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Antagonists of Aldosterone and Proteinuria in Patients With CKD:An Uncontrolled Pilot Study

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

Background: Experimental evidence suggests that aldosterone may contribute to progressive kidney disease.lthough angiotensin-converting enzyme (ACE) inhibitors and angiotensin type 1 receptor antagonists (ARBs)uppress the renin-angiotensin system, these agents do not adequately control plasma aldosterone levels. Hence,dministration of aldosterone receptor antagonists may provide additional renal benefits to the ACE inhibitors andRBs. Methods: In the present uncontrolled pilot study, we evaluate the short-term (8 weeks) effects of spironolac-

one on proteinuria in 42 patients with chronic kidney disease (CKD) already treated with ACE inhibitors and/orRBs. Results: Spironolactone (25 mg/d for 8 weeks) decreased proteinuria from protein of 2.09 � 0.16 to 1.32 �.08 g/24 h after 2 weeks and 1.05 � 0.08 g/24 h after 8 weeks. Four weeks after discontinuation of spironolactoneherapy, proteinuria returned to close to baseline values. Baseline proteinuria correlated significantly with plasmaldosterone level (r � 0.81; P < 0.0001). Moreover, baseline aldosterone level correlated significantly with degree ofeduction in proteinuria after treatment with spironolactone (r � 0.70; P < 0.0001). Spironolactone caused aignificant increase in serum potassium levels (from 4.4 � 0.1 mEq/L [mmol/L] at baseline to 4.8 � 0.1 mEq/Lmmol/L] after 8 weeks of treatment; P < 0.01). Conclusion: This study shows that spironolactone may effectivelyeduce proteinuria in patients with CKD. Concerns remain in regard to the risk for hyperkalemia in patients withKD. Prospective randomized trials are necessary to confirm the efficacy and safety of antagonists of aldosteronen proteinuria and progression of CKD. Am J Kidney Dis 46:45-51.2005 by the National Kidney Foundation, Inc.

NDEX WORDS: Aldosterone; aldosterone receptor antagonists; spironolactone; proteinuria; chronic kidney

isease (CKD).

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HE INCIDENCE AND prevalence of end-stage renal disease are increasing alarm-

ngly.1 Several factors contribute to the progres-ion of chronic kidney disease (CKD), includingenal hemodynamic derangements, vasoactiveormones, cytokines, growth factors, and inflam-ation.2-4 Numerous studies have shown an im-

ortant role of the renin-angiotensin system inhe progression of CKD.5,6 Inhibitors of theenin-angiotensin system, such as angiotensin-onverting enzyme (ACE) inhibitors and angio-ensin type 1 receptor antagonists (ARBs), haveeen used successfully to retard CKD progres-ion.7-10 However, neither ACE inhibitors norRBs abrogate the progression of kidney diseaser completely normalize urine protein excretion.lternative or adjunctive therapeutic strategies

re needed.In recent years, a number of studies suggested

hat aldosterone may participate in the progres-ion of kidney and cardiovascular disease throughemodynamic effects and direct cellular ac-ions.11-13 Studies in experimental rat modelshowed that aldosterone may contribute to therogression of kidney disease and antagonists ofldosterone may reduce proteinuria and retardhe progression of kidney disease independentlyf effects on blood pressure (BP).14,15 Plasma

ldosterone level correlated with rate of progres-

merican Journal of Kidney Diseases, Vol 46, No 1 (July), 2005: p

ion of kidney disease,16,17 and the increase inate of kidney disease progression caused byigh protein intake was attributable in part toldosterone.18 ACE inhibitors and ARBs are un-ble to reduce plasma aldosterone levels longerm, a phenomenon known as “aldosterone syn-hesis escape,” thus leaving potentially detrimen-al effects of aldosterone unabated.19

From Unità Operativa Nefrologica, Spedali Riuniti diivorno, Livorno, Italy; and Division of Nephrology, Keckchool of Medicine, University of Southern California, Losngeles, CA.Received December 30, 2004; accepted in revised formarch 14, 2005.Originally published online as doi:10.1053/j.ajkd.2005.03.007

n April 29, 2005.S.B. and R.B. participated in the planning and perfor-

ance of the study and preparation of the manuscript, and.M.C. participated in planning of the study, evaluation ofata, and preparation of the manuscript.The investigators supported this study with private fund-

ng.Address reprint requests to Vito M. Campese, MD, Keck

chool of Medicine, USC, 1200 North State St, Los Angeles,A 90033. E-mail: campese@usc.edu© 2005 by the National Kidney Foundation, Inc.0272-6386/05/4601-0006$30.00/0

doi:10.1053/j.ajkd.2005.03.007

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BIANCHI, BIGAZZI, AND CAMPESE46

The available clinical evidence for a role ofldosterone antagonists on proteinuria and pro-ression of kidney diseases is scanty.20,21

In this uncontrolled pilot study, we evaluateffects of spironolactone on proteinuria in pa-ients with CKD without diabetes already treatedith ACE inhibitors and/or ARBs.

METHODS

This is a prospective, open-label, uncontrolled study.orty-two patients with CKD (28 men, 14 women) with anstimated glomerular filtration rate (GFR) ranging from 20o 138 mL/min (0.33 to 2.30 mL/s) and proteinuria withrotein ranging from 0.9 to 4.9 g/24 h were enrolled. Theseubjects were screened from among more than 300 patientsith CKD followed up in our outpatient clinic. To be

ncluded, all patients had to have a clinical diagnosis ofdiopathic chronic glomerulonephritis. This diagnosis wasased on the presence of proteinuria with protein greaterhan 0.9 g/24 h and no evidence of systemic diseases knowno cause glomerulonephritis. In 15 of these patients, theiagnosis of chronic glomerulonephritis was confirmed byenal biopsy: 8 patients had immunoglobulin A nephropathy;patients, membranoproliferative glomerulonephritis; 4 pa-

ients, focal and segmental glomerulosclerosis; and 1 pa-ient, microscopic vasculitis. In the remaining patients, weannot exclude the possibility of renal diseases other thanlomerulonephritis because a renal biopsy was not per-ormed.

Twenty-six patients were hypertensive (office systolicP � 140 mm Hg and diastolic BP � 90 mm Hg). Patientsith diabetes mellitus, renovascular or malignant hyperten-

ion, secondary glomerular disease, malignancies, myocar-ial infarction or cerebrovascular accident in the 6 monthsreceding the study, congestive heart failure, hepatic dysfunc-ion, serum potassium level greater than 5 mEq/L (mmol/L),

odification of Diet in Renal Disease (MDRD) GFR lesshan 20 mL/min (�0.33 mL/s), and a history of allergy toCE inhibitors or ARBs were excluded. Also excluded wereatients recently treated with steroids, nonsteroidal anti-nflammatory drugs, or immunosuppressive agents.

The Human Research Committee of the Spedali Riuniti diivorno, Italy, approved the study, and all subjects gave their

nformed consent.Before inclusion in this trial, all patients had been fol-

owed up in the outpatient clinic for at least 1 year. Duringhis time, 18 subjects were treated with an ACE inhibitorusually enalapril, 20 mg/d, or equivalent doses of otherCE inhibitors); 7 patients, an ARB (usually irbesartan, 300g/d, or equivalent doses of other ARBs); and 17 patients, a

ombination of these 2 drugs. Twenty-eight patients weredministered hydrochlorothiazide or furosemide. Other anti-ypertensive drugs were administered as needed to achieve aarget BP of less than 125/75 mm Hg, and 25 of 42 patientschieved this target. Eighteen patients were administered aalcium channel blocker; 4 patients, a �-blocker; 3 patients,lonidine; and 2 patients, an �-blocking drug. Twenty-sevenatients also were treated with atorvastatin (20 to 40 mg/d)

or at least 1 year before the initiation of this study. Patients [

lso were advised to ingest a diet low in sodium (�2 to 3 g/df sodium), and if estimated GFR was less than 60 mL/min�1.00 mL/s), they were counseled to ingest 0.8 g/kg/d ofrotein. Compliance with these dietary restrictions was noterified by measurements of urinary sodium and urea excre-ion.

After the baseline evaluation, patients were administeredpironolactone, 25 mg/d, for 8 weeks. Thereafter, spironolac-one therapy was discontinued and patients were followedp for an additional 4 weeks. Patients were seen in the clinict 8:00 AM at baseline and after 2, 4, and 8 weeks ofreatment with spironolactone and 4 weeks after discontinu-tion of the drug. At each clinic visit, BP and heart rate wereeasured at least 3 times after resting supine for at least 30inutes, and the average of these measurements was re-

orded. A blood sample was drawn to determine serumotassium, creatinine, and plasma aldosterone levels afterhe patient had rested supine for 30 minutes. A 24-hour urineample was collected for measurement of protein excretionefore initiation of the study and before each clinic visit.The choice of a spironolactone dose of 25 mg/d was based

n several considerations. First, previous studies showed anffective decrease in proteinuria with this dose.21,22 Second,his dose was used in the Randomized Aldactone Evaluationtudy.23 Finally, we were concerned that greater doses ofpironolactone might increase the risk for hyperkalemia.he rationale for the 8-week duration of treatment withpironolactone was based on the pilot nature of the study.

nalytic ProceduresBP was measured using a mercury sphygmomanometer.

ody mass index was calculated as weight (in kilograms)ivided by height (in meters) squared.Urinary protein and serum creatinine and potassium wereeasured using standard methods. GFR was estimated using

he MDRD formula.24 Plasma aldosterone was measuredsing a commercially available kit (Nichols Advantage Aldo-terone; Nichols Institute Diagnostics, San Clemente, CA).

For statistical analysis, we used the Kolmogorov-Smirnovest for comparison of nonparametric parameters. Differ-nces between baseline and values during therapy and afterrug discontinuation were analyzed by using analysis ofovariance for repeated measurements. Relations betweenldosterone and urine protein excretion were evaluated byeans of regression analysis. To identify multivariate predic-

ors of reduction in proteinuria, stepwise multiple linearegression analyses were performed using 2-week percent-ge of reduction in proteinuria as a dependent variable andasal systolic and diastolic BP, plasma aldosterone level,FR, sex, body mass index, and proteinuria as independent

xplanatory variables.

RESULTS

Baseline and follow-up clinical characteristicsf all patients included in the study are listed inable 1. Baseline BP was 131.9 � 1.5/79 � 0.8m Hg, and estimated GFR was 56.8 � 4.7L/min (0.95 � 0.08 mL/s; 22 to 138 mL/min

0.37 to 2.30 mL/s]). Baseline proteinuria was

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SPIRONOLACTONE AND PROTEINURIA 47

rotein of 2.09 � 0.16 g/24 h, and mean base-ine plasma aldosterone level was 184.3 � 12.6g/mL.Spironolactone had no significant effects on

P (Table 1), but reduced proteinuria in allatients (Fig 1). Proteinuria decreased from pro-ein of a mean of 2.09 � 0.16 to 1.32 � 0.08 g/24

after only 2 weeks of treatment and to 1.05 �.08 g/24 h after 8 weeks of treatment withpironolactone. Four weeks after discontinuationf spironolactone therapy, proteinuria returned torotein of 1.57 � 0.11 g/24 h, but it was stilless (P � 0.05) than the baseline value. Protein-ria decreased more in patients administered

Table 1. Patient Clinical Characteristics at Baseline;Weeks After Spiron

Basal 2 W

o. of patients (M/F) 42 (28/14)ge (y) 54.7 � 1.9ody mass index (kg/m2) 25.1 � 0.4lasma aldosterone (pg/mL) 184.3 � 12.6ystolic BP (mm Hg) 131.9 � 1.5 131.1 �iastolic BP (mm Hg) 79 � 0.8 78.2 �stimated GFR* (mL/min) 56.8 � 4.7 54.2 �rine protein (g/24 h) 2.09 � 0.16 1.32 �erum potassium (mEq/L) 4.4 � 0.1 4.7 �

NOTE. Data expressed as mean � SEM. Post indicatonvert GFR in mL/min to mL/s, multiply by 0.01667; potas*MDRD formula.†P � 0.01 versus basal values.‡P � 0.05 versus basal values.§P � 0.001 versus 8 weeks of treatment with spironolact

Fig 1. Line graphs show proteinuria levels in all 42atients at baseline; during treatment with spironolac-

mone, 25 mg/d; and 4 weeks after discontinuation of therug.

iuretics than in those not administered diuretics�39.8% � 3.0% versus �22% � 4.3%; P �.001).During administration of spironolactone, esti-ated GFR decreased (P � 0.001) from 56.8 �

.7 to 53.3 � 4.5 mL/min (0.95 � 0.08 to 0.89 �

.08 mL/s) after 8 weeks of treatment, but re-urned to close to baseline levels (55.6 � 4.5L/min [0.93 � 0.08 mL/s]) 4 weeks after

iscontinuation of the drug. The decrease in GFRid not correlate with the decrease in proteinuria.eductions in proteinuria and GFR observeduring treatment with spironolactone were moreronounced among patients with an estimatedFR less than 60 mL/min (�1.00 mL/s) than

mong those with a GFR greater than 60 mL/min�1.00 mL/s; Table 2). Mean serum potassiumevel increased from 4.4 � 0.1 mEq/L (mmol/L)t baseline to 4.9 � 0.1 mEq/L (mmol/L) after 4eeks and 4.8 � 0.1 mEq/L after 8 weeks of

reatment (P � 0.05). In 5 patients, all with anstimated GFR less than 60 mL/min (�1.00L/s), serum potassium reached levels greater

han 5.5 mEq/L (mmol/L), but less than 6.0Eq/L (mmol/L). Serum potassium levels in-

reased more in patients administered diureticshan in those not administered diuretics (4.9 �.1 versus 4.7 � 0.2 mEq/L [mmol/L]; P �.01). Plasma aldosterone levels were greater inatients with a GFR less than 60 mL/min (�1.00L/s) than in those with a GFR greater than 60

, 4, and 8 Weeks of Spironolactone Treatment; and 4ne Discontinuation

4 Weeks 8 Weeks Post

131.6 � 1.7 131.4 � 1.8 131.4 � 1.678.6 � 0.9 78.8 � 0.7 78.7 � 0.653.5 � 4.7† 53.3 � 4.5† 55.6 � 4.51.15 � 0.09† 1.05 � 0.08† 1.57 � 0.11‡4.9 � 0.1† 4.8 � 0.1† 4.6 � 0.1†§

eeks after discontinuation of spironolactone therapy. TomEq/L to mmol/L, multiply by 1.

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BIANCHI, BIGAZZI, AND CAMPESE48

� 0.005). Baseline plasma aldosterone levelslso were greater in patients administered di-retics than in those not administered diuretics201 � 14.4 versus 150 � 22.2 pg/mL; P �.05) and in the 18 patients administered ACEnhibitors alone (211 � 3 pg/mL) or the 7atients administered ARBs alone (181 � 3g/mL) than in the 17 patients administeredCE inhibitors and ARBs combined (164 � 6g/mL; P � 0.01). The percentage of reductionn proteinuria was greater in patients treatedith an ACE inhibitor (�37% � 5.9%) or anRB alone (�34% � 4.2%) than in patients

reated with a combination of ACE inhibitorsnd ARBs (�29% � 5.8%; P � 0.01). Thencrease in serum potassium level was greater inatients treated with a combination of ACE inhibi-ors and ARBs (5.0 � 0.4 mEq/L [mmol/L]) thann patients treated with an ACE inhibitor alone4.7 � 0.2 mEq/L [mmol/L]) or an ARB alone4.7 � 0.2 mEq/L [mmol/L]). We observed aignificant correlation between baseline valuesf aldosterone and proteinuria (r � 0.81; P �.0001; Fig 2). Moreover, baseline aldosteroneevel correlated significantly with percentage ofeduction in proteinuria after treatment with spi-

Table 2. Proteinuria, Estimated GFR, and Serum PTreatment With Spironolactone; and 4 W

Basal 2 Weeks

roteinuria (g/24 h)GFR � 60 mL/min 2.37 � 0.2 1.42 � 0.1

(�37% v basalGFR � 60 mL/min 1.58 � 0.2 1.13 � 0.1

(�24.5% v basFR-MDRD (mL/min)GFR � 60 mL/min 36.7 � 2.2 33.9 � 2.2

(�7.8% v basaGFR � 60 mL/min 93 � 3.9 90.6 � 4.1

(�2.7% v basaerum potassium (mEq/L)GFR � 60 mL/min 4.6 � 0.07 4.9 � 0.07

(�7.5% v basaGFR � 60 mL/min 4.1 � 0.1 4.3 � 0.09

(�6% v basal)

NOTE. To convert GFR in mL/min to mL/s, multiply by 0.*P � 0.01 between percentage of change in GFR in patFR greater than 60 mL/min.†P � 0.05 between percentage of change in GFR in patFR greater than 60 mL/min.

onolactone (r � 0.70; P � 0.0001; Fig 3). r

Stepwise multiple linear regression analysessing 2-week percentage of reduction in protein-ria as a dependent variable and basal systolicnd diastolic BP, plasma aldosterone level, GFR,ex, body mass index, and proteinuria as indepen-ent explanatory variables showed that onlylasma aldosterone level predicted the reductionn proteinuria that followed spironolactone treat-ent (P � 0.001). Stepwise multiple regression

nalyses also showed that treatment with an ACEnhibitor or ARB alone was more predictive of

ium Values at Baseline; After 2, 4, and 8 Weeks offter Discontinuation of Spironolactone

4 Weeks 8 Weeks4 Weeks After

Discontinuation

1.21 � 0.1 1.09 � 0.1 1.66 � 0.147% v basal)* (�52% v basal)*† (�72% v 8 wk)1.05 � 0.1 0.99 � 0.1 1.39 � 0.130.9% v basal) (�34% v basal) (�47% v 8 wk)

33.1 � 2.2 33.3 � 2.3 35.7 � 2.39.9% v basal)* (�9.6% v basal)* (�8% v 8 wk)*89.9 � 4.1 89 � 2.9 91.6 � 2.73.2% v basal) (�3.6% v basal) (�3.2% v 8 wk)

5.1 � 0.07 5.1 � 0.08 4.8 � 0.0711% v basal) (�11% v basal)* (�1.6% v 8 wk)*

4.4 � 0.1 4.3 � 0.1 4.3 � 0.18% v basal) (�5.7% v basal) (�6.3% v 8 wk)

potassium in mEq/L to mmol/L, multiply by 1.ith a GFR less than 60 mL/min and that in patients with a

ith a GFR less than 60 mL/min and that in patients with a

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SPIRONOLACTONE AND PROTEINURIA 49

eduction in proteinuria that the combination ofoth drugs.

DISCUSSION

This study shows that spironolactone causes aubstantial and statistically significant reductionn urine protein excretion in patients with CKDlready treated with ACE inhibitors and/or ARBs.he reduction in proteinuria was evident afternly 2 weeks of treatment and was not related toeductions in BP. The lack of decrease in BP withpironolactone may seem surprising. However,hrysostomou and Becker22 also failed to ob-

erve a decrease in BP despite a 54% reduction inroteinuria in 8 patients with CKD already treatedith an ACE inhibitor. Plasma aldosterone level

orrelated highly with baseline proteinuria levelnd predicted the degree of decrease in protein-ria that followed treatment with spironolactone.he decrease in proteinuria was less pronounced

n patients administered a combination of ACEnhibitors and ARBs compared with those admin-stered an ACE inhibitor or ARB alone. Thisrobably was the result of lower aldosteroneevels in the former compared with the latterroup, suggesting more effective inhibition ofhe renin-angiotensin-aldosterone system withhe combination than with any single drug. Spi-onolactone also caused a transitory minimaleduction in estimated GFR. Reductions in pro-einuria and GFR were more pronounced inatients with an estimated GFR less than 60

Fig 3. The regression line between baseline aldoste-one levels and percentage of decrease in proteinxcretion after 8 weeks of treatment with spironolac-one, 25 mg/d, is shown.

L/min (�1.00 mL/s) than in patients with a r

FR greater than 60 mL/min (�1.00 mL/s). Theeduction in estimated GFR was minimal and ofifficult interpretation given the limitations ofstimated GFR using the MDRD formula.

Substantial experimental evidence indicates thatldosterone may contribute to renal injury.25-27

uan et al28 showed that structural renal injury,roteinuria, and hypertension were less prevalent inats that underwent subtotal nephrectomy and adre-alectomy than rats with intact adrenal glands. Inhe deoxycorticosterone acetate-salt rat model ofypertension, exogenous administration of miner-locorticoid induced lesions of malignant nephro-clerosis in rats.29

Spironolactone and eplerenone are 2 agentshat directly block the actions of aldosterone30

nd have been used to probe the role of aldoste-one in vascular and renal injury. Spironolactoneeduced proteinuria and vascular injury, whereasldosterone infusion abrogated the beneficial ef-ects of an ACE inhibitor in stroke-prone sponta-eously hypertensive rats.14,15 Similarly,plerenone prevented the development of protein-ria and renal lesions in saline-drinking stroke-rone spontaneously hypertensive rats. Theseffects occurred despite the absence of majoreductions in BP.15

Evidence that spironolactone and eplerenoneay reduce proteinuria or affect the progression

f kidney disease in patients with CKD is scanty.n an uncontrolled trial of 8 patients with variousenal diseases and proteinuria with protein greaterhan 1 g/d, spironolactone consistently reducedroteinuria.22 Sato et al21 studied patients withiabetes who had been on ACE inhibitor therapynd had “aldosterone escape.” Treatment withpironolactone reduced urinary albumin excre-ion. Epstein et al31 showed that eplerenonettenuates proteinuria more effectively than anCE inhibitor in patients with type 2 diabetesellitus. A combination of eplerenone and ACE

nhibitor was more effective than any single drugdministered alone in reducing proteinuria.

Our study extends these observations to indicatehat the decrease in proteinuria occurs very rapidlyafter only 2 weeks), suggesting that these effectsrobably are not related to structural, but rather tounctional, changes in the permselectivity of thelomerular basement membrane.

Mechanisms for the beneficial effects of spi-

onolactone on proteinuria probably are com-

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lex. The classic view holds that aldosterone is aineralocorticoid hormone synthesized in the

drenal glomerulosa, which has a critical role inlectrolyte homeostasis. More recently, evidenceas shown that aldosterone binds to mineralocor-icoid receptors in nonepithelial tissues, such ashe heart, brain, and blood vessels, where it isapable of mediating several pathophysiologicalctions.32-37 Experimental studies showed thatldosterone may mediate hypertension throughctions on the central nervous system38 and mayause stroke, malignant nephrosclerosis, hyper-rophy of cardiac ventricles39,40 and vascularmooth muscle cells,41 and myocardial necrosisnd fibrosis.42,43 Aldosterone may stimulate plas-inogen activator inhibitor 1, which is centrally

nvolved in the pathogenesis of glomerulosclero-is and tubulointerstitial nephritis,44,45 and trans-orming growth factor �, a cytokine that pro-otes fibroblast differentiation and proliferation

nd collagen synthesis.46

The beneficial effects of spironolactone on pro-einuria in patients with a renin-angiotensin systemlready suppressed by means of ACE inhibitors orRBs can be explained best by inadequate suppres-

ion of aldosterone secretion, a phenomenon knowns aldosterone escape.47,48 Our study suggests thathe combination of ACE inhibitors and ARBs mayeduce aldosterone levels more effectively than anyrug administered alone.

This study has several limitations. Study dura-ion and number of patients included were notdequate to evaluate long-term effects of spirono-actone on proteinuria and progression of kidneyisease. The study was open label and not pla-ebo controlled. Therefore, selection bias and theossibility that the findings simply represent theegression to the mean cannot be excluded com-letely. Substantial concerns remain in regard tohe safety of spironolactone, particularly whendministered to patients with stage 3 to 4 CKDlready treated with ACE inhibitors or ARBs inombination. Although the incidence of hyperka-emia in our trial was moderate (11.9%), the riskas greater in patients with more advanced CKD.nalysis of the rate of hospital admission foryperkalemia and rate of deaths associated withyperkalemia in patients with heart failure admin-stered ACE inhibition showed a more substan-ial rate of complication than originally reported

n the Randomized Aldactone Evaluation Study.23 S

In conclusion, this uncontrolled, pilot, short-erm study shows that antagonists of aldosteroneay reduce proteinuria in patients with CKD.oncerns remain in regard to potential hyperka-

emia and long-term effects on GFR. Long-termrospective randomized trials are necessary toonfirm the efficacy and safety of antagonists ofldosterone on proteinuria and progression ofidney disease.

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tier CT: Mineralocorticoid blockade reduces vascular in-

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SPIRONOLACTONE AND PROTEINURIA 51

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

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