eroid dehydrogenase-1 and -2 expression in rat brain andidney: in situ studies. Mol Cell Endocrinol. 1995;111:R1-7.

37. Watisaka M, Spiro MJ, Spiro RG. Synthesis of typeV collagen by cultured glomerular cells and comparison ofts regulation by glucose and other factors with that of typeV collagen. Diabetes. 1995;43:95-103.

38. Sun Y, Zhang J, Zhang JQ, Ramires FJA. Localngiotensin II and transforming growth factor-b in renalbrosis in rats. Hypertension. 2000;35:1078-1084.39. Brown NJ, Agirbasli MA, Williams GH, et al. Effect

f activation and inhibition of the renin-angiotensin system

n plasma PAI-I. Hypertension. 1998;32:965-971. 8

40. Shibata S, Nagase M, Yoshida S, Kawachi H, Fujita. Podocyte as the target for aldosterone: roles of oxidativetress and sgkl. Hypertension. 2007;49:355-364.

41. Kobayashi N, Hara K, Tojo A, et al. Eplerenonehows renoprotective effect by reducing LOX-1 mediateddhesion molecule, PKCe-MAPK-p90RSK, and rho-kinaseathway. Hypertension. 2005;45:538-544.

42. Chrysostomou A, Pedagogos E, MacGregor L, et al.ouble-blind, placebo controlled study on the effects of the

ldosterone receptor antagonist spironolactone in patientsho have persistent proteinuria and are on long-term angio-

ensin-converting enzyme inhibitory therapy, with or with-ut an angiotensin II receptor blocker. Clin J Am Socephrol. 2006;1:256-262.43. Schjoedt KJ, Rossing K, Juhl TR, et al. Beneficial

mpact of spironolactone in diabetic nephropathy. Kidneynt. 2005;68:2829-2836.

44. Rossing K, Schjoedt KJ, Smidt U, et al. Beneficialffects of adding spironolactone to recommended antihyper-ensive treatment in diabetic nephropathy. Diabetes Care.005;28:2106-2112.45. Campese VM, Park J. HMG-CoA reductase inhibi-

ors and the kidney. Kidney Int. 2007;71:1215-1222.46. Appel GB, Radhakrishnan J, Avram MM, et al. Anal-

sis of metabolic parameters as predictors of risk in theENAAL Study. Diabetes Care. 2003;26:1402-1407.47. Sandhu S, Wiebe N, Fieed LF, Tonelli M. Statins for

mproving renal outcomes: a meta-analysis. J Am Soc Neph-ol. 2006;17:2006-2016.

48. Gupta S, Rifici V, Crowley S, Braunlee M, Zihe S,chlondorff D. Interactions of LDL and modified LDL withesangial cells and matrix. Kidney Int. 1992;41:1161-1169.49. Keane WF, O’Donnell MP, Kasiske BL, Kim Y.

xidative modification of low density lipoproteins by mes-ngial cells. J Am Soc Nephrol. 1993;4:187-194.

50. O’Donnell MP, Kasiske BL, Kim Y, Atluru D, KeaneF. Lovastatin inhibits proliferation of rat mesangial cells.

Clin Invest. 1993;91:83-87.51. Quenn MT, Parthasarathy S, Fong LG, Steimberg D.

xidatively modified low density lipoproteins: a potentialole in recruitment and retention of monocyte/macrophagesuring atherogenesis. Proc Natl Acad Sci U S A. 1987;84:995-2998.52. Galle J, Heermeier K. Angiotensin II and oxidized

DL. An unholy alliance creating oxidative stress. Nephrolial Transplant. 1999;14:2585-2589.53. Horiuchi M, Cui TX, Li Z, et al. Fluvastatin enhances

he inhibitory effects of a selective angiotensin II type 1eceptor blocker, valsartan, on vascular neointimal forma-ion. Circulation. 2003;107:106-112.

54. Nazzaro P, Manzari M, Merlo M, et al. Distinct andombined vascular effects of ACE blockade and HMG-CoAeductase inhibition in hypertensive subjects. Hypertension.999;33:719-725.55. Klahr S, Levey AS, Beck GJ, et al. The effects of

ietary protein restriction and blood-pressure control on therogression of chronic renal disease. Modification of Diet inenal Disease Study Group. N Engl J Med. 1994;330:877-

84.