the relationship between albuminuria and hormone therapy in postmenopausal women
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The Relationship Between Albuminuria and Hormone Therapy inPostmenopausal Women
Mamta Agarwal, MD, MS, Vani Selvan, MD, Barry I. Freedman, MD, Yongmei Liu, MD, PhD, andLynne E. Wagenknecht, DrPH
Background: Elevated urinary albumin excretion and hormone therapy (HT) are associated with increased risk forardiovascular events. We assessed the relationship between albuminuria and the use of hormonal preparations inostmenopausal women. Methods: Data from the Insulin Resistance Atherosclerosis Study were obtained ataseline and 5-year follow-up for analysis. The generalized estimating equation procedure accounting for repeatedeasures was used for this analysis. HT was the main predictor variable, and loge urine albumin-creatinine ratio
ACR) was the main outcome variable. Results: Four hundred ninety-one menopausal women were included in thenalysis, 36% (n � 179) of whom received HT (either oral estrogen, progesterone, or combination therapy). Ataseline, abnormal albuminuria (ACR > 25 mg/g) was present in 11% of women on HT and 17% not on HT (P � 0.02).fter adjusting for demographics, the presence of diabetes and hypertension, and kidney function, HT wasssociated with a 19% reduction in ACR (P � 0.008) and an odds ratio of 0.67 (95% confidence interval, 0.43 to 1.01;� 0.06) for the presence of abnormal albuminuria. Other predictors of abnormal albuminuria included diabetes,
lood pressure, and triglyceride level. Conclusion: Results of this study suggest that HT is associated with aeduction in urinary albumin excretion in postmenopausal women. Am J Kidney Dis 45:1019-1025.
2005 by the National Kidney Foundation, Inc.
NDEX WORDS: Urine albumin-creatinine ratio (ACR); postmenopausal; hormone therapy; women.
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HE ONSET OF menopause can producesymptoms of discomfort, along with ad-
erse effects on a woman’s long-term health.bservational studies suggest that reduced estro-en levels in women undergoing menopause leado alterations in levels of cholesterol, other serumipids, and fibrinogen, thereby increasing the riskor heart disease and stroke.1,2 Cardiovascularisease is the leading cause of morbidity andortality in postmenopausal women.3,4 Hor-one therapy (HT), such as estrogen alone or in
ombination with progesterone, decreases meno-ause-associated hot flashes and/or vasomotorymptoms5,6 and osteoporosis.7
More than 60 studies have assessed the rela-ionship between HT and coronary heart disease.lthough observational studies showed a benefi-
ial effect of HT on cardiovascular risk factorsnd mortality,8-11 randomized clinical trials failedo confirm their results. The Postmenopausalstrogen/Progestin Interventions,11 Heart Estro-en and Progestin Replacement Study,12 andomen’s Health Initiative13 focused on defining
he risks and benefits of strategies that couldeduce the incidence of heart disease and stroken postmenopausal women. These trials reportedconsistent negative effect of HT on the primarynd secondary prevention of cardiovascularvents.
Microalbuminuria is associated independently
ith increased cardiovascular risk in subjectsmerican Journal of Kidney Diseases, Vol 45, No 6 (June), 2005:
ith diabetes and hypertension14,15 and appearso be a marker of endothelial dysfunction.16
xisting data are limited on the effects of HT onlbuminuria. One observational study reportedhat women receiving HT had an increased riskor microalbuminuria,17 although 2 small clini-al trials18,19 showed contradictory effects inostmenopausal women with type 2 diabetes.he purpose of this study is to determine thessociation of HT with urine albumin-creatinineatio (ACR) over time.
METHODS
esignData from the Insulin Resistance Atherosclerosis Study
IRAS) were obtained at baseline and 5-year follow-up. TheRAS is a multicenter epidemiological study designed toxplore relationships between insulin resistance in various
From the Departments of Internal Medicine/Nephrology,ypertension, and Public Health Sciences, Wake Forestniversity Health Sciences, Winston-Salem, NC.Received November 15, 2004; accepted in revised form
ebruary 28, 2005.Originally published online as doi:10.1053/j.ajkd.2005.02.025
n April 7, 2005.Address reprint requests to Mamta Agarwal, MD, Depart-
ent of Internal Medicine/Nephrology, Wake Forest Univer-ity Health Sciences, Medical Center Blvd, Winston-Salem,C 27157. E-mail: [email protected]© 2005 by the National Kidney Foundation, Inc.0272-6386/05/4506-0006$30.00/0
doi:10.1053/j.ajkd.2005.02.025pp 1019-1025 1019
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thnic groups across a spectrum of glucose tolerance (fromormal to type 2 diabetes). IRAS participants ranged from0 to 69 years of age. A full description of the design andethods of the IRAS has been published previously.20
In brief, the total IRAS population of 1,625 subjects wasecruited from 4 clinical centers. San Antonio, TX, and Sanuis Valley, CO, recruited Hispanics and non-Hispanichites, and Los Angeles and Oakland, CA, recruited Africanmericans and non-Hispanic whites. Recruitment was de-
igned to yield equal numbers among ethnic, sex, andlucose tolerance groups.This report focuses on 491 women classified as postmeno-
ausal for whom HT use was known. Menopausal status wasetermined by interview-administered questionnaire. Use ofostmenopausal hormones, such as oral progesterone and/orstrogen, and other medication use, including angiotensin-onverting enzyme (ACE) inhibitors, angiotensin receptorlockers (ARBs), and lipid-lowering agents, was determinedy interview. Anthropometric measures, resting blood pres-ure, blood sampling, and spot urine collection were per-ormed at baseline and 5 years. Laboratory assays includedrine albumin and creatinine, serum creatinine, total choles-erol, low-density lipoprotein, high-density lipoproteinHDL), triglycerides, fasting glucose, and blood chemistries.pot urine collection was performed for urine ACR. Urinereatinine concentration was measured by using an auto-ated alkaline picrate method, run on an Abbot TDX ana-
yzer (Abbot Park, IL). Urine albumin concentration waseasured by using a radioimmunoassay from the Diagnos-
ics Products Corp kit (Newington, NH).Women who self-reported menopause or were withoutenses for longer than 12 months were considered postmeno-
ausal, as were those with a history of bilateral ovariectomy.ubjects administered any formulation of estrogen, proges-
erone, or combination therapy were combined to be defineds HT users. Hypertension is defined as systolic bloodressure of 140 mm Hg or greater and diastolic bloodressure of 85 mm Hg or greater or use of antihypertensiveedications. Abnormal albuminuria is defined as urine ACR
f 25 mg/g or greater.21 Glomerular filtration rate, as aeasure of kidney function, was calculated by using theockcroft-Gault formula.22 Subjects administered either ACE
nhibitors and/or ARBs were defined as ACE-inhibitor users.imilarly, subjects administered either statins and/or fibratesere combined and classified as lipid medication users.
tatistical AnalysisDescriptive statistics are provided with respect to HT use.
hi-square and t-tests were used to obtain P. The general-zed estimating equation procedure accounting for repeatedeasures (using data from both baseline and 5-year follow-
p) under exchangeable correlation was used for this analy-is. The generalized estimating equation also was used tovaluate associations between albuminuria and various de-ographic and laboratory measures. A separate analysis was
erformed for the overall cohort that had data at baselinenly. HT use is the main predictor variable of interest. In therst model, loge ACR (transformed to achieve normality)as used as a continuous outcome variable, and in the
econd model, abnormal albuminuria (albumin � 25 mg/g)
as used as a dichotomous outcome variable. The following uovariates were included in the analysis of HT on ACR: age,ace, body mass index, diabetes status, blood pressure,riglyceride level, HDL cholesterol level, glomerular filtra-ion rate, and smoking status. Statistical analysis was per-ormed using SAS software, version 8.2 (SAS Institute,ary, NC). P of 0.05 or less indicates statistical significance.
RESULTS
At the baseline visit, there were 744 postmeno-ausal women and HT use data were availableor all except 1 woman. After 5 years, a fol-ow-up examination of this cohort was con-ucted using the baseline protocol. The responseate was 66% (n � 491), and those who attendedhe follow-up examination were similar to thoseho did not attend (n � 253) in terms of age,
thnicity, sex, body mass index, diabetes status,nd HT use (all comparisons, P � 0.32).
Data from 491 women were analyzed; 179omen (36%) were HT users and 312 women
64%) were HT nonusers. Median duration ofT use was 8 years for HT users (171 of 179omen; 96%) and 1 year in nonusers (70 of 312omen; 22% had a previous history of HT use in
he nonuser group). Table 1 lists baseline demo-raphic characteristics of subjects by HT usemong postmenopausal women. Of 179 HT us-rs, 47% were white, 27% were black, and 26%ere Hispanic. HT users were significantlyounger (mean age, 57 � 7 years) and had aower body mass index (mean, 29 � 5 kg/m2)ompared with HT nonusers. Forty-eight percentf HT users were ever smokers (current or past),nd 25% had diabetes. Eleven percent of HTsers and 17% of HT nonusers had an ACR of 25g/g or greater (P � 0.02). Median ACR was
ignificantly lower among HT users comparedith HT nonusers (7.76 versus 9.14; P � 0.001).In univariate analysis, HT was associated with19% absolute decrease in ACR (95% confi-
ence interval [CI], �4% to �36%; P � 0.01)nd a 40% lower risk for abnormal albuminuriaP � 0.03). Table 2 lists results of multivariatenalysis for the overall cohort at baseline (n �44), modeling loge ACR and abnormal albumin-ria. There was an 18.5% reduction in ACR inT users (95% CI, �2% to �37%; P � 0.027).Table 3 lists results of multivariate analysis for
he study cohort that had follow-up data (n �91), modeling loge ACR and abnormal albumin-ria. There was a 19% reduction in ACR in HT
sers (95% CI, �4% to �35%; P � 0.008) and a
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3% reduced risk for abnormal albuminuria (P0.06). Diabetes, blood pressure, and triglycer-
de levels also were significant predictors oflbuminuria. There was no significant differencebserved in the direction or magnitude of associa-ion between ACR and HT use among patientsith or without diabetes in our stratified analysis.owever, this study was not powered to compare
he effect of HT between women with (n � 166)nd without diabetes (n � 325).
Some subjects (n � 116) switched from 1reatment group to the other during the 5-yearollow-up period. Therefore, we performed aeparate analysis including only participants who
Table 1. Baseline Demographic Characteristics
Variables
atientsge (y)aceWhiteBlackHispanic
ody mass index (kg/m2)mokersEverNeveriabetesedian duration of diabetes (y)ystolic blood pressure (mm Hg)iastolic blood pressure (mm Hg)riglycerides (mg/dL)DL cholesterol (mg/dL)ow-density lipoprotein cholesterol (mg/dL)ormal albuminuria (�25 mg/g)bnormal albuminuria (�25 mg/g)CRMedianMean (mg/g)
oge ACRMean 2Medianlomerular filtration rate (mL/min)† 105ipid medications‡CE inhibitors§edian duration previous HT use (y) 8istory of cardiovascular disease
NOTE. Values expressed as mean � SD or number (pultiply by 0.01667; HDL and low-density lipoprotein chog/dL to mmol/L, multiply by 0.0113.*By chi-square or t-test.†By Cockcroft-Gault formula.22
‡Lipid medications include statins and fibrates.§Includes ACE inhibitors and ARBs.
emained concordant on HT use throughout the r
tudy period (n � 375; HT user, n � 141; HTonuser, n � 234). Multivariate analysis for thisubgroup showed a 30% reduction in ACR amongT users (95% CI, �14% to �47%; P � 0.0002).
DISCUSSION
Microalbuminuria, a marker for vascular endo-helial damage, is associated with increased riskor cardiovascular events.15 The purpose of thistudy is to determine whether an associationxists between albuminuria and HT use amongostmenopausal women. We show that the use ofT is associated with a reduction in absolute
mount of albuminuria over time and a lower
Total Cohort by HT and Abnormal Albuminuria
s) HT (no) P *
6) 312 (64)7 58 � 7 �0.0001
7) 98 (31) 0.00137) 100 (32)6) 114 (37)5 31 � 6 �0.0001
8) 137 (44) 0.372) 175 (56)5) 121 (39) 0.00231) 4 (n � 84) 0.000119 126 � 17 0.00018 77 � 8 0.000181 148 � 98 �0.000115 46 � 14 �0.000135 149 � 35 �0.00019) 259 (83) 0.021) 53 (17)
9.14 0.000125 30 � 84
0.82 2.43 � 1.07 0.00012.21
� 177) 113 � 39 (n � 299) 0.00010) 23 (7) 0.303) 50 (16) 0.3471) 1 (n � 70) 0.0001
0) 57 (18) 0.70
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Noteworthy in this study is that the averagege of HT users was 57 years and median dura-ion of HT use was 8 years; thus, HT use wastarted at the initiation of menopause. Time ofnitiation of HT use relative to the onset ofenopause is associated significantly with a re-
uction in coronary artery calcification, suggest-ng coronary artery atherosclerosis protection byT.23,24 In monkeys with little or no atheroscle-
osis at the time of surgical menopause, immedi-te treatment with estrogen inhibited coronaryrtery atherosclerosis by approximately 70%.25
hus, the window of therapeutic opportunity toeduce coronary risk by means of HT may beeen in the early stages of menopause. This alsoas shown by the Women’s Health Initiative
Table 2. Multivariate Analys
Variable � Coefficient
T �0.1699 �0ge (y) �0.0182 �0ace (black v white) �0.1499 �0ace (Hispanic v white) �0.0679 �0iabetes 0.4728 0ystolic blood pressure (mm Hg) 0.0177 0iastolic blood pressure (mm Hg) �0.0153 �0riglycerides (mg/dL) 0.0004 �0DL (mg/dL) �0.0008 �0moke ever 0.1161 �0ody mass index (kg/m2) 0.0066 �0lomerular filtration rate (mL/min) �0.0007 �0
NOTE. n � 744. Loge ACR is a continuous variable and a
Table 3. Multivariate Analysis Mode
Variable
L
� Coefficient
T �0.1723 �ge (y) �0.0101 �ace (black v white) 0.0553 �ace (Hispanic v white) 0.0580 �iabetes 0.3400ystolic blood pressure (mm Hg) 0.0182iastolic blood pressure (mm Hg) �0.0109 �riglycerides (mg/dL) 0.0007 �DL (mg/dL) �0.0045 �moke ever �0.0325 �ody mass index (kg/m2) �0.0002 �lomerular filtration rate (mL/min) 0.0004 �
NOTE. n � 491. Loge ACR is a continuous variable and abnorm
tudy when risk ratios for coronary events at 10,0 to 19, and more than 20 years after meno-ause were 0.89, 1.22, and 1.71.26
Overall, 15% of women (72 of 491 women) inhis report had elevated urinary albumin excre-ion. Among these women, 27% (19 women)ere HT users and 73% (53 women) were nonus-
rs. Although the adjusted odds ratio (OR) forhe presence of abnormal albuminuria with HTse was not significant (OR, 0.67; P � 0.06),here was a 16% reduction in ACR among HTsers (P � 0.008). This is in contrast to arevious report by Monster et al17 showing thaticroalbuminuria was more likely to be present
n women administered oral contraceptives orT (adjusted OR, 2.05; 95% CI, 1.12 to 3.77).
eling for the Overall Cohort
R Abnormal Albuminuria
CI P OR 95% CI P
0.0191 0.027 0.95 0.90-1.01 0.090.0070 0.0014 0.99 0.98-0.99 �0.0001.0413 0.12 0.97 0.90-1.04 0.43.0925 0.40 0.97 0.91-1.03 0.40.6509 �0.0001 1.19 1.11-1.28 �0.0001.0238 �0.0001 1.06 1.03-1.08 �0.00010.0029 0.015 0.99 0.98-0.99 0.03.0011 0.33 1.00 0.99-1.00 0.53.0046 0.78 0.99 0.99-1.01 0.67.2565 0.10 1.04 0.98-1.10 0.11.0195 0.31 0.99 0.99-1.01 0.93.0007 0.30 0.99 0.99-1.01 0.60
al albuminuria is a dichotomous variable.
r Women Who Had Follow-Up Data
R Abnormal Albuminuria
CI P OR 95% CI P
-�0.0439 0.008 0.67 0.43-1.01 0.06-0.0011 0.07 0.97 0.93-1.00 0.05-0.2432 0.56 1.49 0.87-2.54 0.14-0.2140 0.46 1.04 0.64-1.65 0.88-0.4790 �0.0001 2.58 1.72-3.87 �0.0001-0.0242 �0.0001 1.04 1.02-1.05 �0.0001-�0.0009 0.03 0.97 0.95-0.99 0.04-0.0015 0.05 1.00 1.00-1.00 0.017-0.0004 0.07 0.99 0.98-1.01 0.92-0.1055 0.64 0.85 0.57-1.25 0.41-0.0153 0.98 0.97 0.93-1.01 0.16-0.0034 0.79 1.00 0.99-1.01 0.49
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here were markedly fewer patients with diabe-es (�11%) in the prior study, whereas 34% ofomen in our analysis had diabetes.Two other reports examined the effect of HT
n albuminuria. A small prospective study fromungary18 evaluated whether HT could reverseroteinuria in women with type 2 diabetes andypertension (n � 16). Participants were admin-stered combination HT for 14 weeks. The studyhowed that HT reduced proteinuria (protein,52 �g/mg at baseline to 370 �g/mg after HTse; P � 0.01).18 A second nonrandomized pro-pective study27 reported that 3 months of trans-ermal HT in postmenopausal women with typediabetes and hypertension did not adversely
ffect proteinuria (protein, 143.7 mg/d baseline,45.2 mg/d after HT; P � 0.64). One random-zed trial19 suggested that 6 months of oral HToes not reverse microalbuminuria caused byrolonged hyperglycemia and other risk factorsnderlying leakage of albumin into the urine inostmenopausal women with diabetes. Meanhange in ACR was not different in womeneceiving HT (mean, 2 mg/g; interquartile range,11 to 21 mg/g; n � 20) compared with placebo
mean, 2 mg/g; interquartile range, �1 to 14 mg/; n � 27). These studies were limited by theirhort-term nature and performance in subjectsith diabetes with preexisting vascular endothe-
ial damage.Several animal studies suggested a potential
rotective effect of HT on albuminuria. In ro-ents,28 estriol and 17�-estradiol 3-benzoate de-reased albuminuria, as well as glomerular andubulointerstitial damage.29 Kang et al30 showedhat 17�-estradiol may protect female rats fromrogressive renal injury by stimulating vascularndothelial growth factor messenger RNA expres-ion in renal tubular cells and vascular smoothuscle cells. Antus et al31 reported that estradiol
eplacement in ovariectomized rats reduced pro-einuria in parallel with diminished glomerularnjury and reduced transforming growth factor1 and platelet-derived growth factor A messen-er RNA expression.Mechanisms by which HT use can reduce
roteinuria in humans remain unclear. Her-ington et al32 reported the beneficial effects ofT on endothelium-dependent vasodilation. Im-rovement in albuminuria also might result from
ecreased intraglomerular pressure mediated by lhe vasodilatory effect of estrogen.33 The abilityf estrogen to reduce monocyte chemotaxis,34
odulate growth, or decrease oxidative stress35,36
lso could affect glomerular function. HT alsoppears to improve glomerular endothelial func-ion and glomerular capillary wall integrity, in-rease insulin sensitivity, and decrease glucoseevels.37
HT has independent and complimentary ef-ects on serum lipid profiles in healthy postmeno-ausal women.38 High HDL cholesterol levelsre believed to protect women from the develop-ent of coronary heart disease. Cleeman andenfant39 reported that small increases in HDLholesterol levels appear to have a large impactn the risk for heart disease. HT also can causen increase in HDL cholesterol levels by increas-ng paraoxonase arylesterase enzyme activity.40
ur study shows increased HDL cholesterol lev-ls among HT users (54 � 15 versus 46 � 14g/dL; P � 0.0001), consistent with the Post-enopausal Estrogen/Progestin Interventions,11
eart Estrogen and Progestin Replacementtudy,12 and Women’s Health Initiative13 trials.Several studies have shown that statins im-
rove albuminuria, renal function, hypertension,nd arterial wall stiffness,41 and these effectsay contribute to the significant reduction in
ascular events.42,43 When statins are combinedith HT, further improvements are observed in
erum lipid levels, which should indirectly de-rease cardiovascular risk.44,45 In the HERS,tatin use was associated with lower rates ofardiovascular events, venous thromboembolicvents, and total mortality.46 In the present re-ort, similar percentages of women were admin-stered lipid-lowering medications among usersnd nonusers of HT (10% versus 7%, respec-ively; P � 0.30).
ACE inhibitors47,48 and ARBs49,50 are associ-ted with cardiovascular and renal protection.oth ACE inhibitors and ARBs prevent andelay the progression of microalbuminuria tovert albuminuria in persons with type 2 diabe-es.51-53 Despite the low prevalence of ACE-nhibitor and ARB use among HT users (13%),he prevalence of microalbuminuria was lower inhis group.
Potential limitations of this analysis includehat HT use was self-reported by subjects, and
ong-term follow-up of ACR and clinical course
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ould be required to determine whether changesn cardiovascular events relating to changes inlbuminuria ultimately develop. It also should betated that this is an observational analysis. Aajor difference between observational and ran-
omized studies is confounding bias, or theealthy user effect, meaning that in observationaltudies, women who choose to use hormonesenerally are healthier than women who do notse hormones. Also, there are unmeasured fac-ors, such as socioeconomic status, level of edu-ation, and lifestyle, that have not been adjustedor in this analysis. These can produce both anverestimate of protective effects and underesti-ation of risks associated with HT.In conclusion, results of this large study of the
ssociation between hormone replacementherapy and albuminuria suggest that HT useay be associated with reductions in albumin-
ria in postmenopausal women. These results arearadoxical in that reductions in ACR typicallyre associated with reduced rates of cardiovascu-ar disease, an effect not observed with HT. Thisay be explained by the timing of initiation ofT relative to the onset of menopause. It will be
mportant to initiate future long-term, random-zed, controlled trials to clarify the associationetween estrogen and albuminuria.
REFERENCES
1. Sultan N, Nawaz M, Sultan A, Fayaz M, Baseer A:ffect of menopause on serum HDL-cholesterol level. Jyub Med Coll Abbottabad 15:24-26, 20032. Bulliyya G: Risk of coronary heart disease in women
fter menopause. J Indian Med Assoc 99:478-480, 20013. Kannel WB, Hjortland MC, McNamara PM: Meno-
ause and risk of cardiovascular disease: The Framinghamtudy. Ann Intern Med 85:447-452, 19764. Wenger NK, Speroff L, Packard B: Cardiovascular
ealth and disease in women. N Engl J Med 329:247-256,9935. North American Menopause Society: Treatment ofenopause-associated vasomotor symptoms: Position state-ent of The North American Menopause Society. Meno-
ause 1:11-33, 20046. Gilligan DM, Badar DM, Panza JA, Quyyumi AA,
annon RO: Acute vascular effects of estrogen in postmeno-ausal women. Circulation 90:786-791, 19947. Lindquist O, Bengtsson C, Hansson T, Roos B: Effect
f age and menopause on osteoporosis. Scand J Soc Meduppl 14:S80-S84, 19778. Grodstein F, Stampfer MJ, Coltz GA, et al: Postmeno-
ausal hormone therapy and mortality. N Engl J Med 336:
769-1775, 1997 59. Grodstein F, Stampfer MJ, Manson JE, et al: Postmeno-ausal estrogen and progestin use and the risk of cardiovas-ular disease. N Engl J Med 335:453-461, 1996
10. Pan CX, Boal J: Hormone replacement therapy forecondary prevention of coronary heart disease. JAMA81:794-797, 199911. The Writing Group for the PEPI Trial: Effects of
strogen or estrogen/progestin regimens on heart diseaseisk factors in postmenopausal women: The Postmenopausalstrogen/Progestin Interventions (PEPI) trial. JAMA 273:99-208, 199512. Hulley S, Grady D, Bush T, et al, for the Heart and
strogen/Progestin Replacement Study Research Group:andomized trial of estrogen plus progestin for secondaryrevention of coronary heart disease in postmenopausalomen. JAMA 280:605-613, 199813. Writing Group for the Women’s Health Initiative
nvestigators: Risks and benefits of estrogen plus progestinn healthy postmenopausal women: Principal results fromhe Women’s Health Initiative randomized controlled trial.AMA 288:321-333, 2002
14. Jarret RJ, Viberti GC, Argyropoulos A, et al: Micoalbu-inuria predicts mortality in non-insulin dependent diabet-
cs. Diabet Med 1:17-19, 198415. Jensen JS, Feldt-Rasmussen B, Borch-Johnsen K,
lausen P: Microalbuminuria and its relation to cardiovascu-ar disease and risk factors: A population based study of 154ypertensive individuals. J Hum Hypertens 11:727-732,99716. Remuzzi G: Abnormal protein traffic through the
lomerular barrier induces proximal tubular cell dysfunctionnd causes renal injury. Curr Opin Nephrol Hypertens 4:339-42, 199517. Monster TB, Janssen WM, de Jong PE, de Jong-van
en Berg LT: Prevention of Renal and Vascular End Stageisease Study Group. Oral contraceptive use and hormone
eplacement therapy are associated with microalbuminuria.rch Intern Med 161:2000-2005, 200118. Szekacs B, Vajo Z, Varbiro S, et al: Postmenopausal
ormone replacement improves proteinuria and impairedreatinine clearance in type 2 diabetes mellitus and hyperten-ion. Br J Obstet Gynaecol 107:1017-1021, 2000
19. Manning PJ, Sutherland WH, Allum AR, de Jong SA,ones SD: HRT does not improve urinary albumin excretionn postmenopausal diabetic women. Diabetes Res Clin Pract0:33-39, 200320. Wagenknecht LE, Mayer EJ, Reweres M, et al: The
nsulin Resistance Atherosclerosis Study (IRAS): Objec-ives, design, and recruitment results. Ann Epidemiol 5:464-72, 199521. Warram JH, Gearin G, Laffel L, et al: Effect of
uration of type I diabetes on the prevalence of diabeticephropathy defined by urinary albumin/creatinine ratio.Am Soc Nephrol 7:930-937, 199622. Cockroft DW, Gault MH: Prediction of creatinine
learance from serum creatinine. Nephron 16:31-41, 197623. Akhrass F, Evans AT, Wang Y, et al: Hormone replace-ent therapy is associated with less coronary atherosclerosis
n postmenopausal women. Clin Endocrinol Metab 88:5611-
614, 2003
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HORMONE THERAPY AND ALBUMINURIA 1025
24. Mikkola TS, Clarkson TB, Notelovitz M: Postmeno-ausal hormone therapy before and after the Women’sealth Initiative study: What consequences? Ann Med 36:02-413, 200425. Clarkson TB, Anthony MS, Morgan TM: Inhibition
f postmenopausal atherosclerosis progression: A compari-on of the effects of conjugated equine estrogens and soyhytoestrogens. Clin Endocrinol Metab 86:41-47, 200126. Manson JE, Hsia J, Johnson KC, et al: Estrogen plus
rogestin and the risk of coronary heart disease. N EnglMed 349:523-534, 200327. Fenkci S, Fenkci V, Yilmazer M, Serteser M, Koken
: Effects of short-term transdermal hormone replacementherapy on glycemic control, lipid metabolism, C-reactiverotein and proteinuria in postmenopausal women with typediabetes and hypertension. Hum Reprod 18:866-870, 200328. Gross ML, Adamczak M, Rabe T, et al: Beneficial
ffects of estrogens on indices of renal damage in uninephrec-omized SHRsp rats. J Am Soc Nephrol 15:348-358, 2004
29. Maric C, Sandberg K, Hinojoa-Laborde C: Glomeru-osclerosis and tubulointerstitial fibrosis are attenuated with7� estradiol in the aging Dahl salt sensitive rat. J Am Socephrol 15:1546-1556, 200430. Kang DH, Yu ES, Yoon K, Johnson R: The impact of
ender on progression of renal disease. Potential role ofstrogen mediated vascular endothelial growth factor regula-ion and vascular protection. Am J Pathol 164:679-688, 2004
31. Antus B, Hamar P, Kokeny G, et al: Estradiol isephroprotective in the rat remnant kidney. Nephrol Dialransplant 18:54-61, 200332. Herrington DM, Espeland MA, Crouse JR III, et al:
strogen replacement and brachial artery flow-mediatedasodilation in older women. Arterioscler Thromb Vasc Biol1:1955-1961, 200133. Gerhard M, Walsh BW, Tawakol A, et al: Estradiol
herapy combined with progesterone and endothelium-ependent vasodilation in postmenopausal women. Circula-ion 98:1158-1163, 1998
34. Pervin S, Singh R, Rosenfeld ME, Navab M,haudhuri G, Nathan L: Estradiol suppresses MCP-1 expres-
ion in vivo: Implications for atherosclerosis. Arteriosclerhromb Vasc Biol 18:1575-1582, 199835. Ghanam K, Javellaud J, Ea-Kim L, Oudart N: The
rotective effect of 17 beta-estradiol on vasomotor re-ponses of aorta from cholesterol-fed rabbit is reduced bynhibitors of superoxide dismutase and catalase. Biochemiophys Res Commun 249:858-864, 199836. Seeger H, Mueck AO, Lippert TH: The inhibitory
ffect of endogenous estrogen metabolites on copper-ediated in vitro oxidation of LDL. Int J Clin Pharmacolher 36:383-385, 199837. Espeland MA, Hogan PE, Fineberg SE, et al: Effect
f postmenopausal hormone therapy on glucose and insulin
oncentrations. PEPI Investigators (Postmenopausal Estro- cen/Progestin Interventions). Diabetes Care 21:1589-1595,99838. Binder EF, Birge SJ, Kohrt WM: Effects of endurance
xercise and hormone replacement therapy on serum lipidsn older women. J Am Geriatr Soc 44:231-236, 1996
39. Cleeman JI, Lenfant C: The National Cholesterolducation Program: Progress and prospects. JAMA 280:099-2104, 199840. Sutherland WH, Manning PJ, de Jong SA, Allum AR,
ones SD, Williams SM: Hormone-replacement therapy in-reases serum paraoxonase arylesterase activity in diabeticostmenopausal women. Metabolism 50:319-324, 200141. Elisaf M, Mikhailidis DP: Statins and renal function.
ngiology 53:493-502, 200242. Tsiara S, Elisaf M, Mikhailidis DP: Early vascular
enefits of statin therapy. Curr Med Res Opin 19:540-556,00343. Daniel KR, Herrington DM: Statin therapy in the
eart and Estrogen/Progestin Replacement Study. Minervainecol 55:209-215, 200344. Mueck AO, Seeger H: Statins and menopausal health.
Br Menopause Soc 8:141-146, 200245. Moghadasian MH: Statins and menopause. Drugs
2:2421-2431, 200246. Herrington DM, Vittinghoff E, Lin F, et al: Statin
herapy, cardiovascular events, and total mortality in theeart and Estrogen/Progestin Replacement Study (HERS).irculation 105:2962-2967, 200247. Lewis EJ, Hunsicker LG, Bainthe RP, Rohde RD:
he effect of angiotensin-converting-enzyme inhibition oniabetic nephropathy. N Engl J Med 329:1456-1462, 199348. Trevisan R, Tiengo A: Effect of low-dose ramipril onicroalbuminuria in normotensive or mild hypertensive
on-insulin-dependent diabetic patients. North-East Italyicroalbuminuria Study Group. Am J Hypertens 8:876-883,
99549. Viberti G, Wheeldon NM: Microalbuminuria reduc-
ion with valsartan in patients with type 2 diabetes mellitus:blood pressure-independent effect. Circulation 106:672-
78, 200250. Parving HH, Lehnert H, Brochner-Mortensen J, Gomis
, Andersen S, Arner P: The effect of irbesartan on theevelopment of diabetic nephropathy in patients with type 2iabetes. N Engl J Med 345:870-878, 2001
51. Raij L: Recommendations for the management ofpecial populations: Renal disease in diabetes. Am J Hyper-ens 16:S46-S49, 2003 (suppl 1)
52. Deferrari G, Ravera M, Berruti V, Leoncini G, Deferrari: Optimizing therapy in the diabetic patient with renal disease:ntihypertensive treatment. J Am Soc Nephrol 15:S6-S11,004 (suppl 1)
53. Lasaridis AN, Sarafidis PA: Diabetic nephropathynd antihypertensive treatment: What are the lessons from
linical trials? Am J Hypertens 16:689-697, 2003