Americn Journl of Nephrology Originl Report: Ptient-Oriented, Trnsltionl Reserch DOI: 10.1159/000106672 Received: Mrch 26, 2007 Accepted: June 26, 2007 Published online: July 27, 2007 Proteinuri Is Determinnt of Qulity of Life in Dibetic Nephropthy: Modeling Lgged Effects with Pth Anlysis Ken Kelley O. Tolg Arick b Robert P. Light c, d Rjiv Agrwl c, d Inquiry Methodology Progrm nd b Eductionl Psychology, Indin University, Bloomington, Ind., c Division of Nephrology, Deprtment of Medicine, Indin University School of Medicine, nd d Richrd L. Roudebush VA Medicl Center, Indinpolis, Ind., USA Key Words Chronic kidney disese Dibetic nephropthy, qulity of life End-stge renl disese Glipizide Kidney disese burden Mentl component score Physicl component score Pioglitzone Proteinuri Type 2 dibetes mellitus Pth nlysis Abstrct Bckground: Dibetic nephropthy with overt proteinuri often progresses relentlessly to end-stge renl disese (ESRD). Mteril nd Methods: To nswer the question whether it is impired glomerulr filtrtion rte (GFR) or its precursor proteinuri which is more relted with multiple domins of helth-relted qulity of life (HRQOL), we mesured GFR nd proteinuri in 44 ptients with type 2 dibetes nd overt nephropthy nd repeted the mesurements fter 4 months. 38 ptients with ESRD due to dibetic nephropthy served s control group. We used pth nlysis to exmine the ssocition of bseline proteinuri nd GFR with bseline nd subsequent HRQOL scles. Results: Compred to ptients with ESRD, ptients with non-dilysis CKD hd Kidney Disese Burden (KDB) tht ws, on scle from 0 to 100, 19.8 better (95% CI 6.9 32.8) (p = 0.003). Mentl component score (MCS) did not differ nd physicl component score (PCS) ws worse in non-dilysis CKD ptients by 8.5 (p! 0.001). Proteinuri t bseline ws predictor of PCS, MCS nd KDB score t 4 months, suggesting lgged effect of proteinuri on HRQOL fter controlling for the utoregressive effects. GFR ws not shown to hve significnt impct on HRQOL. One log unit increse in proteinuri ws ssocited with 3.8 (p = 0.011) fll in PCS, 3.3 (p = 0.043) fll in MCS nd 10.6 (p = 0.006) fll in KDB. Conclusion: In ptients with dvnced dibetic nephropthy, we found tht proteinuri hs lgged nd profound effect on multiple domins of HRQOL. Copyright 2007 S. Krger AG, Bsel Introduction Ptients with dibetes mellitus rte their helth fir or poor three times s often s helthy people [1]. Among ptients with dibetes mellitus, those with multiple comorbidities re prticulrly susceptible to poor helthrelted qulity of life (HRQOL) [2]. Ptients with chronic kidney disese (CKD) hve lower HRQOL thn the generl popultion [3]. Although the time when HRQOL is impired in reltion to the stge of CKD is not known, it is well recognized tht ptients on dilysis hve much lower HRQOL thn those in the generl popultion nd tht dilysis is relted to mortlity nd hospitliztion [4]. Proteinuri is modifible renl nd crdiovsculr risk fctor tht medites progression of CKD [5, 6]. The risk of progression of kidney disese, dilysis or deth is Fx +41 61 306 12 34 E-Mil krger@krger.ch www.krger.com 2007 S. Krger AG, Bsel 0250 8095/07/0275 0488$23.50/0 Accessible online t: www.krger.com/jn Rjiv Agrwl, MD VAMC, 111N, 1481 West 10th Street Indinpolis, IN 46202 (USA) Tel. +1 317 988 2241, Fx +1 317 988 2171 E-Mil rgrwl@iupui.edu
Tble 1. Bseline chrcteristics of the study smple CKD not on dilysis Hemodilysis Age, yers 6689 54810 <0.001 Mles, % 44 (100) 41 (100) >0.2 White, % 35 (80) 8 (20) <0.001 Blck, % 9 (20) 33 (80) BMI, kg/m 2 32.685.5 28.586.6 0.003 Current smoker, % 14 (32) 11 (27) >0.20 Insulin, % 28 (64) 28 (68) >0.2 Vsculr disese, % 28 (64) 18 (46) 0.11 24-Hour systolic BP, mm Hg 150818 137817 0.001 24-Hour distolic BP, mm Hg 76810 77812 >0.2 24-Hour hert rte, bpm 69811 79811 <0.001 HgbA1c, % 7.782.3 NA NA BUN, mg/dl 43.7814.0 51.4813.8 0.08 Albumin, g/dl 3.780.4 3.880.5 >0.2 Hemoglobin, g/dl 13.182 12.681.3 0.15 GFR, ml/min 44831 NA NA Protein/cretinine, g/g 2.57!/ 2.31 NA NA Totl smple size is 44 for CKD ptients nd 41 for hemodilysis ptients. directly relted to proteinuri [7]. Whether proteinuri is lso relted to HRQOL hs not been evluted. Furthermore, if remission of proteinuri is ssocited with improvement in HRQOL, it offers n opportunity to impct HRQOL with therpies tht lower proteinuri. In other words, if remission of proteinuri is ssocited with improvement in HRQOL, besides modifying crdiovsculr risk nd progression of renl injury, we cn directly mke ptients feel better. The reltionship of glomerulr filtrtion rte (GFR) to HRQOL is controversil. Three lrge studies hve exmined the cross-sectionl reltionship of GFR with HRQOL in ptients with CKD. In two of these studies, no reltionship ws observed between GFR nd HRQOL, nd in one study there ws reltionship. None of these studies used repeted mesurements to study longitudinl chnge. The purpose of this short-term study in dult men with proteinuri nd type 2 dibetes mellitus ws to evlute the impct of directly mesured GFR nd proteinuri on their impct on HRQOL. We sked the question whether it is GFR or proteinuri tht is more relted to multiple domins of HRQOL in ptients with CKD. To compre the impct of GFR we directly compred bseline level of HRQOL in non-dilysis CKD ptients with those with end-stge renl disese (ESRD). p M e t h o d s Subjects We nlyzed HRQOL dt from 44 ptients with type 2 dibetes mellitus who completed 16-week rndomized controlled tril of pioglitzone or glipizide rndomly llocted in n equl rtio. The study ws blinded to those performing the nlyses but open lbel to the ptients nd treting physicin nd hs been reported previously [8]. Bseline chrcteristics of the smple re given in tble 1. Ptients with estblished dibetic nephropthy were recruited from the renl clinic t the Roudebush Veterns Administrtion Medicl Center in Indinpolis, Ind., USA. In order to qulify for inclusion in the study, ptients with type 2 dibetes mellitus requiring tretment with orl hypoglycemic drugs or insulin were required to hve urine protein/cretinine rtio of 1 1.0 g/g on single voided specimen nd cretinine clernce of 1 20 ml/min by Cockcroft-Gult formul [9]. Exclusion criteri included the presence of liver disese, New York Hert Assocition Clss III or IV hert filure, unstble ngin, myocrdil infrction or stroke in the previous 3 months, non-steroidl nti-inflmmtory drug use, or body mss index of 6 40 kg/m 2. The study ws pproved by the Institutionl Review Bord of Indin University nd the Reserch nd Development Committee of the Roudebush Veterns Administrtion Medicl Center in Indinpolis nd ll ptients gve their written informed consent. The primry end-point in the study ws reduction in proteinuri, which hs been reported elsewhere nd is not the subject of this report [8]. Kidney Disese Qulity of Life Questionnire The Kidney Disese Qulity of Life (KDQOL TM ) instrument is self-report mesure tht includes 36-item helth survey s the generic core, supplemented with multi-item scles trgeted t prticulr concerns of individuls with kidney disese nd on dilysis (symptom/problems, effects of kidney disese on dily life, burden of kidney disese, cognitive function, work sttus, sexul function, qulity of socil interction, sleep). Ech scle is scored from 0 to 100 (worst to best) using stndrd lgorithms. The mjor scles of interest in qulity of life were Physicl Helth Composite Score (PCS), Mentl Helth Composite Score (MCS) nd Kidney Disese Burden (KDB). In the generl popultion, the PCS nd MCS hve men score of 50 ech with stndrd devition of 10. The questionnires were self-dministered by study prticipnts t bseline nd gin t 4 months but were exmined for completeness by reserch nurse. Sttisticl Anlysis Pth nlysis is method used to evlute theoreticl model with direct nd possibly indirect effects between exogenous (predictor/independent) nd endogenous (outcome/dependent) vribles [10, 11]. The reltionship between vribles is quntified with pth coefficients, which re much like regression coefficients in generl liner model context. Pth coefficients represent the chnge in n endogenous vrible s function of 1 unit chnge in more exogenous vrible tht re linked vi pth (which represents direct effect), holding everything else constnt. Although pth nlysis nd multiple regressions re similr models, the pth nlysis model provides frmework for specifying prticulr theoreticl model bout the reltionship mong set of Proteinuri s QOL Determinnt 489
Initil physicl 0.63*** Finl physicl (R 2 = 0.48) 7.5 Fig. 1. Pth digrm of proteinuri ( ) nd GFR ( b ) on PCS for CKD ptients. Singleheded rrows in the pth digrm illustrte the direct effect of one vrible on nother; the number ssocited with ech of the single-heded rrows is the pth coefficient; curved two-heded rrow connecting two vribles is the correltion coefficient between the two vribles; circles represent the errors in the prediction of the endogenous vribles, with the number inside the circle being the stndrd devition of the error; R 2 represents the proportion of vrince in the endogenous vrible ccounted for by the exogenous vrible(s). * * * p! 0.001, * * p! 0.01, * p! 0.05. r = 0.20 r = 0.01 b Initil log Initil physicl Initil GFR 3.8* 0.70*** 0.04 0.99*** Finl log (R 2 = 0.44) Finl physicl (R 2 = 0.41) Finl GFR (R 2 = 0.90) 0.69 7.87 10.24 exogenous nd endogenous vribles. Although pth nlysis is widely used in some disciplines, to our knowledge, pth nlysis hs been used little in nephrology. One spect of evluting the model is compring the observed nd the model implied covrince mtrices to ssess generl greement. The goodness of fit of the model cn be quntified nd referenced to 2 distribution, ssuming normlity nd sufficiently lrge smple size. A sttisticlly significnt 2 sttistic implies tht differences exist in the observed nd model implied covrince mtrices, which provides evidence of model misfit. Another wy to evlute the fit of model is by using the root men squre error of pproximtion (RMSEA), with widely used rule of thumb being vlues! 0.05 represent good fit [12]. In ddition to evluting the overll model fit, ech of the direct nd indirect effects hs n estimted pth coefficient nd stndrd error. The pth nlysis models discussed momentrily were fitted using Amos [13]. GFR ws mesured with iothlmte clernce nd proteinuri by duplicte collections of 24-hour urine protein t bseline nd t 4 months. 24-Hour urine protein excretion ws clculted per grm urinry cretinine. Results of the two 24-hour urine collections for ech visit were verged to reflect protein excretion rte t bseline nd gin t the month 4 visits. For the purposes of sttisticl nlysis, the protein excretion rte per grm cretinine ws log e trnsformed to better pproximte norml distribution. We pplied pth nlysis models to understnd the reltionship between MCS, PCS, nd KDB s function of proteinuri nd GFR. Comprisons of (undjusted) group mens were conducted with the ordinry independent groups t tests. Comprisons of initil scores versus finl scores for non-dilysis CKD were conducted with the ordinry pired smples t test. Group mens were lso compred for initil non-dilysis CKD versus hemodilysis, where the men difference ws djusted for ge nd ethnicity. The djusted comprison ws performed in n nlysis of covrince context, which cn be considered n djusted independent groups t test since there were only two groups. We evluted the reltionship of MCS, PCS, nd KDB t the finl time point using either log or GFR, while controlling for utoregressive effects (the pth between the vrible t the initil time nd the vrible t the finl time). These models were fitted seprtely in series of six models. Figure 1 reports the specific pth digrms fit with MCS s the outcome vrible conditionl on () log nd (b) GFR. Figures 2 nd 3 re nlogous to figure 1 with PCS nd KDB replcing MCS, respectively. Less the pth nlysis, the MBESS [14] R pckge [15] nd SPSS [16] were used, s pproprite, for the specific nlyses tht follow. R e s u l t s Study Prticipnts Fifty-four subjects qulified nd consented to prticipte in the study, nd 44 were rndomized to tretment. This report is limited to the 44 ptients who were rndomized nd hd repeted mesurements of GFR, proteinuri nd HRQOL. Actul subject study prticiption occurred between November 2001 nd December 2003. Two subjects withdrew following rndomiztion, 1 under dvice of primry cre physicin, nd the other following hospitliztion for gstrointestinl bleed. One subject died due to metsttic denocrcinom. Finlly, 1 subject ws unble to present for the finl study visit. Thus, 40 subjects 19 in the glipizide rm nd 21 in the pioglitzone rm completed the study. 490 Kelley /Arick /Light /Agrwl
Initil mentl Finl mentl (R 2 = 0.48) 8.27 r = 0.04 3.3* Initil log Finl log (R 2 = 0.44) 0.69 Initil mentl 0.79*** Finl mentl (R 2 = 0.45) 8.61 r = 0.20 0.02 Fig. 2. Pth digrm of proteinuri ( ) nd GFR ( b ) on MCS for CKD ptients. * * * p! 0.001, * * p! 0.01, * p! 0.05. b Initil GFR 0.99*** Finl GFR (R 2 = 0.90) 10.24 Initil kidney disese burden 0.41*** Finl kidney disese burden (R 2 = 0.41) 19.75 r = 0.09 10.58** Initil log Finl log (R 2 = 0.44) 0.69 Initil kidney disese burden 0.46*** Finl kidney disese burden (R 2 = 0.32) 21.31 r = 0.00 0.01 Fig. 3. Pth digrm of proteinuri ( ) nd GFR ( b ) on KDB for CKD ptients. * * * p! 0.001, * * p! 0.01, * p! 0.05. b Initil GFR 0.99*** Finl GFR (R 2 = 0.90) 10.24 Bseline chrcteristics of ptients with dibetic nephropthy not on dilysis nd those with ESRD secondry to dibetes mellitus on hemodilysis re shown in tble 1. All but 8 ptients were tking n ACE inhibitor or n ngiotensin receptor blocker. ESRD ptients were younger nd more Africn-Americn. The reltionship of HRQOL domins with CKD nd ESRD is shown in tble 2. It is cler tht ptients with ESRD due to dibetes hve worse KDB by nerly 20 points compred to those not on dilysis, which implies stndrdized men difference of 0.69 (95% CI 0.24 1.14). However, those on dilysis hd men PCS of 8.5 points better thn CKD (95% CI 3.5 13.2). The MCS ws similr between the two groups (46.8 for CKD nd 46.6 for ESRD) nd did not differ significntly fter djusting for ethnicity nd ge. After djusting for ethnicity nd ge, KDB ws 15.9 worse in ESRD (95% CI 33.1 to 1.4; p = 0.071) nd PCS 7.3 better in ESRD (95% CI 1.2 13.4). Neither ge nor ethnicity ws significnt for ny of the models. Proteinuri s QOL Determinnt 491
Tble 2. Impct of CKD stge on KDQOL subscles CKD, non-esrd Hemodilysis Difference (95% CI) CKD initil vs. HD initil finl Adjusted difference (95% CI) 1 CKD initil vs. HD Mentl Composite Score 46.8810.0 48.2811.8 46.687.8 0.13 ( 4.27 to 4.02) 2.7 ( 2.7 to 8.1) Physicl Composite Score 33.789.5 33.8810.5 42.2810.9 8.5 (3.5 to 13.2)*** 7.3 (1.2 to 13.4)* Kidney Disese Burden 67.6832.3 64.9826.0 47.8823.8 19.8 ( 6.9 to 32.8)** 15.9 ( 33.1 to 1.4) (p = 0.071) Scores re on 100-point scle where 0 is worst nd 100 is best. * p < 0.05; ** p < 0.01; *** p < 0.001; hemodilysis vs. CKD initil. 1 Adjusted for ge nd ethnicity (neither of which ws significnt for the three nlyses). Tble 3. Person zero-order correltion coefficients for the CKD ptients between KDQOL subscles nd GFR/proteinuri log GFR initil finl initil finl Mentl Composite Score Initil 0.03 0.023 0.21 0.08 Finl 0.29, p = 0.607 0.07 0.07 0.06 Physicl Composite Score Initil 0.20 0.30, p = 0.071 0.01 0.02 Finl 0.41** 0.33* 0.14 0.09 Kidney Disese Burden Initil 0.09 0.10 0.00 0.02 Finl 0.40** 0.27, p = 0.095 0.01 0.08 log Initil 1.00 0.64*** 0.24 0.32, p = 0.051 Finl 0.64*** 1.00 0.42** 0.40* GFR Initil 0.24 0.42** 1.00 0.95*** Finl 0.32, p = 0.051 0.40* 0.95*** 1.00 MCS, PCS nd KDB re bsed on 0- to 100-point scle, where 0 is worst nd 100 is best. Probbility vlues re bsed on the t test for Person zero-order correltion coefficients. * p < 0.05; ** p < 0.01; *** p < 0.001 (ll two-tiled). The zero-order Person product moment correltion coefficients between PCS, MCS nd KDB versus GFR nd proteinuri for the CKD ptients re shown in tble 3. Wek nd non-significnt correltions re seen between GFR nd HRQOL subscles. On the other hnd, significnt reltionships emerged between finl HRQOL subscle scores nd bseline log e protein/cretinine rtio (which is consistent with the pth for the lgged effect of proteinuri t bseline nd HRQOL t the finl time). The six pth nlysis models re represented in figures 1 3. The single-heded rrows in the pth digrms illustrte the direct effect of n exogenous vrible (proteinuri or GRF) on n endogenous vrible (MCS, PCS, or KDB). The number ssocited with ech of the singleheded rrows is the pth coefficient tht quntifies the chnge in the endogenous vrible s function of 1 unit chnge in the exogenous vrible. The curved twoheded rrow connecting two vribles (i.e., the bseline exogenous vribles) is the correltion coefficient between the two vribles. The circles represent the errors in the prediction of the endogenous vribles, with the number inside the circle being the stndrd devition of the error. Notice tht n R 2 vlue is given for ech of the endogenous vribles. The vlue of R 2 represents the proportion of vrince in the endogenous vrible ccounted for by the exogenous vrible(s) given the model speci- 492 Kelley /Arick /Light /Agrwl
fied, which is nlogous to the squred multiple correltion coefficient in generl liner model context. In fct, if finl GFR or finl proteinuri were removed from the pth models, the pth models would literlly become multiple regression models, which is specil cse of pth model. Bseline GFR did not significntly correlte with bseline HRQOL domins or predict finl HRQOL domins. However, bseline proteinuri ws predictor of finl PCS, MCS nd KDB. There ws no reltionship of bseline proteinuri nd bseline PCS, MCS nd KDB, suggesting lgged effect of finl HRQOL conditionl on bseline proteinuri. In other words, the effect of chnge in proteinuri my not be immedite, but rther requires the pssge of time for the effect to mnifest. A 1 log unit increse in proteinuri ws ssocited with 3.8 (p = 0.011) chnge in PCS, 3.3 (p = 0.043) in MCS nd 10.6 (p = 0.006) chnge in KDB. Ech of the models fit well, with the estimted RMSEA being! 0.05 for ech of the pth models nd 2 goodness of fit ws not significnt for ny of the models. Discussion The mjor findings of our study re tht proteinuri profoundly impcts ll mjor domins of HRQOL in dose-dependent mnner with lgged effect. GFR on the other hnd hd little impct on HRQOL. The impct of GFR in cross-sectionl studies of HRQOL hs been subject of debte. For exmple, in the Africn-Americn Study of Kidney Disese, KDQOL ws dministered to 1,094 Africn-Americn men nd women. Men GFR ws 46 ml/min, PCS ws 43.4 8 10.9 nd MCS ws 51.3 8 10.3. Both scores were higher in men thn in women, but neither ws relted to GFR [17]. On the other hnd, in the Modifiction of Diet in Renl Disese, in 1,284 ptients the mgnitude of HRQOL nd symptoms were negtively correlted with GFR [18]. Finlly, in the cross-sectionl nlysis of the Renl Reserch Institute Study, GFR ws not significntly ssocition with HRQOL [19]. None of the studies reported the ssocition of HRQOL with proteinuri. Since ptients prticipting in the MDRD study were more proteinuric thn the AASK study, it is possible tht the confounding effect of proteinuri on HRQOL ws missed. In longitudinl study of ptients with type 1 dibetes mellitus, microlbuminuri ws not ssocited with impired HRQOL [20]. Thus, it ppers tht overt lbuminuri, especilly in the nephrotic rnge, my be relted to impired HRQOL. Although longer period of mny observtions would be helpful for evluting this hypothesis, rndomized controlled tril would be necessry to definitively show support for this hypothesis. Thus, cusend-effect reltionship cnnot be estblished. In the generl popultion, PCS nd MCS verges 50 nd hs stndrd devition of 10 [21]. The verge PCS in non-esrd ptients ws 33.7 nd MCS ws 46.8. PCS in the Renl Reserch Institute-CKD study ws 37.3 slightly higher thn our smple, but nerly 1.3 stndrd devitions below the generl popultion, which is considered substntil impirment [19]. Thus, much greter impirment in PCS is imposed by CKD t stge tht predtes dilysis. CKD induced by dibetes mellitus my hve greter dverse effect on HRQOL compred to CKD induced by other cuses [22]. For exmple, compred to ptients with hypertension-induced CKD prticipting in the AASK study who hd similr GFR, the PCS in our smple ws lower by 9.7 units (95% CI 6.3 13.1), p! 0.001, nd MCS ws lower by 4.5 units (95% CI 1.3 7.8), p = 0.006 [17]. In ptients strting dilysis, those with type 2 dibetes mellitus hve lower HRQOL compred to those without dibetes [23]. Ethnicity my hve n independent effect on HRQOL Africn-Americns pper to enjoy greter HRQOL. Tble 1 shows tht ESRD ptients were younger nd more Africn-Americn. Whether impirment in PCS in our study ws due to n independent effect of dibetes mellitus or it ws due to fewer Africn-Americns or older ge is not cler [24]. Compred to ptients not on dilysis, ptients with ESRD hd KDB tht ws nerly 20 points higher. This is not surprising given the burden imposed on the ptient by renl replcement therpy. Somewht unexpectedly, ptients on dilysis hd higher PCS compred to those not on dilysis. This my be due to survivl bis. PCS is strongly relted to mortlity, n effect tht my mnifest before the onset of ESRD [4, 25]. Thus, those with poor PCS my hve died leving those with higher PCS on dilysis. An lterntive though less likely explntion for this finding is tht dilysis improved PCS in those with CKD. The strengths of our study re the direct mesurements of GFR, nd duplicte mesurements of 24-hour urine protein collection t ech clinic visit nd excellent dherence to protocol. Limittions of our study re the reltively short follow-up nd limited number of subjects. Ptients with CKD nd ESRD hd different proportionl ethnicities: 80% of the CKD ptients were white, while 80% of the ESRD ptients were blck. Adjustment for Proteinuri s QOL Determinnt 493
these different ethnicities did not lter the results. The results of our study pply to only men, since we did not study women. It is conceivble tht longer durtion or recruiting lrger number of subjects or both would mke the ssocition of proteinuri with HRQOL even more cliniclly relevnt, or possibly to show n ssocition between GFR nd HRQOL. In summry, in this single-center study in ptients with dvnced type 2 dibetic nephropthy we found greter impct of proteinuri on multiple domins of HRQOL compred to directly mesured GFR. Future studies should ddress the impct of reduction in proteinuri on HRQOL. If cusl reltionship is confirmed, proteinuri reduction my not only impct the time to dilysis nd crdiovsculr events but lso qulity of life in ptients with dibetic nephropthy. References 1 CDC: Self-rted fir or poor helth mong dults with dibetes United Sttes, 1996 2005. 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