ORIGINAL RESEARCH & CONTRIBUTIONS

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1 Effect of Advncing Age nd Multiple Chronic Conditions on Mortlity in Ptients with End-Stge Renl Disese fter Implntble Crdioverter-Defibrilltor Plcement Ashok Krishnswmi, MD, MAS; Mry-Lou Kiley, MBA; Fith F Anthony, MA; Yuexin Chen; Json Chen, MA; Sumnth Rjgopl, MD; Tylor I Liu, MD, PhD; Chrlie Young, MD; Elizbeth W Pxton, MA Perm J 2016 Winter;20(1): ABSTRACT Context: There is insufficient informtion on the effect tht dvncing ge nd multiple chronic conditions (MCC) hve on mortlity fter plcement of n implntble crdioverter-defibrilltor in ptients with end-stge renl disese (ESRD) vs non-esrd. Objective: To ssess whether differentil effect of ge nd MCC exists between ESRD nd non-esrd. Design: Popultion-bsed, retrospective cohort study using dt from the ntionl Kiser Permnente Crdic Device Registry of ptients who underwent plcement of n implntble crdioverter-defibrilltor between Jnury 1, 2007, nd December 31, Min Outcome Mesures: All-cuse mortlity. Results: Of 7825 ptients with implntble crdioverter-defibrilltor plcement, ESRD-ffected ptients constituted 4.0% of the cohort (n = 311), were similr in ge (p = 0.91), nd presented with lrger comorbidity burden (3.3 ± 1.3 vs 2.4 ± 1.5, p < 0.001). The effect of dvncing ge (every 5 yers) on mortlity in the ESRD cohort (hzrd rtio [HR] = 1.11, 95% confidence intervl [CI] = ) ws less thn in the non-esrd cohort (HR = 1.28, 95% CI = ). Similrly, the effect of ech dditionl comorbidity in the ESRD cohort ws less (HR = 1.04, 95% CI = ) thn in the non-esrd group (HR = 1.20, 95% CI = ). Lstly, ESRD ws independently ssocited with 3-fold greter hzrd of mortlity. Conclusions: Advncing ge nd incresing number of MCC hve differentil effect on mortlity risk in ptients with ESRD compred with their non-esrd counterprts. Future studies should focus on ssessment of nonliner reltionships of ge, MCC, nd nturlly occurring clusters of MCC on mortlity. INTRODUCTION The US Deprtment of Helth nd Humn Services projects tht by the yer 2050 there will be 80 million dults over the ge of 65 yers. 1 Advncing ge is well known to be ssocited with multiple co-occurring conditions or comorbidities, henceforth clled multiple chronic conditions (MCC). 2 It is projected tht the prevlence of dults in the US with MCC will be 81 million by the yer Current guidelines hve focused on single disese mngement with miniml or no ttempt towrd the mngement of individuls with MCC. 2,4 The importnce of understnding the helth nd monetry costs of dvncing ge nd MCC is crucil becuse ptients with more thn 1 chronic condition hve substntil impirment in their ctivities of dily living nd ccount for 95% of Medicre expenditures. 3 Ptients with end-stge renl disese (ESRD) re known to be t high-risk of crdiovsculr disese nd sudden crdic deth. 5 Although dvncing ge nd MCC 6-9 hve known unfvorble risk profile in the generl popultion, little is known of the role these hve in ptients with ESRD fter plcement of n implntble crdioverter-defibrilltor (ICD) compred with those without ESRD. The Kiser Permnente (KP) Crdic Device Registry, 10 with its lrge smple nd qulity control nd dt vlidtion processes, supports observtionl studies of ICDs in rel-world sitution. Using the registry, the primry im of the current study ws to improve the understnding of the role tht dvncing ge nd MCC hve on mortlity in ptients with ESRD compred with their nondilysis counterprts fter ICD plcement. Our null hypothesis is tht dvncing ge nd incresing number of comorbidities hve n equl effect in ptients with ESRD nd those without ESRD. METHODS We performed retrospective cohort study from our source popultion of KP members from 6 geogrphicl Regions of the US between Jnury 1, 2007, nd December 31, KP is n integrted helth cre delivery system tht provides Ashok Krishnswmi, MD, MAS, is Crdiologist t the Sn Jose Medicl Center in CA. E-mil: shok.krishnswmi@kp.org. Mry-Lou Kiley, MBA, is the Group Leder for Surgicl Outcomes nd Anlysis for Kiser Permnente in Sn Diego, CA. E-mil: mry.lou.kiley@kp.org. Fith F Anthony, MA, is Project Mnger for Surgicl Outcomes nd Anlysis for Kiser Permnente in Sn Diego, CA. E-mil: fith.nthony@kp.org. Yuexin Chen is Senior Dt Consultnt for Surgicl Outcomes nd Anlysis for Kiser Permnente in Sn Diego, CA. E-mil: yuexin.chen@kp.org. Json Chen, MA, is Project Mnger for Surgicl Outcomes nd Anlysis for Kiser Permnente in Sn Diego, CA. E-mil: json.x.chen@kp.org. Sumnth Rjgopl, MD, is n Infectious Disese Specilist t the Vcville Medicl Center in Vllejo, CA. E-mil: sumnth.rjgopl@kp.org. Tylor I Liu, MD, PhD, is n Electrophysiologist t the Snt Clr Medicl Center in CA. E-mil: tylor.i.liu@kp.org. Chrlie Young, MD, is n Electrophysiologist t the Snt Clr Medicl Center in CA. E-mil: chrlie.young@kp.org. Elizbeth W Pxton, MA, is the Director of the Surgicl Outcomes nd Anlysis Deprtment t Kiser Permnente in Sn Diego, CA. E-mil: liz.w.pxton@kp.org. The Permnente Journl/ Winter 2016/ Volume 20 No. 1 27

2 comprehensive cre to more thn 9.5 million members cross vrious prts of the country, nd its membership is representtive of the locl popultion. 11,12 Detiled informtion on qulity control nd dt vlidtion processes hs been previously published. 10 Briefly, this registry collects ptient, implnt, surgeon, nd hospitl dt for ll ptients undergoing ICD implnttions, using internl dministrtive dtbses, including the systemwide electronic medicl record. Vlidted electronic lgorithms re pplied to the dt to serch for postimplnt complictions, including infections, erly clinicl complictions, nd device replcements. Complictions re verified by mnul review by cliniclly trined registry stff. Outcomes Our primry predictors were dvncing ge nd incresing MCC s continuous vrible. The primry outcome of interest ws ll-cuse mortlity obtined from Helth Pln dtbses nd Socil Security Administrtion files. Secondry outcomes of interest were deep nd superficil surgicl site infections, 13 crdic tmponde, hemtom, pneumothorx, nd pulse genertor replcement due to ny cuse. The presence of ESRD ws obtined through Helth Pln dtbses. The covrites included were ptient ge t implnt, sex, body mss index (BMI), implnt model type (single, dul, or crdic resynchroniztion therpy), nd bseline comorbidities (hypertension, dibetes mellitus, congestive hert filure, Tble 1. Comprison of bseline chrcteristics between ptients with nd without end-stge renl disese Vrible Overll (N = 7825) ESRD (n = 311) Non-ESRD (n = 7514) p vlue Age, yers Men (SD) 64.3 (13.13) 64.9 (10.95) 64.3 (13.21) Medin (IQR) 65.8 ( ) 65.7 ( ) 65.8 ( ) Age ctegory, yers < (21.5) 50 (16.1) 1630 (21.7) < (26.6) 100 (32.2) 1983 (26.4) (29.7) 112 (36.0) 2211 (29.4) > (22.2) 49 (15.8) 1690 (22.5) Sex Femle 2064 (26.4) 83 (26.7) 1981 (26.4) Mle 5760 (73.6) 228 (73.3) 5532 (73.6) BMI, kg/m 2 < (28.3) 109 (35.0) 2106 (28.0) (35.6) 108 (34.7) 2678 (35.6) > (35.8) 94 (30.2) 2707 (36.0) ICD model type CRT 1776 (22.7) 44 (14.1) 1732 (23.1) < ICD-dul 3083 (39.4) 144 (46.3) 2939 (39.1) ICD-single 2966 (37.9) 123 (39.5) 2843 (37.8) Comorbidities Hypertension 4232 (54.1) 259 (83.3) 3973 (52.9) < Dibetes mellitus 3121 (39.9) 235 (75.6) 2886 (38.4) < Congestive hert filure 904 (11.6) 28 (9.0) 876 (11.7) Myocrdil infrction 2787 (35.6) 151 (48.6) 2636 (35.1) < Chronic lung disese 1285 (16.4) 51 (16.4) 1234 (16.4) Stroke 442 (5.6) 23 (7.4) 419 (5.6) Ischemic hert disese 5205 (66.5) 265 (85.2) 4940 (65.7) < Dt re number (%) except p vlue or if otherwise indicted. Missing dt: 1 (0.01%) for Sex; 23 (0.3%) for BMI; nd 400 (5.1%) for comorbidities. BMI = body mss index; CRT = crdic resynchroniztion therpy; ESRD = end-stge renl disese; ICD = implntble crdioverter-defibrilltor; IQR = interqurtile rnge; SD = stndrd devition. myocrdil infrction, chronic lung disese, stroke, nd ischemic hert disese) within six months before the device implnttion. The bseline comorbidities mentioned, including hert filure, were bsed on the Interntionl Clssifiction of Diseses, Ninth Edition codes nd not on chrt review. Institutionl Review Bord pprovl ws obtined before the strt of the study. Sttisticl Anlysis The cohort chrcteristics nd the postimplnt outcomes were described using frequencies, proportions, medin, interqurtile rnge, nd mens nd stndrd devitions. Ctegoricl chrcteristics were compred using χ 2 tests. Age ws compred using nonprmetric Wilcoxon rnk sum (Mnn-Whitney) test. Survivl nlysis for the primry outcome, ll-cuse mortlity, ws performed using Cox proportionl hzrd model. Anlyses were performed using SAS 9.2 softwre (SAS Institute, Cry, NC) with p vlue of < 0.05 used s the sttisticl threshold for significnce. RESULTS There were 7825 ptients included in the study, of which 311 (4.0%) were ptients with ESRD. Bseline ptient demogrphics nd clinicl chrcteristics re shown in Tble 1. Compring the ESRD group with the non-esrd group, the men ge (64.9 vs 64.3 yers, p = 0.91) s well s the proportion of men nd women were similr (p = 0.90). Most ptients in both groups hd BMI below 30 kg/m 2, with pproximtely one-third of the popultion in ech group hving BMI bove 30 kg/m 2. Ptients with ESRD hd higher proportion of hypertension (83.3% vs 52.9%, p < 0.001), dibetes mellitus (75.6% vs 38.4%, p < 0.001), myocrdil infrction (48.6% vs 35.1%, p < 0.001), nd ischemic hert disese (85.2% vs 65.7%, p < 0.001). Ptients with ESRD hd higher prevlence of 3 or more comorbidities compred with the non-esrd popultion (76.5% vs 45.9%, p < 0.001) s well s n increse in the men number (± stndrd devition) of comorbidities (3.3 ± 1.27, 2.4 ± 1.47, p < 0.001; Tble 2). 28 The Permnente Journl/ Winter 2016/ Volume 20 No. 1

3 Figure 1. Ptient entry into study. EMR = electronic medicl record; ESRD = end-stge renl disese; KP = Kiser Permnente. Tble 2. Comprison of the number of comorbidities between ptients with nd without end-stge renl disese (ESRD) No. of comorbidities ESRD, n (%) Non-ESRD, n (%) Totl, n (%) p vlue 0 8 (2.57) 851 (11.33) 859 (10.98) < (8.36) 1327 (17.66) 1353 (17.29) 2 39 (12.54) 1490 (19.83) 1529 (19.54) 3 91 (29.26) 1675 (22.29) 1766 (22.57) (34.73) 1287 (17.13) 1395 (17.83) 5 32 (10.29) 423 (5.63) 455 (5.81) 6 6 (1.93) 58 (0.77) 64 (0.82) 7 1 (0.32) 3 (0.04) 4 (0.05) Tble 3. Comprison of erly nd lte complictions fter device plcement between ptients with nd without end-stge renl disese (ESRD) Totl, no. (%) ESRD, no. (%) Non-ESRD, no. (%) Outcome 7825 (100) 311 (3.97) 7514 (96.03) p vlue Erly compliction ( 30 dys) Deth 62 (0.79) 8 (2.57) 54 (0.72) < Tmponde 22 (0.28) 8 (0.32) 21 (0.28) b Hemtom 26 (0.33) 3 (0.96) 23 (0.31) b Pneumothorx 24 (0.31) 2 (0.64) 22 (0.29) b Device-relted infection 14 (0.18) 0 (0) 14 (0.19) > 0.99 b Device replcement 32 (0.41) 5 (1.61) 27 (0.36) b Lte compliction (> 30 dys) Deth 1646 (21.04) 146 (46.95) 1500 (19.96) < Device-relted infection 53 (0.68) 7 (2.25) 46 (0.61) < Device replcement 654 (8.36) 17 ( (8.48) p vlue is derived from the χ 2 test unless otherwise indicted. b p vlue is derived from the Fisher exct test. Ptient entry into the study is shown in Figure 1. The yerly volume of implnts in the ESRD nd non-esrd cohorts is shown in Figure 2. The undjusted outcomes re reported in Tble 3, nd the Kpln-Meier survivl curve, s expected, noted worse survivl of ptients with ESRD vs non-esrd (p < 0.001; Figure 3). ESRD ws independently ssocited with 3-fold greter hzrd of mortlity compred with non-esrd. Predictors of mortlity in the entire cohort re shown in Tble 4. In model with ge, number of comorbidities, sex, nd body mss index, the effect of dvncing ge (every 5 yers) nd incresing number of comorbidities demonstrted differentil effect in the ESRD vs non-esrd cohort. We noted decrese in the hzrd of dvncing ge t implnttion on mortlity in the ESRD cohort compred with the non-esrd cohort (HR = 1.11, 95% CI = vs HR = 1.28, 95% CI = ). Similrly, we noted decrese in the hzrd of incresing number of comorbidities in the ESRD cohort (HR = 1.04, 95% CI = ) compred with the non-esrd cohort (HR = 1.20, 95% CI = ; Tble 5). DISCUSSION The im of this study ws not to compre the effect of ESRD vs non- ESRD or ICD vs non-icd plcement, nor to determine whether mortlity ws crdiovsculr or noncrdiovsculr. Numerous studies hve lredy mde hedwy into this re nd clerly demonstrted the poorer prognosis of ptients with ESRD However, there is pucity of dt on the possible differentil effects of ge nd multiple chronic conditions between the 2 forementioned groups. In the ging popultion with hert filure, MCC re well known to occur. In fct, more thn 75% of ptients in recent study of ptients with hert filure hd 3 or more co-occurring conditions. 17 Current guidelines hve focused primrily on single disese mngement nd do not often incorporte older dults with multimorbidity. 2,4,18 The findings from this study clerly demonstrte tht ge nd MCC hd differentil effect in Possible implictions of these findings could be tht in ptients with ESRD, considertion of referrl for n ICD should be done t erlier ges with cliniclly cceptble comorbidity burden The Permnente Journl/ Winter 2016/ Volume 20 No. 1 29

4 Figure 2. Volume of implnttion of implntble crdioverter-defibrilltors in n integrted helth cre delivery system in ptients with end-stge renl disese (ESRD, ) nd without ESRD (non-esrd, b). Figure 3. Kpln-Meier survivl curve with ssocited log-rnk test strtified by presence or bsence of end-stge renl disese (ESRD). Tble 4. Multivrite predictors of mortlity Risk fctor HR (95% CI) p vlue ESRD 3.02 ( ) < Age (per 5 yers) 1.25 ( ) < Mle 1.08 ( ) BMI (per 5 kg/m 2 ) 0.88 ( ) < CRT vs ICD-single 1.21 ( ) ICD-dul vs ICD-single 0.96 ( ) Hypertension 1.08 ( ) Dibetes mellitus 1.60 ( ) < Hert filure 1.10 ( ) Myocrdil infrction 1.01 ( ) Chronic lung disese 1.45 ( ) < Stroke 1.28 ( ) Ischemic hert disese 1.26 ( ) Boldfce indictes sttisticlly significnt t p < BMI = body mss index; CI = confidence intervl; CRT = crdic resynchroniztion therpy; ESRD = end-stge renl disese; HR = hzrd rtio; ICD = implntble crdioverter-defibrilltor. the ESRD cohort. This is despite the fct tht the cohort of ICD recipients is lredy thought of s hving n extremely high mortlity risk. Specificlly, we noted tht lthough dvncing ge ws ssocited with significnt 28% (95% CI = 25%-32%) increse in mortlity in the non-esrd group, this effect ws mrkedly decresed in the ESRD group (11%, 95% CI = 3%-20%). Similrly, when we used the number of comorbidities s continuous vrible, ech dditionl comorbidity ws ssocited with significnt 20% (95% CI = 16%-25%) increse in the hzrd of mortlity in the non- ESRD group; this effect ws mrkedly decresed in the ESRD group (4%, 95% CI = -9% to 19%). Recent studies hve described the effect of ge nd MCC in the overll group of ptients referred for ICD plcement. 9,19,20 Hess et l, 20 using pooled dt from 5 clinicl trils, very clerly demonstrted tht lthough the benefit of ICD plcement exists throughout the ge spectrum, the effect decreses with incresing ge. In nother study restricted to cohort of ptients with chronic kidney disese, Hess et l 19 demonstrted tht dvncing ge (every 5 yers) ws significntly ssocited with 19% increse in mortlity. Steinberg et l 9 ddressed the ssocition of MCC nd outcomes fter ICD plcement. They showed tht n incresing number of bseline comorbidities decresed the survivl benefit fter ICD plcement. In the current study, we first demonstrted tht ge ws indeed powerful predictor of mortlity in the overll cohort (HR = 1.27, 95% CI = ). The increse in the hzrd of ge in our overll popultion my hve been cused by slightly decresed comorbidity burden compred with the second study by Hess et l. 19 Becuse our ptient popultion consisted only of ptients fter ICD plcement, we could not show ny differentil benefits on survivl fter ICD plcement with dvncing ge. Next, we confirmed tht ech dditionl comorbidity ws ssocited with 19% increse in mortlity for the entire cohort of ICD recipients. Our study findings were reltively similr to the study by Steinberg nd ssocites, 9 with slight difference in how the vrible, number of comorbidities, ws modeled. Future studies with lrger smples sizes of ESRD-ffected ptients will need to be undertken to either cknowledge or refute the findings from the current study. Why is there differentil effect of ge nd MCC between ESRD nd non-esrd, nd is this importnt? Although it is well known tht ptients with ESRD hve n incresed risk of mortlity, 5 it is sobering to think tht the presence of ESRD is such powerful dominnt predictor of mortlity tht even dvncing ge nd totl comorbidities ple in comprison. However, we nd others believe tht 30 The Permnente Journl/ Winter 2016/ Volume 20 No. 1

5 Tble 5. Effect of dvncing ge nd number of comorbidities Risk fctor Full cohort, HR (95% CI) therpeutic nihilism 21 is not justified. As n exmple, temporl improvement in survivl in the ESRD popultion fter coronry revsculriztion 22 hs been demonstrted similr to the overll temporl improvement in survivl in the ESRD cohort. 23 The pressing question is not whether we should be implnting ICDs in ptients with ESRD. Herzog et l 245 nd others 14-16, hve shown the benefit of ICD therpy in the ESRD popultion fter crdic rrest. Rther, the question should be, How do we identify the optiml ptient with ESRD who should be referred for ICD plcement? Our findings suggest the possibility tht referrl t n erlier ge my be beneficil becuse dvncing ge ws still ssocited with mortlity in riskdjusted model tht included sex, BMI, nd number of comorbidities. Although dvncing number of comorbidities ws not sttisticlly significnt in the current study, further work should focus on certin combintions of comorbidities tht my be of higher risk compred with others. If we re to try to identify the idel ESRD cohort tht my mximlly benefit, future reserch must improve on risk ssessment, 25 incorporte vribles for frilty, 26 nd understnd the role tht utonomic dysfunction, 27 sympthetic overctivity, 28 nd biomrkers 29 ply, long with obtining dilysis-specific vribles (eg, durtion of dilysis, type of dilysis, frequency of dilysis) nd obtining dt on the mechnism of mortlity (crdiovsculr or noncrdiovsculr). Finlly, of note, muchneeded rndomized clinicl tril being undertken in the Netherlnds my shed further light in this field. 30 Limittions The current study should be evluted by blnce of the strengths nd weknesses. The strengths of our study ESRD, HR (95% CI) Non-ESRD, HR (95% CI) Advncing ge (every 5 yers) 1.27 ( ) 1.11 ( ) 1.28 ( ) Advncing number of comorbidities 1.19 ( ) 1.04 ( ) 1.20 ( ) Model contins ge, body mss index, number of comorbidities (s continuous vrible), nd gender. CI = confidence intervl; ESRD = end-stge renl disese; HR = hzrd rtio. include ccurte outcome mesurements using well-vlidted methods. Bseline comorbidities were crefully ssessed using multiple KP dtbses. Our limittions include not hving importnt dditionl covrites such s those for frilty, type nd frequency of dilysis, other dilysis-specific vribles, ssessment of residul renl function, nd novel electrophysiologic vribles tht my hve further refined the model. However, we do not believe tht those vribles would hve significntly chnged the summry estimte of the ssocition of ge nd MCC to mortlity the min focus of the current study. To improve our knowledge in this re, lrger studies with greter number of ptients with ESRD will need to be conducted. CONCLUSIONS The current study demonstrted tht ge nd dvncing comorbidities were ssocited with 15% to 20% incresed risk in the non-esrd group compred with the ESRD group. In both groups, dvncing ge hd 7% to 8% higher ssocited risk compred with incresing comorbidities. Possible implictions of these findings could be tht in ptients with ESRD, considertion of referrl for n ICD should be done t erlier ges with cliniclly cceptble comorbidity burden, nd in the non-esrd ptients, referrl for ICD implnttion could be done t lter ges, tking into considertion the comorbidity burden. Future work will need to ssess nonliner reltionships of ge nd MCC on mortlity s well s the ssocition of nturlly occurring clusters of chronic conditions 3 on mortlity in this cohort. v Disclosure Sttement The uthor(s) hve no conflicts of interest to disclose. Acknowledgments This study is dedicted to the memory of Michel R Luer, MD, who ws n integrl chmpion nd mentor for the development of the Kiser Permnente Crdic Device Registry. Kthleen Louden, ELS, of Louden Helth Communictions provided editoril ssistnce. References 1. He W, Sengupt M, Velkoff VA, DeBrros KA. 65+ in the United Sttes: Pub no. P Wshington, DC: US Census Bureu; 2005 Dec. 2. Guiding principles for the cre of older dults with multimorbidity: n pproch for clinicins: Americn Geritrics Society Expert Pnel on the Cre of Older Adults with Multimorbidity. J Am Geritr Soc 2012 Oct;60(10):E1-E25. DOI: dx.doi.org/ /j x. 3. Vogeli C, Shields AE, Lee TA, et l. Multiple chronic conditions: prevlence, helth consequences, nd implictions for qulity, cre mngement, nd costs. J Gen Intern Med 2007 Dec;22 Suppl 3: DOI: org/ /s Tinetti ME, Bogrdus ST Jr, Agostini JV. Potentil pitflls of disese-specific guidelines for ptients with multiple conditions. New Engl J Med 2004 Dec 30;351(27): DOI: org/ /nejmsb Go AS, Mozffrin D, Roger VL, et l; Americn Hert Assocition Sttistics Committee nd Stroke Sttistics Subcommittee. Hert disese nd stroke sttistics 2013 updte: report from the Americn Hert Assocition. Circultion 2013 Jn 1;127(1):e6-e245. DOI: org/ /cir.0b013e d. 6. de Bie MK, vn Dm B, Gsbeek A, et l. The current sttus of interventions iming t reducing sudden crdic deth in dilysis ptients. Eur Hert J 2009 Jul;30(13): DOI: dx.doi.org/ /eurhertj/ehp Arnett DK, Goodmn RA, Hlperin JL, Anderson JL, Prekh AK, Zoghbi WA. AHA/ACC/HHS strtegies to enhnce ppliction of clinicl prctice guidelines in ptients with crdiovsculr disese nd comorbid conditions: from the Americn Hert Assocition, Americn College of Crdiology, nd US Deprtment of Helth nd Humn Services. Circultion 2014 Oct 28;130(18): DOI: CIR Clegg A, Young J, Iliffe S, Rikkert MO, Rockwood K. Frilty in elderly people. Lncet 2013 Mr 2;381(9868): DOI: org/ /s (12) Errtum in: Lncet 2013 Oct 19;382(9901):1328. DOI: dx.doi.org/ /s (13)62139-x. 9. Steinberg BA, Al-Khtib SM, Edwrds R. Outcomes of implntble crdioverter-defibrilltor use in ptients with comorbidities: results from combined nlysis of 4 rndomized clinicl trils. JACC Hert Fil 2014 Dec;2(6): DOI: dx.doi.org/ /j.jchf Pxton EW, Incio MC, Kiley ML. The Kiser Permnente implnt registries: effect on ptient sfety, qulity improvement, cost effectiveness, nd reserch opportunities. Perm J 2012 Spring;16(2): DOI: /TPP/ Koebnick C, Lnger-Gould AM, Gould MK, et l. Sociodemogrphic chrcteristics of members of lrge, integrted helth cre system: comprison with US Census Bureu dt. Perm J The Permnente Journl/ Winter 2016/ Volume 20 No. 1 31

6 2012 Summer;16(3): DOI: /TPP/ Krter AJ, Ferrr A, Liu JY, Moffet HH, Ackerson LM, Selby JV. Ethnic disprities in dibetic complictions in n insured popultion. JAMA 2002 My 15;287(19): DOI: dx.doi.org/ /jm Errtum in: JAMA 2002 Jul 3;288(1):46. DOI: /jm Horn TC, Andrus M, Dudeck MA. CDC/NHSN surveillnce definition of helth cre-ssocited infection nd criteri for specific types of infections in the cute cre setting. Am J Infect Control 2008 Jun;36(5): DOI: org/ /j.jic Chen TH, Wo HT, Chng PC, Wng CC, Wen MS, Chou CC. A met-nlysis of mortlity in endstge renl disese ptients receiving implntble crdioverter defibrilltors (ICDs). PloS One 2014 Jul 18;9(7):e DOI: /journl.pone Pun PH, Al-Khtib SM, Hn JY, et l. Implntble crdioverter-defibrilltors for primry prevention of sudden crdic deth in CKD: met-nlysis of ptient-level dt from 3 rndomized trils. Am J Kidney Dis 2014 Jul;64(1):32-9. DOI: org/ /j.jkd Mkki N, Swminthn PD, Hnmer J, Olshnsky B. Do implntble crdioverter defibrilltors improve survivl in ptients with chronic kidney disese t high risk of sudden crdic deth? A met-nlysis of observtionl studies. Europce 2014 Jn;16(1): DOI: Sczynski JS, Go AS, Mgid DJ, et l. Ptterns of comorbidity in older dults with hert filure: the Crdiovsculr Reserch Network PRESERVE study. J Am Geritr Soc 2013 Jn;61(1): DOI: Cox L, Kloseck M, Crilly R, McWillim C, Dichun L. Underrepresenttion of individuls 80 yers of ge nd older in chronic disese clinicl prctice guidelines. Cn Fm Physicin 2011 Jul;57(7):e Hess PL, Hellkmp AS, Peterson ED, et l. Survivl fter primry prevention implntble crdioverter-defibrilltor plcement mong ptients with chronic kidney disese. Circ Arrhythm Electrophysiol 2014 Oct;7(5): DOI: Hess PL, Al-Khtib SM, Hn JY, et l. Survivl benefit of the primry prevention implntble crdioverter-defibrilltor mong older ptients: does ge mtter? An nlysis of pooled dt from 5 clinicl trils. Circ Crdiovsc Qul Outcomes 2015 Mr;8(2): DOI: org/ /circoutcomes Herzog CA. Crdiovsculr disese nd dilysis ptients: is therpeutic nihilism justified? Semin Dil 1999 Oct-Nov;12(5): DOI: dx.doi.org/ /j x x. 22. Krishnswmi A, Leong TK, Hltky MA, Chng TI, Go AS. Temporl trends in mortlity fter coronry rtery revsculriztion in ptients with end-stge renl disese. Perm J 2014 Summer;18(3):11-6. DOI: Srn R, Li Y, Robinson B, et l. US renl dt system 2014 nnul dt report: epidemiology of kidney disese in the United Sttes. Am J Kidney Dis 2015 Jun;65(6 Suppl 1):A7. DOI: org/ /j.jkd Herzog CA, Li S, Weinhndl ED, Strief JW, Collins AJ, Gilbertson DT. Survivl of dilysis ptients fter crdic rrest nd the impct of implntble crdioverter defibrilltors. Kidney Int 2005 Aug;68(2): DOI: org/ /s (03) Srvnn P, Dvidson NC. Risk ssessment for sudden crdic deth in dilysis ptients. Circ Arrhythm Electrophysiol 2010 Oct;3(5): DOI: CIRCEP Afillo J, Alexnder KP, Mck MJ, et l. Frilty ssessment in the crdiovsculr cre of older dults. J Am Coll Crdiol 2014 Mr 4;63(8): DOI: jcc Chn CT, Levin NW, Chertow GM, Lrive B, Schulmn G, Kotnko P; Frequent Hemodilysis Network Dily Tril Group. Determinnts of crdic utonomic dysfunction in ESRD. Clin J Am Soc Nephrol 2010 Oct;5(10): DOI: Nishimur M, Tokoro T, Nishid M, et l. Sympthetic overctivity nd sudden crdic deth mong hemodilysis ptients with left ventriculr hypertrophy. Int J Crdiol 2010 Jun 25;142(1):80-6. DOI: ijcrd Hickmn PE. Biomrkers nd crdic disese in ptients with end-stge renl disese on dilysis. Clin Biochem Rev 2011 My;32(2): de Bie MK, Lekkerkerker JC, vn Dm B, et l. Prevention of sudden crdic deth: rtionle nd design of the Implntble Crdioverter Defibrilltors in Dilysis ptients (ICD2) Tril prospective pilot study. Curr Med Res Opin 2008 Aug;24(8): DOI: org/ / Hrdness of the Kidneys The signs of hrdness of the kidneys re tht the quntity of the urine is diminished, tht there is heviness of the kidneys, nd of the spine with some pin: nd the belly begins to swell up fter time nd dropsy is produced the second dy. Gulielmus de Slicento, , Itlin surgeon nd cleric 32 The Permnente Journl/ Winter 2016/ Volume 20 No. 1