Jonathan Winston
HIV and CKD Epidemiology
Icahn School of Medicine at Mount Sinai
nephrologists serve many important functions hivinfected patients including identifying risks developing kidney disease detecting diagnosing kidney disease distinguishing antiretroviralinduced kidney injury kidney disease setting antiretroviral therapy comanaging clinical course complications ckd preparing patients dialysis andor transplantation epidemiology kidney disease hiv informs us functions describing natural history disease frequent occurrence highrisk communities potential causes risk factors drive ckd hiv black race hypertension diabetes hiv viral replication low cd4 cell counts high viral load acquired immune deficiency syndromedefining conditions antiretroviral agents nephrotoxic potential prevalence risk factors population determines magnitude problem range low 2 high 30 recent research focuses kidney health hiv important links hiv viral replication glomerular filtration rate even patients normal kidney function reported review data provides foundation better understanding kidney disease hopefully better treatment patients hiv nephrologists serve many important functions hivinfected patients including identifying risks developing kidney disease detecting diagnosing kidney disease distinguishing antiretroviralinduced kidney injury kidney disease setting antiretroviral therapy comanaging clinical course complications ckd preparing patients dialysis andor transplantation epidemiology kidney disease hiv informs us functions describing natural history disease frequent occurrence highrisk communities potential causes risk factors drive ckd hiv black race hypertension diabetes hiv viral replication low cd4 cell counts high viral load acquired immune deficiency syndromedefining conditions antiretroviral agents nephrotoxic potential prevalence risk factors population determines magnitude problem range low 2 high 30 recent research focuses kidney health hiv important links hiv viral replication glomerular filtration rate even patients normal kidney function reported review data provides foundation better understanding kidney disease hopefully better treatment patients hiv remarkable story unfolds examining recent reports kidney disease hiv entire spectrum kidney disease covered genetic susceptibility early clinical markers organ failure requiring dialysis transplantation nephrologists practiced early stages acquired immunodeficiency syndrome aids epidemic descriptions earlystage kidney disease transplantation almost unimaginable hiv infection untreatable kidney disease almost synonymous immunosuppression opportunistic infections esrd antiretroviral combinations predictably lead durable viral suppression nephrologist faced exciting new challenges hiv medicine ones emphasize kidney health identifying early signs kidney disease working closely collaboration hiv specialists patients practices nephrologists must realize prescribing antiretroviral regimen effectively reduces hiv viral replication longer difficult challenge hiv provider many effective drug combinations available new emphasis risk stratification preventing complications could develop years decades drug therapy selecting antiretroviral regimen hiv providers consider potential drug therapy induce cardiovascular metabolic liver neurologic bone kidney disease kidney disease hiv assumed increasing importance patients living longer hiv years exposure hypertension diabetes dyslipidemia risk atherosclerotic vascular disease another contributor kidney disease tenofovir disoproxil fumarate coformulated efavirenz dual nucleoside reverse transcriptase inhibitor nrti regimen rated preferred option department health human services panel antiretroviral guidelines adults adolescents1panel antiretroviral guidelines adults adolescentsguidelines use antiretroviral agents hiv1infected adults adolescents 1139us department health human services 2008 google scholar surprisingly tenofovir widely prescribed nrti united states cause renal tubule injury reduce kidney function nephrologist serve following critical functions hiv provider patients identifying significant risk kidney disease assisting early detection promptly diagnosing causes distinguishing tenofovirinduced kidney injury kidney disease tenofovirtreated patient comanaging course complications established ckd preparing patients dialysis andor transplantation epidemiologically black race important determinant kidney disease prevalence hivinfected persons least united states strong evidence implicates genetic modifiable causes latter exacerbated directly resulting health care disparities evidence genetic link race kidney disease comes association hivassociated nephropathy hivan black race clinical picture sizable minority 1020 hivinfected patients presenting kidney disease heavy proteinuria moderate severe reductions glomerular filtration rate gfr patients almost inevitably progress esrd almost exclusively black exact cause ckd always precisely known kidney biopsy performed highly likely cases hivan support role health care disparities case series large cohort studies show disproportionate risk esrd among blacks invariably include significant proportion patients risk underutilizing health care services whether low socioeconomic status injection drug use low medical literacy asyetundefined factors2mugavero mj lin hy allison jj et alracial disparities hiv virologic failure missed visits matterj acquir immune defic syndr 2009 50 100108crossref pubmed scopus 146 google scholar united states 88 incident hivinfected esrd patients 2002 2006 blacks3us renal data systemusrds 2008 annual data report atlas endstage renal disease united states bethesda maryland national institutes health national institute diabetes digestive kidney diseases bethesda md2008google scholar racial disparities somewhat less dramatic examining prevalence earlier stages ckd microalbuminuria detected 11 hivinfected patients compared 2 controls fifteen percent blacks affected compared 7 whites4szczech la grunfeld c scherzer r et almicroalbuminuria hiv infectionaids 2007 21 10031009crossref pubmed scopus 121 google scholar another report dipstick proteinuria 1 detected many 32 hivinfected persons abnormalities found 39 blacks compared 25 whites 24 hispanics5szczech la gange sj van der horst c et alpredictors proteinuria renal failure among women hiv infectionkidney int 2002 61 195202crossref pubmed scopus 185 google scholar comparison blacks whites analysis 2 million patients receiving care veterans affairs system showed equal rates ckd defined gfr 60 mlmin173 m2 approximately 7 blacks whites nevertheless esrd developed often blacks 126816 patients 73 events1000 personyears multivariate hazard ratio hr 456 344605 black compared white race6choi ai rodriguez ra bacchetti p et alracial differences endstage renal disease rates hiv infection versus diabetesj soc nephrol 2007 18 29682974crossref pubmed scopus 102 google scholar even stronger risk developing esrd described among 4259 patients followed johns hopkins hiv clinical cohort 1990 2004 ckd gfr 60 mlmin173 m2 prevalence 4fold higher blacks approximately 13 compared 3 whites whereas ckd incidence 2fold higher 125 cases1000 personyears hr19 95 confidence interval 1228 ckd diagnosis however 39 blacks progressed esrd compared 3 whites hr177 95 ci 251277lucas gm lau b atta mg et alchronic kidney disease incidence progression endstage renal disease hivinfected individuals tale two racesj infect dis 2008 197 15481557crossref pubmed scopus 168 google scholar hivan notwithstanding racial disparities tempered recent reports retrospective crosssectional analysis 845 hivinfected patients attending outpatient clinic st louis mo 2005 overall prevalence stage 3 ckd estimated gfr 3060 mlmin173 m2 75 differ across race8overton et nurutdinova freeman j et alfactors associated renal dysfunction within urban hivinfected cohort era highly active antiretroviral therapyhiv med 2009 10 343350crossref pubmed scopus 72 google scholar many 25 patients dipstick proteinuria least 1 occasion threshold positive urinalysis defined cohort 3439 patients followed united kingdom 1998 2005 prevalence stage 3 ckd 24 equally low among black white patients 20 vs 26 respectively9campbell lj ibrahim f fisher et alspectrum chronic kidney disease hivinfected patientshiv med 2009 10 329336crossref pubmed scopus 103 google scholar 26 affected black patients 16 presumed diagnosis hivan operationally defined fulfilling following criteria proteinuria 15 gd echogenic unobstructed kidneys sonogram absence hypertension diabetes vascular disease urinary tract obstruction drug toxicity remainder black patients virtually white patients 95 kidney disease association hypertension diabetes atherosclerosis drug toxicity group patients normal mildly impaired gfr time hiv diagnosis 74 mlmin173 m2 moderately reduced gfr time ckd diagnosis 55 mlmin173 m2 reasonably stable gfr 4 years ckd diagnosis compared patients normal kidney function patients older 536 vs 377 years lower median cd4 cell counts 76 vs 19 cellsl likely aidsdefining diagnosis 48 vs 23 hivan patients hand presented severely reduced gfr time hiv diagnosis mean 25 mlmin173 m2 2 progressed stage 5 ckd within months clearly subset ckd patients highest risk esrd consists black patients heavy proteinuria moderate severe reductions gfr presentation always hivan another primary glomerular disease majority patients ckd however exact cause unclear ckd tends occurs older patients antiretroviral drug experienced low cd4 cell count aids defining illness coexisting hypertension diabetes presumed atherosclerotic vascular disease precise etiology kidney disease patients difficult ascertain clinical grounds alone liberal use kidney biopsy could clarify underlying causes10fine dm perazella lucas gm et alkidney biopsy hiv beyond hivassociated nephropathyam j kidney dis 2008 51 504514abstract full text full text pdf pubmed scopus 44 google scholar however diagnostic approach kidney disease individualized evidence wholesale reliance kidney biopsy hivinfected patients would yield clinically valuable information similar reliance general nephrology practice many patients ckd managed without tissue diagnosis explainable causes hypertension type 2 diabetes dyslipidemia atherosclerosis prognosis patients nonprimary ckd often favorable gfr remaining stable many years compare data race ckd hiv know race ckd general population racial predilection allcause ckd blacks unique hiv infection blacks account 10 us population 30 patients esrd11us renal data systemusrds 2007 annual data report atlas chronic kidney disease endstage renal disease united states national institutes health national institute diabetes digestive kidney diseases bethesda md2007google scholar coronary artery risk development young adults study prevalence elevated serum creatinine among white men 06 compared 48 young black men12stehmanbreen co gillen steffes et alracial differences earlyonset renal disease among young adults coronary artery risk development young adults cardia studyj soc nephrol 2003 14 23522357crossref pubmed scopus 26 google scholar five new cases esrd develop every 100 cases ckd blacks 1 new esrd case every 100 whites13hsu cy lin f vittinghoff e et alracial differences progression chronic renal insufficiency endstage renal disease united statesj soc nephrol 2003 14 29022907crossref pubmed scopus 363 google scholar hiv effect race progression esrd must also considered context stage hiv infection durability virologic response see later progression esrd hivan inevitable virologic suppression cannot achieved14szczech la gupta sk habash r et althe clinical epidemiology course spectrum renal diseases associated hiv infectionkidney int 2004 66 11451152crossref pubmed scopus 293 google scholar allcause ckd common drugexperienced patients aidsdefining condition however unclear role race may play risk developing ckd progressing esrd viral suppression maintained diabetes hypertension effectively managed black race significant risk factor kidney disease hiv expect see high rates kidney disease studies africa particularly people receive antiretroviral therapy outlive endemic infectious diseases opportunistic infections development antiretroviral therapy trial randomized 3316 antiretroviral therapy artnaive hivinfected patients subsaharan africa receive tripledrug art compared clinical monitoring alone clinical laboratory monitoring outcomes15stohr w walker munderi p et alestimating glomerular filtration rate hivinfected adults africa comparison cockcroftgault modification diet renal disease formulaeantivir ther 2008 13 761770pubmed google scholar baseline prevalence stage 3 worse ckd 7 classifying people using cockcroftgault formula 3 using modification diet renal disease equation end 96 weeks treatment serum creatinine increased art median 088 093 mgdl body weight bmi also increased prevalence ckd actually decreased time analysis gfr cohort artnaive patients western kenya estimated gfr 60 mlmin 11 using cockcroftgault formula 48 using modification diet renal disease equation 62 people dipstickpositive proteinuria16woolskaloustian k gupta sk muloma e et alrenal disease antiretroviralnaive hivinfected outpatient population western kenyanephrol dial transplant 2007 22 22082212crossref pubmed scopus 81 google scholar higher prevalence kidney disease one consistent hypothesis epidemic kidney disease africa horizon comes report southern nigeria17emem cp arogundade f sanusi et alrenal disease hivseropositive patients nigeria assessment prevalence clinical features risk factorsnephrol dial transplant 2008 23 741746crossref pubmed scopus 83 google scholar thirtyeight percent n152 400 consecutive patients attending hiv clinic ckd defined 1 albuminuria least 2 occasions serum creatinine 15 mgdl estimated gfr 60 mlmin 50 patients diabetes mellitus hypertension 2 frequent causes ckd general population increase ckd risk almost 10fold account 71 esrd11us renal data systemusrds 2007 annual data report atlas chronic kidney disease endstage renal disease united states national institutes health national institute diabetes digestive kidney diseases bethesda md2007google scholar 18coresh j byrdholt astor bc et alchronic kidney disease awareness prevalence trends among us adults 1999 2000j soc nephrol 2005 16 180188crossref pubmed scopus 705 google scholar diabetes hypertension increasingly frequent among persons hiv multicenter aids cohort study prevalence diabetes 14 4fold higher seronegative controls19brown tt cole sr li x et alantiretroviral therapy prevalence incidence diabetes mellitus multicenter aids cohort studyarch intern med 2005 165 11791184crossref pubmed scopus 678 google scholar risk seems associated cumulative exposure nrtis20brown tt li x cole sr et alcumulative exposure nucleoside analogue reverse transcriptase inhibitors associated insulin resistance markers multicenter aids cohort studyaids 2005 19 13751383crossref pubmed scopus 215 google scholar 21tien pc schneider mf cole sr et alantiretroviral therapy exposure incidence diabetes mellitus womens interagency hiv studyaids 2007 21 17391745crossref pubmed scopus 149 google scholar hypertension hiv 3fold higher compared age sexmatched controls 342 vs 119 p 0001 hypertensive patients hiv likely insulin resistance metabolic syndrome 643 vs 169 p 000122gazzaruso c bruno r garzaniti et alhypertension among hiv patients prevalence relationships insulin resistance metabolic syndromej hypertens 2003 21 13771382crossref pubmed scopus 194 google scholar proteinuria23jung bickel ditting et alhypertension hiv1infected patients impact renal cardiovascular integritynephrol dial transplant 2004 19 22502258crossref pubmed scopus 56 google scholar crosssectional cohort studies prevalence documented hypertension diabetes mellitus approaches 55 20 respectively9campbell lj ibrahim f fisher et alspectrum chronic kidney disease hivinfected patientshiv med 2009 10 329336crossref pubmed scopus 103 google scholar 19brown tt cole sr li x et alantiretroviral therapy prevalence incidence diabetes mellitus multicenter aids cohort studyarch intern med 2005 165 11791184crossref pubmed scopus 678 google scholar 24elsadr wm lundgren jd neaton jd et alcd4 countguided interruption antiretroviral treatmentn engl j med 2006 355 22832296crossref pubmed scopus 1941 google scholar 25wyatt cm winston ja malvestutto cd et alchronic kidney disease hiv infection urban epidemicaids 2007 21 21012103crossref pubmed scopus 141 google scholar 26young b buchacz k baker rk et alrenal function tenofovirexposed tenofovirunexposed patients receiving highly active antiretroviral therapy hiv outpatient studyj int assoc physicians aids care chic ill 2007 6 178187crossref pubmed scopus 43 google scholar data underscore importance optimizing blood pressure achieving glycemic control means minimizing impact ckd hiv angiotensinconverting enzyme inhibitors angiotensin receptor blockers drugs choice proteinuric patients27chobanian av bakris gl black hr et althe seventh report joint national committee prevention detection evaluation treatment high blood pressure jnc 7 reportjama 2003 289 25602572crossref pubmed scopus 16922 google scholar 28molitch defronzo ra franz mj et alnephropathy diabetesdiabetes care 2004 27 s79s83pubmed google scholar 29gupta sk eustace ja winston ja et alguidelines management chronic kidney disease hivinfected patients recommendations hiv medicine association infectious diseases society americaclin infect dis 2005 40 15591585crossref pubmed scopus 524 google scholar although concomitant use protease inhibitors block metabolism blockers nondihydropyridine calciumchannel blockers antihypertensives widely used adverse events rarely reported low gfr associated lower cd4 cell counts higher viral loads5szczech la gange sj van der horst c et alpredictors proteinuria renal failure among women hiv infectionkidney int 2002 61 195202crossref pubmed scopus 185 google scholar 30gardner li holmberg sd williamson jm et aldevelopment proteinuria elevated serum creatinine mortality hivinfected womenj acquir immune defic syndr 2003 32 203209crossref pubmed scopus 145 google scholar 31gardner li klein rs szczech la et alrates risk factors conditionspecific hospitalizations hivinfected uninfected womenj acquir immune defic syndr 2003 34 320330crossref pubmed scopus 51 google scholar 32szczech la hoover dr feldman jg et alassociation renal disease outcomes among hivinfected women receiving receiving antiretroviral therapyclin infect dis 2004 39 11991206crossref pubmed scopus 158 google scholar direct relationship exists viral replication kidney disease hivan hiv viral replication renal cells prerequisite disease development circulating viral rna viral load associated kidney disease progression effective inhibition viral replication improves kidney function prolongs renal survival33atta mg gallant je rahman mh et alantiretroviral therapy treatment hivassociated nephropathynephrol dial transplant 2006 21 28092813crossref pubmed scopus 127 google scholar 34ross mj klotman pe hivassociated nephropathyaids 2004 18 10891099crossref pubmed scopus 62 google scholar 35szczech la edwards lj sanders et alprotease inhibitors associated slowed progression hiv related renal diseasesclin nephrol 2002 57 336341crossref pubmed scopus 107 google scholar 36winston ja bruggeman la ross md et alnephropathy establishment renal reservoir hiv type 1 primary infectionn engl j med 2001 344 19791984crossref pubmed scopus 281 google scholar possibility similar relationship viral replication gfr patients hiv hivan also normal kidney function subject several recent reports strategies management antiretroviral therapy smart trial randomized 5472 persons cd4 cell counts 350 cellsmm3 received either uninterrupted antiretroviral therapy according standard guidelines 2003 viral suppression group n2752 interrupted therapy drug conservation group n272024elsadr wm lundgren jd neaton jd et alcd4 countguided interruption antiretroviral treatmentn engl j med 2006 355 22832296crossref pubmed scopus 1941 google scholar experimental drugconservation group antiretroviral therapy deferred cd4 cell counts fell 250 cellsmm3 interrupted cd4 cell counts rose 350 cellsmm3 resumed levels fell 250 cellsmm3 trial prematurely terminated primary endpoints allcause mortality opportunistic infections secondary events major cardiovascular hepatic renal events developed drug conservation group major renal events defined esrd requiring dialysis transplant rare occurred frequently drugconservation group 9 vs 2 events viral suppression group p05 consistent hypothesis viral replication directly results kidney disease rate renal events decreased significantly trial completion drugconservation patients treated according standard guidelines achieved sustained viral suppression37elsadr wm grund b neuhaus j et alrisk opportunistic disease death reinitiating continuous antiretroviral therapy patients hiv previously receiving episodic therapy randomized trialann intern med 2008 149 289299crossref pubmed scopus 122 google scholar results substudy smart trial focused kidney disease recently published38mocroft wyatt c szczech l et alinterruption antiretroviral therapy associated increased plasma cystatin caids 2009 23 7182crossref pubmed scopus 49 google scholar serum samples saved biomarker analysis 500 patients 250 group differences serum creatinine estimated gfr groups baseline 12 months randomization however small statistically significant differences serum cystatin c detected clinical significance cystatin c area active investigation epidemiologic evidence cystatin c may accurate measure gfr serum creatinine alone may biomarker cardiovascular disease associated kidney disease39shlipak mg cystatin c research priorities targeted clinical decision makingam j kidney dis 2008 51 358361abstract full text full text pdf pubmed scopus 15 google scholar drugconservation group mean rise cystatin c levels 005 mgdl contrasted small decrease viral suppression group 002 mgdl p 0001 proportion patients experiencing least 015mgdl increase cystatin c greater drugconservation group 218 compared viral suppression group 106 increases correlated increases creactive protein crp interleukin6 il6 serum amyloid ddimer levels decreases highdensity lipoprotein hdl total cholesterol investigators interpreted findings evidence nonsustained viral suppression drugconservation group induced systemic inflammation concurrent may contributed renal injury another study estimated gfr tracked 1776 patients enrolled various aids clinical trials groupsponsored clinical trials 1997 2004 primary goal study test initial new art regimens40kalayjian rc franceschini n gupta sk et alsuppression hiv1 replication antiretroviral therapy improves renal function persons low cd4 cell counts chronic kidney diseaseaids 2008 22 481487crossref pubmed scopus 101 google scholar estimated gfr 60 mlmin173 m2 6 patients 767 drug naive baseline whole gfr declined rate 003 mlmin173 m2 increased whose gfr 60 mlmin173 m2 baseline mean increase28 mlmin173 m2 results reinforce importance following trends serum creatinine rather relying exclusively 1 baseline measure gfr increased 60 mlmin173 m2 24 31 subjects originally classified stage 3 ckd supporting contention antiviral therapy improves kidney function however change gfr could also explained simple regression mean underscoring importance biologic laboratory variation serum creatinine measurements misclassification ckd may occur diagnosis based 1 creatinine measurement overall clinical significance changes normal kidney function hiv changes inform us kidney health kidney disease remains determined renal results smart study would compelling could shown small changes cystatin c levels reflect gfr systemic inflammation induced viral replication41mauss berger f kuschak et alcystatin c marker renal function affected hiv replication leading underestimation kidney function hiv patientsantivir ther 2008 13 10911095pubmed google scholar studies suggest sustained virologic suppression direct beneficial effects kidney function health disease research needed sort many confounding influences may link 2 discussion effects viral replication viral suppression kidney function would complete without discussing tenofovir detailed analysis found elsewhere issue tenofovir often impugned frequent cause ckd42labarga p barreiro p martincarbonero l et alkidney tubular abnormalities absence impaired glomerular function hiv patients treated tenofoviraids 2009 23 689696crossref pubmed scopus 259 google scholar 43woodward cl hall williams ig et altenofovirassociated renal bone toxicityhiv med 2009 10 482487crossref pubmed scopus 244 google scholar support contention studies must distinguish drug effect background kidney disease prevalence estimated 10 15 discussed earlier considering clinical significance associations drug ckd one must consider whether particular study includes sufficient number patients properly selected control group comparison reasonable followup data reports mainly observational design show significant falls gfr time patients hiv clinically important decrements kidney function 25 1 2 years develop 20 28 respectively nrtitreated patients taking tenofovir44moore rd gallant j renal function use tenofovir part initial art regimen washington dc 48th annual interscience conference antimicrobial agents chemotherapy icaac october 2528 2008 abstr h2297google scholar longitudinal studies show low levels drug discontinuation 12 small changes gfr 5 mlmin 13 years tenofovirtreated patients26young b buchacz k baker rk et alrenal function tenofovirexposed tenofovirunexposed patients receiving highly active antiretroviral therapy hiv outpatient studyj int assoc physicians aids care chic ill 2007 6 178187crossref pubmed scopus 43 google scholar 45gallant je winston ja dejesus e et althe 3year renal safety tenofovir disoproxil fumarate vs thymidine analoguecontaining regimen antiretroviralnaive patientsaids 2008 22 21552163crossref pubmed scopus 101 googl