The Role of Nephrectomy of the Atrophic Kidney in Bearers of
Renovascular Hypertension
Myrian J. Thomaz, Antonio M. Lucon, Jose N. Praxedes, Luis A. Bortolotto, Miguel Srougi
Department of Urology, Faculty of Medicine, University of Sao Paulo, Sao Paulo, Brazil
ABSTRACT
Purpose:(YDOXDWLRQRIWKHEHQH¿FLDOHIIHFWRIQHSKUHFWRP\RIWKHDWURSKLFNLGQH\RQEORRGSUHVVXUH%3DQGUHQDO
IXQFWLRQ
Materials and Methods: $UHWURVSHFWLYHVWXG\RISDWLHQWVZLWKUHQRYDVFXODUK\SHUWHQVLRQ59+EHDUHUVRIDWURSKLF
NLGQH\GXHWRVHYHUHVWHQRVLVRURFFOXVLRQRIWKHUHQDODUWHU\$YHUDJHDJHZDV\HDUVWKHPHGLDQFUHDWLQLQH FOHDUDQFHZDVP/PLQDYHUDJHV\VWROLF%36%3PP+JDYHUDJHGLDVWROLF%3'%3PP+J DQGWKHPHGLDQQXPEHURIK\SRWHQVRUVWRSHUSDWLHQWSHUGD\%ORRGSUHVVXUHDQGVHUXPFUHDWLQLQHZHUHDQDO\]HG IURPWRPRQWKVDIWHUWKHQHSKUHFWRP\
Results:7KHUHZDVDVLJQL¿FDQWLPSURYHPHQWLQWKHDYHUDJH6%3LQWKHSHULRGVIURPWRPRQWKVSDQGIRU
WKHDYHUDJH'%3IURPWRPRQWKVDIWHUWKHQHSKUHFWRP\SDFFRPSDQLHGE\DVLJQL¿FDQWUHGXFWLRQLQWKH XVHRIK\SRWHQVRUVIURPWRPRQWKVS2QH\HDUDIWHUWKHQHSKUHFWRP\WKHUHZDVDLPSURYHPHQWLQ EORRGSUHVVXUHDQGLPSURYHPHQWLQUHQDOIXQFWLRQRISDWLHQWV
Conclusion:7KHUHPRYDORIDWURSKLFNLGQH\LQSDWLHQWVZLWK59+LVDVDIHSURFHGXUHZKLFKSUHVHQWVEHQH¿WVIRUWKH
FRQWURORIDUWHULDOK\SHUWHQVLRQDQGUHQDOIXQFWLRQLQEHDUHUVRIUHQRYDVFXODUK\SHUWHQVLRQ
Key words: nephrectomy; atrophic; kidney renovascular; hypertension
Int Braz J Urol. 2010; 36: 159-70
INTRODUCTION
$PRQJWKHFDXVHVRIVHFRQGDU\K\SHUWHQVLRQ
ZHHPSKDVL]HUHQRYDVFXODUK\SHUWHQVLRQUHVXOWLQJ IURPUHQDOLVFKHPLDFDXVHGE\WKHWRWDORUSDUWLDOVWH-QRVLVRIWKHUHQDODUWHU\SUHVHQWLQJDQDWKHURVFOHURWLF HWLRORJ\LQRIWKHFDVHVDQG¿EURG\VSODVLDRIWKH DUWHU\LQ,WLVWKHVHFRQGPRVWFRPPRQ FDXVHRIVHFRQGDU\K\SHUWHQVLRQRQO\DIWHUSDUHQ-FK\PDOUHQDOGLVHDVHV,WRFFXUVLQIURPWRRI WKHDGXOWK\SHUWHQVLYHSRSXODWLRQEXWLQFUHDVHVLQWKH
HOGHUO\GLDEHWLFVDQGEHDUHUVRIV\VWHPLFDWKHURVFOH-doi: 10.1590/S1677-55382010000200005
URWLFOHVLRQV,WKDVJURZLQJSDUWLFLSDWLRQDVD FDXVHRIGLDO\WLFUHQDOLQVXI¿FLHQF\
WKHUHQDOIXQFWLRQZKHQWKHUHYDVFXODUL]DWLRQRIWKH DUWHU\ZDVQRORQJHUSRVVLEOH
MATERIALS AND METHODS
7KLVZDVDUHWURVSHFWLYHREVHUYDWLRQDOVWXG\ RISDWLHQWVZLWKDGLDJQRVLVRI59+ZKRXQGHU-ZHQWQHSKUHFWRP\GXULQJWKHSHULRGIURP-DQXDU\ WR-DQXDU\7HQSDWLHQWVZHUHORVWWRIRO-ORZXS7KHJHQHUDOGDWDRIWKHSDWLHQWVLVIRXQGLQ 7DEOH7KHDYHUDJHDJHRIWKHSDWLHQWVZDV \HDUVZLWKDSUHGRPLQDQFHRIWKHIHPDOHVH[DQG
WKHUHQDODUWHULHVWKHVWHQRVLVZKLFKPDGHXS RIWKHGLDPHWHURIWKHEORRGYHVVHOZHUHFRQVLGHUHG DVKHPRG\QDPLFDOO\VLJQL¿FDQWOHVLRQV7KHIXQFWLRQ RIWKHDWURSKLFNLGQH\PHDVXUHGE\UHQDOVFLQWLJUDSK\ ZLWKWKHUDGLRLVRWRSH'73$DQGFDSWRSULOZDV
7KHPHDVXUHPHQWRIWKHSODVPDUHQQLQDF-WLYLW\35$ZDVSHUIRUPHGE\UDGLRLPPXQRDVVD\ *DPPD&RDW35$,5LD.LWE\WKHFROOHFWLRQRI EORRGE\VHOHFWLYHFDWKHWHUL]DWLRQRIWKHUHQDOYHLQV DQGFDYDLQIHULRU
2I WKH RI SDWLHQWV ZKR ZHUH
EHDUHUVRIVLJQL¿FDQWELODWHUDOOHVLRQ
Table 1 – General data of the 51 patients with renovascular hypertension who underwent nephrectomy.
$YHUDJHDJH\HDUV6'PLQLPXPPD[LPXP
6H[IHPDOHPDOH
&RORUZKLWHQRQZKLWH
3HULRGRIDUWHULDOK\SHUWHQVLRQ\HDUVPHGLDQ PRQWK\HDUV $YHUDJHV\VWROLFEORRGSUHVVXUHLQPP+J $YHUDJHGLDVWROLFEORRGSUHVVXUHLQPP+J
1RRIK\SRWHQVRUGUXJVSDWLHQWGD\
3UHRSHUDWLYHPHGLDQVHUXPFUHDWLQLQHPJG/
+\SHUFKROHVWHUROHPLD
6PRNHUDQGH[VPRNHU
'LDEHWHVPHOOLWXV
3UHYLRXVFDUGLDFGLVHDVH
3UHYLRXVFHUHEURYDVFXODUGLVHDVH
UHTXLUHGUHYDVFXODUL]DWLRQE\SHUFXWDQHRXVWUDQVOX-PLQDODQJLRSODVW\37$RIWKHFRQWUDODWHUDODUWHU\ 7KH SUHYLRXV VXUJLFDO UHYDVFXODUL]DWLRQ E\ PHDQV RIDQDXWRWUDQVSODQWRIWKHFRQWUDODWHUDONLGQH\ZDV FDUULHGRXWLQRIWKHSDWLHQWV RIZKRPQRORQJHUUHTXLUHGGLDO\VLV(LJKWSHUFHQW GLGQRWXQGHUJRDQ\SURFHGXUH
7KHDUWHULRJUDSK\SHUIRUPHGE\PHDQVRI
VHOHFWLYH FDWKHWHUL]DWLRQ RI WKH UHQDO DUWHULHV ZDV SHUIRUPHGLQRIWKHFDVHV7KHPDJQHWLF UHVRQDQFHDQJLRJUDSK\RIWKHUHQDODUWHULHVZDVSHU-IRUPHGLQRIWKHSDWLHQWVDQGLWVSULQFLSDO LQGLFDWRUZDVWKHSUHVHQFHRIFUHDWLQLQHHTXDOWRRU JUHDWHUWKDQPJG/ 7KHUHFRPPHQGDWLRQIRUWKHQHSKUHFWRP\RI WKHDWURSKLFNLGQH\ZDVPDGHRQO\DIWHUWRWDORUVLJ-QL¿FDQWRFFOXVLRQRIWKHUHQDODUWHU\DVVRFLDWHGZLWK WKHDEVHQFHRIUHQDOIXQFWLRQKDGEHHQGHPRQVWUDWHG ,QRIWKHSDWLHQWVQHSKUHFWRPLHVE\YLGHRODSD-URVFRS\ZHUHSHUIRUPHGDQGLQWKHUHPDLQLQJ QHSKUHFWRPLHVE\OXPERWRP\
RIPRQWKVDQGUHPDLQHGFRQVWDQWXQWLOP K\SRWHQVRUVGD\DIWHUWKHQHSKUHFWRP\
2QH\HDUDIWHUWKHQHSKUHFWRP\SDWLHQWV
ZHUHVWLOOEHLQJIROORZHGXSDQGWKH%3RIRI WKHPKDGLPSURYHGLQDFFRUGDQFHZLWKWKHFULWHULD SUHYLRXVO\PHQWLRQHG7KHUHZDVRQHGHDWKDQG RQHGLDO\WLFUHQDOLQVXI¿FLHQF\ZKLFKZHUH H[FOXGHGIURPWKHVDPSOH7KHYDOXHRIWKHYDULDWLRQV RIWKH'%3DQG6%3DWPRQWKVIRUHDFKSDWLHQWDUH VKRZQLQ)LJXUHVDQGUHVSHFWLYHO\ZKHUHLQWKH ORZHUSDUWRIHDFK¿JXUHDUHVKRZQWKHSDWLHQWVZKRVH SUHVVXUHOHYHOVLPSURYHG7KHUHZDVDQ
FXUHUDWHRI59+RIWKHSDWLHQWVKDG¿EURPXVFXODU G\VSODVLDRIWKHUHQDODUWHU\
6L[W\QLQHSHUFHQWRIWKHSDWLHQWV
ZHUHFRQVLGHUHGUHVSRQGHUVDVWKH\KDGVKRZQDQ LPSURYHPHQWLQEORRGSUHVVXUHDQGRI WKHSDWLHQWVDVQRQUHVSRQGHUVDVWKHLUEORRGSUHVVXUH KDGZRUVHQHG7KHUHZDVQRVLJQL¿FDQWGLIIHUHQFH S!EHWZHHQWKHJURXSVIRUDQ\RIWKHIDF-WRUVDQDO\]HGDJHVH[FRORULQLWLDOEORRGSUHVVXUH LQLWLDOFUHDWLQLQHELODWHUDOGLVHDVHULVNIDFWRUVDQG FRPRUELGLWLHV7DEOH7KHUHQDOIXQFWLRQRIWKH SDWLHQWVZDVFKHFNHGE\WKHPHDVXUHPHQWRIVHUXP
Table 2 – Averages of the systolic blood pressures from the pre-operative period until 60 months pos-nephrectomy.
mm Hg Pre 12 m 24 m 36 m 48 m 60 m
$YHUDJH
'3
0HGLDQ
0LQLPXP
0D[LPXP
1RREVHUYHG
FUHDWLQLQHWDNHQHYHU\PRQWKVXSWRPRQWKV SRVWQHSKUHFWRP\DQGWKHHVWLPDWHGFUHDWLQLQHFOHDU-DQFH0'5'ZDVFDOFXODWHG7KHUHZDVDIROORZXS ORVVRIRIWKHSDWLHQWV
)LJXUHVKRZVWKHSURJUHVVLQUHQDOIXQFWLRQ
RYHUWKHPRQWKVRIREVHUYDWLRQ7ZHOYHPRQWKV SRVWQHSKUHFWRP\RIWKHSDWLHQWVSUHVHQW-HGDQLPSURYHPHQWLQFUHDWLQLQHFOHDUDQFH0'5' UHSUHVHQWHGE\WKHDVFHQGLQJFXUYHV
)LJXUHVKRZVWKHSURJUHVVLQUHQDOIXQFWLRQ
RYHUPRQWKV2QHFDQREVHUYHWKH RISDWLHQWVZKRVHUHQDOIXQFWLRQZRUVHQHGIDOOLQJ FXUYHV:RUWK\ RI QRWH DPRQJ WKLV JURXS DUH WKH RISDWLHQWVZKRLQLWLDOO\ORVWUHQDOIXQFWLRQEXW ZKRGHPRQVWUDWHGUHFRYHU\RIWKLVIXQFWLRQGXULQJ WKHIROORZXSSHULRG'LDO\VLVZDVQHFHVVDU\LQ RIWKHSDWLHQWVRYHUWKHPRQWKSHULRG :KHQWKHFKDUDFWHULVWLFVRIWKHSDWLHQWVGL-YLGHGLQWRJURXSVDFFRUGLQJWRWKHLPSURYHPHQWRU
ZRUVHQLQJRIWKHLUUHQDOIXQFWLRQZHUHVWXGLHGWKH\ ZHUHIRXQGWREHKRPRJHQHRXVWKDWLVWRVD\ZLWK-RXWDQ\VWDWLVWLFDOO\VLJQL¿FDQWGLIIHUHQFHDPRQJWKH YDULDEOHVVWXGLHGS!LHWKHVHVDPHIDFWRUV DVZHUHDQDO\]HGIRUWKHEORRGSUHVVXUH7DEOH
6L[W\SHUFHQWRIWKHFDVHVRIWKLVVWXG\
KDGOHYHOVRIVHUXPUHQQLQDFWLYLW\/DWHUDOL]DWLRQRI WKHUHQQLQZDVIRXQGLQRIWKHSDWLHQWVGLYLGHG DPRQJWKHGLIIHUHQWJURXSVZLWKQRVWDWLVWLFDOVLJQL¿-FDQFH
,Q HOHYHQ SDWLHQWV WKHUH ZDV QR
VHJPHQWDOVWHQRVLVRIWKHYHVVHO,QWKHKLVWRSDWKR-ORJLFDODQDO\VLVRIWKHUHQDODUWHU\RIWKHUHPDLQLQJ SDWLHQWVZHIRXQGDWKHURVFOHURVLVRIWKHUHQDODUWHU\ LQRIWKHFDVHV¿EURPXVFXODUG\VSODVLDLQ DQG7DND\DVXDUWHULWLVLQ7KHKLVWRORJLFDOGDWD REWDLQHGIURPWKHUHQDOSDUHQFK\PDDUHLVFKHPLF DWURSK\RIWKHUHQDOSDUHQFK\PDLQRIWKHFDVHV
EHQLJQQHSKURVFOHURVLVLQPDOLJQDQWQHSKUR-Table 3 – Averages of the diastolic blood pressures (DBP) from the pre-operative period until 60 months pos-nephrec-tomy.
mm Hg Pre 12 m 24 m 36 m 48 m 60 m
$YHUDJH
'%3
0HGLDQ
0LQLPXP
0D[LPXP
1RREVHUYHG
Table 4 – Differences in systolic and diastolic pressures as between the pre-operative period and each of the instants as-sessed in patients with RVH (in mm Hg).
Months ǻ6$36$3SRVWOHVV6$3SUHY ǻ'$3'$3SRVWOHVV'$3SUHY
P S SJ
P S S
P S S
P S S
VFOHURVLV LQ LVFKHPLF LQIDUFWLRQ RI WKH UHQDO SDUHQFK\PDLQRIWKHSDWLHQWVLQWHUVWLWLDOQHSKULWLV LQFKURQLFS\HORQHSKULWLVLQDQGPDOLJQDQW UHQDOQHRSODVPVRIOHVVWKDQFPLQRIWKHFDVHV VWXGLHG
,QWKHJURXSZLWKLPSURYHPHQWRIWKHUHQDO
IXQFWLRQRIWKHSDWLHQWVKDGDGLDJQRVLVRI ¿EURPXVFXODUG\VSODVLDDQGRIWKHFDVHVKDG DWKHURVFOHURVLVDQGE\PHDQVRIWKHDSSOLFDWLRQRI
WKHJHQHUDOL]DWLRQRI)LVKHU¶V([DFW7HVWDVWDWLVWL-FDOO\VLJQL¿FDQWDVVRFLDWLRQZDVREVHUYHGS EHWZHHQWKLVKLVWRORJLFDOW\SHDQGWKHLPSURYHPHQW LQUHQDOIXQFWLRQ1RHPEROLFFRPSOLFDWLRQVZHUH LGHQWL¿HGLQWKLVVHULHV
COMMENTS
59+WUHDWPHQWKDVFKDQJHGRYHUUHFHQW\HDUV
7KHXVHRIQHSKUHFWRP\KDVGHFOLQHGDVDUHVXOWRIWKH
Figure 2 – Variation of SBP of each patient 12m after nephrectomy (n = 49). Ɣreduction , Ÿsame and Ŷincreased number of hypo-tensors.
ULVHRIQHZK\SRWHQVRUGUXJVGHYHORSHGRQWKHEDVLV RIWKHNQRZOHGJHWKHDOGRVWHURQHDQJLRWHQVLQUHQQLQ V\VWHPDQGWKHGHYHORSPHQWRIDQJLRSODVW\WHFKQLTXHV 37$ZLWKWKHLPSODQWLQJRI³VWHQWV´0RUH UHFHQWO\WKHLPSURYHGXQGHUVWDQGLQJRIWKHPHFKD-QLVPVZKLFKKDUPGHSHQGHQWHQGRWKHOLDOGLODWLRQDQG R[LGDWLYHVWUHVVHVSHFLDOO\DVUHODWHGWRKLJKOHYHOV RIDQJLRWHQVLQ,,SDUWLFXODUO\LQWKHDWKHURVFOHURWLF OHVLRQKHUDOGQHZIRUPVRIWUHDWPHQWIRUWKHIXWXUH
7KHUHPRYDORIWKHDWURSKLFNLGQH\FDXVHGE\
WKHVHYHUHVWHQRVLVRIWKHUHQDODUWHU\ZDVFDUULHGRXW
LQSDWLHQWVZLWKUHIUDFWRU\DUWHULDOK\SHUWHQVLRQZLWK QRSRVVLELOLW\RIUHYDVFXODUL]DWLRQ
9DULRXV VWXGLHV KDYH EHHQ UHSRUWHG LQ WKH OLWHUDWXUHFRPSDULQJSHUFXWDQHRXVUHYDVFXODUL]DWLRQ DQGFRQVHUYDWLYHFOLQLFDOWUHDWPHQWLQWKHWUHDWPHQW RI59+EXWWKHUHDUHIHZVHULHVUHJDUGLQJWKH QHSKUHFWRP\RIWKHDWURSKLFNLGQH\DVDQDOWHUQD-WLYHIRUPRIWUHDWPHQWIRUWKHEHDUHURIUHQRYDVFXODU K\SHUWHQVLRQZLWKEORRGSUHVVXUHRIGLI¿FXOWFRQWURO
7KLV VWXG\ DQDO\]HG QHSKUHFWRPLHV RI
WKHDWURSKLFNLGQH\IRUFRPSOHWHREVWUXFWLRQRIWKH
Table 5 – Characteristics of the patients with renovascular hypertension, in accordance with the pressure response to nephrectomy.
Responders
1 Non Responders1 p Value
$JH\HDUV
6H[0DOH)HPDOH
&RORU:KLWH1RQZKLWH
7LPHRIK\SHUWHQVLRQLQ\HDUV
6\VWROLF%RRG3UHVVXUHSUHYPP+J
'LDVWROLF%ORRG3UHVVXUHSUHYPP+J
1RK\SRWHQVRUV
6HUXP&UHDWLQLQHPJG/
&OHDUDQFHRI&UHDWLQLQHP/PLQ
86DWURSKLFNLGQH\FP
/HVLRQ!RIFRQWUDODWHUDOUHQDODUWHU\RQ'RSSOHU
6FLQWLJUDSK\FRP'73$DWURSKLFNLGQH\
&RQWUDODWHUDONLGQH\
/DWHUDOL]DWLRQRIVHUXPUHQQLQ<HV1R
+\SHUFKROHVWHUROHPLD<HV1R
6PRNLQJ<HV1R
+HDUW'LVHDVH<HV1R !
6WURNH<HV1R !
'LDEHWHV0HOOLWXV<HV1R !
3HULSKHUDO$UWHULDO'LVHDVH
<HV1R !
$RUWLF$QHXULVP<HV1R !
UHQDODUWHU\7KHUHZDVDSUHGRPLQDQFHRIWKHYLGHR ODSDURVFRSLFWHFKQLTXHZKLFKZDVXVHGLQRI WKHFDVHV$\HDUDIWHUQHSKUHFWRP\6%3ZDV PP+JDQG'%3RIPP+JVLJQL¿FDQWO\ ORZHUWKDQWKHLQLWLDOOHYHOVDQGWKH\ZHUHWKXVPDLQ-WDLQHGIRUPRQWKVDQGPRQWKVUHVSHFWLYHO\ WRJHWKHUZLWKDVLJQL¿FDQWUHGXFWLRQLQWKHQXPEHU RIK\SRWHQVRUV
7KH GLYLVLRQ LQWR JURXSV RQ WKH EDVLV RI UHVSRQVHLQWHUPVRIEORRGSUHVVXUHDQGUHQDOIXQF-WLRQRQH\HDUDIWHUQHSKUHFWRP\ZDVSHUIRUPHGWR LGHQWLI\WKRVHFKDUDFWHULVWLFVZKLFKGHWHUPLQHGWKH UHVSRQVH 6L[W\HLJKW SHUFHQW RI WKH FDVHV ZKLFK
SUHVHQWHGDQLPSURYHPHQWLQDUWHULDOK\SHUWHQVLRQ ZHUH LQFOXGHG LQ WKH JURXS 5 RI WKHP EH-LQJFXUHGDIWHURQH\HDURIWKHPEHLQJ SDWLHQWVZLWK5+9GXHWR¿EURPXVFXODUG\VSODVLD RIWKHUHQDODUWHU\DQGRIWKHUHPDLQLQJFDVHV EHORQJLQJWRWKH15JURXS7DEOH7KHFUHDWLQLQH FOHDUDQFH0'5'FXUYHZDVXVHGWRHQ-DEOHXVWRFODVVLI\WKHSDWLHQWVE\JURXSLQWRWKRVH ZKLFKSUHVHQWHGHLWKHULPSURYHPHQWRUZRUVHQLQJ RIWKHUHQDOIXQFWLRQDWPRQWKV7KHUHZDVDQ LPSURYHPHQWLQFUHDWLQLQHFOHDUDQFHRQH\HDUDIWHU QHSKUHFWRP\LQRIWKHFDVHV)LJXUHDQGD ZRUVHQLQJLQ)LJXUH7ZHOYHSHUFHQWRIWKH
Figure 4 – Patients with improved creatinine clearance (n = 30).
Table 6 – Characteristics of the patients in accordance with the response of their renal function to nephrectomy.
Improvement
1 Worsening1 p Value
$JH\HDUV
6H[0DOH)HPDOH
&RORU:KLWH1RQZKLWH
7LPHRIK\SHUWHQVLRQ\HDUV
6%3SUHYLRXVPP+J
'%3SUHYLRXVPP+J
1K\SRWHQVRUV
6HUXP&UHDWLQLQHPJG/
&OHDUDQFH&UHDWLQLQHP/PLQ
86DWURSKLFNLGQH\FP
/HVLRQ!RIFRQWUDODWUHQDODUWHU\RQ'RSSOHU 6FLQWLJUDSK\ZLWK'73$DWURSKLFNLGQH\ ± ±
&RQWUDODWHUDONLGQH\
/DWHUDOL]DWLRQRIVHUXPUHQQLQ<HV1R
+\SHUFKROHVWHUROHPLD<HV1R
6PRNLQJ<HV1R
+HDUWGLVHDVH<HV1R
'LDEHWHV0HOOLWXV<HV1R
6WURNH<HV1R
$RUWLF$QHXULVP<HV1R
† US = renal ultrasound.
SDWLHQWVZLWKFUHDWLQLQHFOHDUDQFHP/PLQDW VXUJHU\FRQWLQXHGQRWWRQHHGGLDO\VLVGXULQJWKH SHULRGRIPRQWKVDQDO\]HG)LJXUHDQG RIWKHSDWLHQWVZKRVHUHQDOIXQFWLRQZRUVHQHGDW PRQWKVVKRZHGUHFRYHU\RIWKHIXQFWLRQRYHUWKH PRQWKV )LJXUH7KHUH ZDV QR VWDWLVWLFDOO\ VLJQL¿FDQWOHVLRQSUHVHQW7DEOH0RGHUDWHUHQDO LQVXI¿FLHQF\ZKLFKPLJKWEHDQLPSRUWDQWIDFWRU OHDGLQJWRD¿QDOQHHGIRUGLDO\VLVZDVQRWVLJQL¿FDQW LQWKLVSDWLHQWSRSXODWLRQSRVVLEO\EHFDXVHRIWKH VPDOOQXPEHURIFDVHVLQYROYHG
,QWKHIRXUJURXSVWKHFKDUDFWHULVWLFVVWXGLHG VXFKDVVH[FRORUDJHVPRNLQJK\SHUFKROHVWHURO-HPLDDQGFRPRUELGLWLHVSUHVHQWHGVLPLODUGLVWULEXWLRQ ZLWKQRVLJQL¿FDQWVWDWLVWLFDOGLIIHUHQFHS!
1RODWHUDOL]DWLRQRIWKHUHQQLQZDVIRXQGDVDSUHG-LFDWLYHIDFWRURIUHVXOWVVLPLODUGDWDDUHGHVFULEHGE\ +DVEDNHWDO7KHIDFWRUVZKLFKZRXOGH[SODLQ WKHDEVHQFHRIWKHODWHUDOL]DWLRQRIUHQQLQDUHELODWHUDO VWHQRVLVRIWKHUHQDODUWHU\VWDWHVRIYROHPLFGHSOHWLRQ FKURQLFXVHRILQKLELWRUVRIWKHFRQYHUVLRQHQ]\PH RIDQJLRWHQVLQ,WR,,,(&$DQGUHQDOLQVXI¿FLHQF\ 5RVVLHWDOIRXQGDFRUUHODWLRQRIWKHODWHUDOL]D-WLRQRIVHUXPUHQQLQDFWLYLW\RQO\LQEHDUHUVRI59+ ZLWKXQLODWHUDODWURSKLFNLGQH\E\FRPSOHWHRFFOXVLRQ RIWKHUHQDODUWHU\WKDWXQGHUZHQWQHSKUHFWRP\EXW WKHUHZDVQRODWHUDOL]DWLRQRIWKHUHQQLQSODVPDLQ SDWLHQWVWUHDWHGZLWKDQJLRSODVW\
7KHSUHVHQFHRIVLJQL¿FDQWOHVLRQ!
K\SHUWHQVLRQEXWZDVLQIHULRUWRUHYDVFXODUL]DWLRQIRU WKHSUHVHUYDWLRQRIWKHUHQDOIXQFWLRQ
7KHDYHUDJHDJHRI\HDUVLQWKLVVHULHVLVLQ-IHULRUWRWKH\HDUVRIRWKHUUHSRUWHGVHULHV 2IWKHZRPHQLQWKLVVWXG\ZHUHRI FKLOGEHDULQJDJHDWULVNRIEHFRPLQJSUHJQDQW7KH SUHYDOHQFHRIUHQRYDVFXODUK\SHUWHQVLRQGXULQJSUHJ-QDQF\LVXQNQRZQZKHUHDVWKHVLJQL¿FDQWO\JUHDWHU ULVN RI SUHHFODPSVLD LQ WKH ZRPDQ ZLWK FKURQLF DUWHULDOK\SHUWHQVLRQLVNQRZQ1HSKUHFWRP\RIWKH DWURSKLFNLGQH\EHIRUHDQHZSUHJQDQF\DIWHUDIDLOXUH FDQLPSURYHWKHPDWHUQDODQGIHWDOSURJQRVLV 7KHUHODWLRQVKLSEHWZHHQVWHQRVLVRIWKHUHQDO DUWHU\DQGRWKHUV\VWHPLFOHVLRQVLVZHOONQRZQ 7KHVLJQL¿FDQWSUHYDOHQFHRIVWHQRVLVRIWKHUHQDO DUWHU\JUHDWHUWKDQLQSDWLHQWVZKRGLHGIURP VWURNHZDVRIWKHFDVHVRIZKRPZLWK FRPSOHWHRFFOXVLRQRIWKHYHVVHO,QWKHOLWHUDWXUH SDWLHQWVZLWKSHULSKHUDOYDVFXODUGLVHDVHDVVRFLDWHG ZLWKVWHQRVLVRIWKHDWKHURVFOHURVFOHURWLFUHQDODUWHU\ VXIIHUHGKLJKHUPRUWDOLW\IURPFDUGLDFFDXVHVGXULQJ WKHWZR\HDUIROORZXSDQGWKHVHYHULW\RIWKH OHVLRQRIWKHUHQDODUWHU\ZDVGLUHFWO\SURSRUWLRQDOWR WKHZRUVWFDUGLDFSURJQRVLV
7KHH[DFWUHODWLRQVKLSEHWZHHQWKHGHJUHH
RIVWHQRVLVDQGWKHORVVRIPDVVLVXQNQRZQ$VWKH 'RSSOHULVQRWDQLQYDVLYHH[DPLQDWLRQLWKDVEHHQ XVHGIRUWKHIROORZXSRIVWHQRWLFOHVLRQV6LJQL¿FDQW VWHQRVLV!DQGVHYHUHDUWHULDOK\SHUWHQVLRQ SURJUHVVHGZLWKRIUHQDODWURSK\RYHUWZR\HDUV IROORZHGXSXVLQJ'RSSOHUH[DPLQDWLRQ
$UWHULRJUDSK\ZDVWKHH[DPLQDWLRQSULPDULO\ XVHGWRGHWHUPLQHWKHSUHVHQFHRIWKHREVWUXFWLRQDQG WKHYLDELOLW\RIWKHDWURSKLFNLGQH\3UHVHQWO\PDJ-QHWLFUHVRQDQFHDQJLRJUDSK\DQGDQJLRWRPRJUDSK\
DQGIDLOXUHRIHQGRYDVFXODUUHYDVFXODUL]DWLRQ,QDQ-RWKHUVHULHVWKHQHSKUHFWRP\RIWKHDWURSKLFNLGQH\ FXUHGWKH59+FDXVHGE\DIDOOZKLFKRFFXUUHGZKHQ UHPRYLQJWKHWUDXPDWLFOHVLRQIURPWKHUHQDODUWHU\ 7KHKLJKLQFLGHQFHRIWKURPERVLVLVGXHWRWKH IDFWWKDWWKHUHQDODUWHULHVLQWKHVHFDVHVDUHVPDOO GLI¿FXOWWRPDQLSXODWHDQGSRVVHVVOHVLRQVDJJUDYDWHG E\SUHYLRXVSURFHGXUHV
7KHGLDJQRVLVRI¿EURPXVFXODUG\VSODVLDRI
WKHUHQDODUWHU\ZDVDVVRFLDWHGZLWKEHWWHUUHVXOWVDV UHJDUGVERWKSUHVVXUHDQGUHQDOIXQFWLRQUHQDOGLDO\WLF LQVXI¿FLHQF\EHLQJDUDUHFDXVH
)URP WKH SK\VLRORJLFDO SRLQW RI YLHZ WKH UHGXFWLRQLQWKHOHYHOVRIDQJLRWHQVLQ,,DIWHUWKHQH-SKUHFWRP\RIWKHDWURSKLFNLGQH\ZRXOGFDXVHOHVVHU R[LGDWLYHVWUHVVDQGFRXOGOHDGWRWKHUHVWRUDWLRQRI WKHGHSHQGHQWHQGRWKHOLDOGLODWLRQUHVSRQVLEOHLQWKH ¿QDODQDO\VLVIRUWKHYDVFXODUOHVLRQVUHQDOFRURQDU\ DQGFHUHEUDOPDLQO\WKRVHRIDWKHURVFOHURWLFHWLRO-RJ\,WLVNQRZQWKDWKLJKOHYHOVRIDQJLRWHQVLQ,, DUHUHODWHGWRDQLQFUHDVHLQWKHSUR¿EURWLFIDFWRUV ZLWKWKHFRQVHTXHQWUHSODFHPHQWRIWKHIXQFWLRQLQJ JORPHUXOXVE\¿EURVLVOHDGLQJWRDORVVRIUHQDOPDVV DQGWKHDGYDQFHRIUHQDOLQVXI¿FLHQF\+\SHUFKROHV-WHUROHPLDHVSHFLDOO\WKHLQFUHDVHLQWKHR[LGL]HG/'/ DVVRFLDWHGZLWKVWHQRVLVRIWKHUHQDODUWHU\VSHHGVXS WKHGHYHORSPHQWRI¿EURVLVLQWKHLVFKHPLFNLGQH\E\ WKHVSUHDGRISUR¿EURWLFPHFKDQLVPV1)ȕ7*)ȕ R[LGDWLYHVWUHVVDPRQJRWKHUVDQGVXSSUHVVLRQRIWKH UHPRGHOLQJRIWKHWLVVXHV
,QWKHIXWXUHZHVKRXOGKDYHPRUHRSWLRQV
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
CONFLICT OF INTEREST
1RQHGHFODUHG REFERENCES 6D¿DQ5'7H[WRU6&5HQDODUWHU\VWHQRVLV1(QJO -0HG 6ORYXW'32OLQ-:)LEURPXVFXODUG\VSODVLD1(QJO -0HG *DURYLF9'7H[WRU6&5HQRYDVFXODUK\SHUWHQVLRQ DQG LVFKHPLF QHSKURSDWK\ &LUFXODWLRQ 5LPPHU-0*HQQDUL)-$WKHURVFOHURWLFUHQRYDVFXODU GLVHDVHDQGSURJUHVVLYHUHQDOIDLOXUH$QQ,QWHUQ0HG +DQVHQ.-(GZDUGV06&UDYHQ7(&KHUU*6-DFN -VRQ6$$SSHO5*HWDO3UHYDOHQFHRIUHQRYDVFXODU GLVHDVHLQWKHHOGHUO\DSRSXODWLRQEDVHGVWXG\-9DVF 6XUJ *DUFtD'RQDLUH-$$OFi]DU-0,VFKHPLFQHSKURSD -WK\GHWHFWLRQDQGWKHUDSHXWLFLQWHUYHQWLRQ.LGQH\,QW 6XSSO6 /RVFDO]R-1LWULFR[LGHDQGYDVFXODUGLVHDVH1(QJO -0HG 6HHOLJ+37KH-DIIHUHDFWLRQZLWKFUHDWLQLQH=.OLQ &KHP.OLQ%LRFKHP 5XQGEDFN-+6DFNV'.HQW.&&RRSHU&-RQHV' 0XUSK\7HWDO*XLGHOLQHVIRUWKHUHSRUWLQJRIUHQDO DUWHU\UHYDVFXODUL]DWLRQLQFOLQLFDOWULDOV$PHULFDQ +HDUW$VVRFLDWLRQ&LUFXODWLRQ 3RJJLR(':DQJ;:HLQVWHLQ'0,VVD1'HQQLV 9:%UDXQ:(HWDO$VVHVVLQJJORPHUXODU¿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
*URXSRQ5HQRYDVFXODU+\SHUWHQVLRQ+\SHUWHQVLRQ DQGUHQRYDVFXODUGLVHDVHIROORZXSRQUHQDOYHLQ UHQLQVDPSOLQJV-+XP+\SHUWHQV 5RVVL*3&HVDUL0&KLHVXUD&RURQD00LRWWR' 6HPSOLFLQL$3HVVLQD$&5HQDOYHLQUHQQLQPHDVXUH -PHQWVDFFXUDWHO\LGHQWLI\UHQRYDVFXODUK\SHUWHQVLRQ FDXVHGE\WRWDORFFOXVLRQRIUHQDODUWHU\-+\SHUWHQ -VLRQ
ZZZPHGVFDSHFRP
1HJRUR+,ZDPXUD+2ND+.DZDNLWD0$UL\RVKL ..RGD<HWDO7UDXPDWLFUHQDODUWHU\WKURPERVLV ZLWKUHQRYDVFXODUK\SHUWHQVLRQ,QW-8URO
/LX;3UDWW5(']DX9-(QGRWKHOLXPWDUJHWHGJHQH DQGFHOOEDVHGWKHUDSLHVIRUFDUGLRYDVFXODUGLVHDVH $UWHULRVFOHU7KURPE9DVF%LRO
Accepted after revision: October 18, 2009
Correspondence address: 'U0\ULDQ-7KRPD] 'HSDUWPHQWRI8URORJ\
)DFXOW\RI0HGLFLQH8QLYHUVLW\RI6DR3DXOR 6DR3DXOR%UD]LO