The impact of HIV on chronic kidney disease outcomes
2007; Elsevier BV; Volume: 72; Issue: 11 Linguagem: Inglês
10.1038/sj.ki.5002541
ISSN1523-1755
AutoresAndy I. Choi, R.A. Rodriguez, Peter Bacchetti, Daniel Bertenthal, Paul A. Volberding, Ann M. O’Hare,
Tópico(s)HIV/AIDS Research and Interventions
ResumoChronic kidney disease (CKD) is a known complication of the human immunodeficiency virus (HIV) but outcomes among HIV-infected patients with kidney disease are unknown. We studied a national sample of 202 927 patients with CKD (stage 3 or higher) for death, end-stage renal disease (ESRD) and the mean annual rate of decline in estimated glomerular filtration rate (eGFR) over a median period of 3.8 years. Within this sample, 0.3% of the patients were diagnosed with HIV, 43.5% were diabetic, whereas the remainder had neither disease. In this national CKD cohort, HIV-infected black patients were at higher risk of death, a similar risk for ESRD and loss of eGFR than black patients with diabetes. HIV-infected white patients experienced higher rates of death but a lower risk of ESRD than their counterparts with diabetes. Our results highlight a need to study mortality and mechanisms of ESRD in the HIV infected population. Chronic kidney disease (CKD) is a known complication of the human immunodeficiency virus (HIV) but outcomes among HIV-infected patients with kidney disease are unknown. We studied a national sample of 202 927 patients with CKD (stage 3 or higher) for death, end-stage renal disease (ESRD) and the mean annual rate of decline in estimated glomerular filtration rate (eGFR) over a median period of 3.8 years. Within this sample, 0.3% of the patients were diagnosed with HIV, 43.5% were diabetic, whereas the remainder had neither disease. In this national CKD cohort, HIV-infected black patients were at higher risk of death, a similar risk for ESRD and loss of eGFR than black patients with diabetes. HIV-infected white patients experienced higher rates of death but a lower risk of ESRD than their counterparts with diabetes. Our results highlight a need to study mortality and mechanisms of ESRD in the HIV infected population. Although highly active antiretroviral therapy has resulted in dramatic improvements in morbidity related to the human immunodeficiency virus (HIV), many contemporary studies indicate that kidney disease is an increasingly frequent complication of HIV infection.1.US Renal Data System (USRDS)Annual data report. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD2001Google Scholar,2.Schwartz E.J. Szczech L.A. Ross M.J. et al.Highly active antiretroviral therapy and the epidemic of HIV+ End-stage renal disease.J Am Soc Nephrol. 2005; 16: 2412-2420Crossref PubMed Scopus (155) Google Scholar In the United States, the prevalence of end-stage renal disease (ESRD) caused by HIV-associated nephropathy doubled between 1995 and 2000 and proteinuria may be present in up to 30% of HIV-infected individuals.1.US Renal Data System (USRDS)Annual data report. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD2001Google Scholar, 3.Szczech L.A. Gange S.J. van der Horst C. et al.Predictors of proteinuria and renal failure among women with HIV infection.Kidney Int. 2002; 61: 195-202Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar, 4.Gupta S.K. Eustace J.A. Winston J.A. et al.Guidelines for the management of chronic kidney disease in HIV-infected patients: recommendations of the HIV Medicine Association of the Infectious Diseases Society of America.Clin Infect Dis. 2005; 40: 1559-1585Crossref PubMed Scopus (512) Google Scholar Kidney disease is also an important predictor of mortality among patients with HIV. Between 1995 and 1999, the proportion of death certificates listing kidney disease as an underlying cause increased from 6 to 9% among HIV-infected individuals nationally.5.Selik R.M. Byers Jr, R.H. Dworkin M.S. Trends in diseases reported on US death certificates that mentioned HIV infection, 1987–1999.J Acquir Immune Defic Syndr. 2002; 29: 378-387Crossref PubMed Scopus (210) Google Scholar Prior work has demonstrated that elevated serum creatinine and proteinuria together or independently predict mortality among patients with HIV.3.Szczech L.A. Gange S.J. van der Horst C. et al.Predictors of proteinuria and renal failure among women with HIV infection.Kidney Int. 2002; 61: 195-202Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar, 5.Selik R.M. Byers Jr, R.H. Dworkin M.S. Trends in diseases reported on US death certificates that mentioned HIV infection, 1987–1999.J Acquir Immune Defic Syndr. 2002; 29: 378-387Crossref PubMed Scopus (210) Google Scholar, 6.Szczech L.A. Gupta S.K. Habash R. et al.The clinical epidemiology and course of the spectrum of renal diseases associated with HIV infection.Kidney Int. 2004; 66: 1145-1152Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar, 7.Atta M.G. Gallant J.E. Hafizur Rahman M. et al.Antiretroviral therapy in the treatment of HIV-associated nephropathy.Nephrol Dial Transplant. 2006; 21: 2809-2813Crossref PubMed Scopus (126) Google Scholar, 8.Estrella M. Fine D.M. Gallant J.E. et al.HIV type 1 RNA level as a clinical indicator of renal pathology in HIV-infected patients.Clin Infect Dis. 2006; 43: 377-380Crossref PubMed Scopus (59) Google Scholar, 9.Laradi A. Mallet A. Beaufils H. et al.HIV-associated nephropathy: outcome and prognosis factors. Groupe d' Etudes Nephrologiques d'Ile de France.J Am Soc Nephrol. 1998; 9: 2327-2335PubMed Google Scholar, 10.Szczech L.A. Hoover D.R. Feldman J.G. et al.Association between renal disease and outcomes among HIV-infected women receiving or not receiving antiretroviral therapy.Clin Infect Dis. 2004; 39: 1199-1206Crossref PubMed Scopus (158) Google Scholar, 11.Gardner L.I. Holmberg S.D. Williamson J.M. et al.Development of proteinuria or elevated serum creatinine and mortality in HIV-infected women.J Acquir Immune Defic Syndr. 2003; 32: 203-209Crossref PubMed Scopus (144) Google Scholar However, relatively few studies have examined clinical outcomes among representative samples of patients with HIV and chronic kidney disease (CKD). Previous studies of outcomes in HIV-infected patients with renal disease were conducted among cohorts undergoing kidney biopsy 3.Szczech L.A. Gange S.J. van der Horst C. et al.Predictors of proteinuria and renal failure among women with HIV infection.Kidney Int. 2002; 61: 195-202Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar, 6.Szczech L.A. Gupta S.K. Habash R. et al.The clinical epidemiology and course of the spectrum of renal diseases associated with HIV infection.Kidney Int. 2004; 66: 1145-1152Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar, 7.Atta M.G. Gallant J.E. Hafizur Rahman M. et al.Antiretroviral therapy in the treatment of HIV-associated nephropathy.Nephrol Dial Transplant. 2006; 21: 2809-2813Crossref PubMed Scopus (126) Google Scholar, 8.Estrella M. Fine D.M. Gallant J.E. et al.HIV type 1 RNA level as a clinical indicator of renal pathology in HIV-infected patients.Clin Infect Dis. 2006; 43: 377-380Crossref PubMed Scopus (59) Google Scholar, 9.Laradi A. Mallet A. Beaufils H. et al.HIV-associated nephropathy: outcome and prognosis factors. Groupe d' Etudes Nephrologiques d'Ile de France.J Am Soc Nephrol. 1998; 9: 2327-2335PubMed Google Scholar and women,10.Szczech L.A. Hoover D.R. Feldman J.G. et al.Association between renal disease and outcomes among HIV-infected women receiving or not receiving antiretroviral therapy.Clin Infect Dis. 2004; 39: 1199-1206Crossref PubMed Scopus (158) Google Scholar,11.Gardner L.I. Holmberg S.D. Williamson J.M. et al.Development of proteinuria or elevated serum creatinine and mortality in HIV-infected women.J Acquir Immune Defic Syndr. 2003; 32: 203-209Crossref PubMed Scopus (144) Google Scholar and thus may not be generalizable to the wider population of patients with HIV and CKD. To date, no studies have examined the incidence of ESRD, death, and loss of kidney function in large population of HIV-infected individuals with established CKD. The objective of this study was to characterize rates of death, ESRD, and kidney function decline among HIV-infected individuals in a national contemporary cohort of patients with CKD and compare them to rates among individuals with diabetes. Among the 202 927 patients included in this study, 534 (0.3%) had HIV, 88 340 (43.5%) had diabetes, and 114 223 (56.3%) did not have either condition (Table 1). Patients with HIV were younger (55.9 years±10.1) than patients with diabetes (73.1 years±8.8) or patients without HIV or diabetes (73.6 years±9.0). Among patients with HIV, 50.4% (n=269) were black, whereas only 13.1% (n=11 575) of those with diabetes and 9.2% (n=10 531) of patients without either condition were black. The prevalence of severe CKD (estimated glomerular filtration rate (eGFR) 15–29 ml/min/1.73 m2) and renal failure (eGFR<15 ml/min/1.73 m2) was higher among patients with HIV (18.0%) compared with patients with diabetes (13.1%) and those without either condition (8.0%). Cardiovascular diseases were common in all groups, but were most prevalent in patients with diabetes. Hepatitis C virus coinfection was found in 27.3% (n=146) of HIV-infected patients, whereas only 1.3% (n=1182) of patients with diabetes and 1.0% (n=1144) of patients without either condition had hepatitis C virus. A higher percentage of patients with HIV (43.6%, n=233) were in the lowest tertile of socioeconomic status compared with patients with diabetes (35.7%, n=31 474) or patients without HIV or diabetes (33.6%, n=38 339). Among HIV-infected individuals, rates of treatment with highly active antiretroviral therapy at the time of cohort entry were comparable between white (20.4%) and black (17.5%) patients (P=0.461). Mean CD4+ T-cell counts and HIV RNA levels were also similar between white and black patients at baseline (328 versus 305 cells/mm3, P=0.412, and 2.86 versus 3.15 log copies/ml, P=0.297, respectively).Table 1Demographic and clinical characteristics of the cohort at baselineVariableTotal cohort n (percent)HIV n (percent)Diabetes n (percent)No HIV or diabetes n (percent)P-value*202 927 (100.0)534 (0.3)88 340 (43.5)114 223 (56.3)<0.001Age (years)aAge expressed as the mean with s.d.73.1±8.855.9±10.172.5±8.573.6±9.0<0.001Race<0.001 White180 638 (89.0)265 (49.6)76 765 (86.9)103 692 (90.8) Black22 289 (11.0)269 (50.4)11 575 (13.1)10 531 (9.2)Sex<0.001 Male196 600 (96.9)529 (99.1)86 195 (97.6)110 045 (96.3) Female6327 (3.1)5 (0.9)2145 (2.4)4178 (3.7)CKD (eGFR)<0.001 45–59120 587 (59.4)298 (55.8)48 152 (54.5)72 226 (63.3) 30–4461 594 (30.4)140 (26.2)28 597 (32.4)32 903 (28.8) 15–2917 838 (8.8)67 (12.6)9908 (11.2)7889 (6.9) <152908 (1.4)29 (5.4)1683 (1.9)1205 (1.1)Serum creatinine (mg/dl)1.75±0.762.31±1.631.83±0.821.69±0.69<0.001Comorbidities HIV534 (0.3)—170 (0.2)— DM88 340 (43.5)170 (31.8)—— HTN183 959 (90.7)367 (68.7)83 586 (94.6)100 156 (87.7)<0.001 CAD123 657 (60.9)136 (25.5)59 778 (67.8)63 809 (55.9)<0.001 CHF70 733 (34.9)93 (17.4)37 884 (42.9)32 802 (28.7)<0.001 CVA57 199 (28.2)62 (11.6)28 263 (32.0)28 907 (25.3)<0.001 PVD61 370 (30.2)67 (12.6)32 358 (36.6)28 976 (25.4)<0.001 COPD79 317 (39.1)153 (28.7)34 650 (39.2)44 574 (39.0)<0.001 HCV2423 (1.2)146 (27.3)1182 (1.3)1144 (1.0)<0.001SES Level<0.001 Lowest69 960 (34.5)233 (43.6)31 474 (35.7)38 339 (33.6) Middle68 409 (33.7)145 (27.2)29 243 (33.1)39 073 (34.2) Highest64 427 (31.8)156 (29.2)27 563 (31.2)36 740 (32.2)CAD, coronary artery disease; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; CVA, cerebrovascular accident; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate in ml/min/1.73 m2; HCV, hepatitis C virus infection; HIV, human immunodeficiency virus; HTN, hypertension; PVD, peripheral vascular disease; SES, socioeconomic status.*P-value for differences between HIV, diabetic, and non-HIV/non-DM groups.a Age expressed as the mean with s.d. Open table in a new tab CAD, coronary artery disease; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; CVA, cerebrovascular accident; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate in ml/min/1.73 m2; HCV, hepatitis C virus infection; HIV, human immunodeficiency virus; HTN, hypertension; PVD, peripheral vascular disease; SES, socioeconomic status. *P-value for differences between HIV, diabetic, and non-HIV/non-DM groups. The median observation time was 3.8 (interquartile range 3.2–4.0) years. A total of 8922 cases of ESRD and 46 032 deaths occurred during 664 446 person-years of observation. Among HIV-infected patients, there were 121 deaths and 102 cases of ESRD over 1536 person-years of observation (Table 2). The majority of these cases (66 deaths and 85 cases of ESRD) occurred among black patients. Among patients with diabetes, there were 5991 cases of ESRD and 22 094 deaths during 272 847 person-years of follow-up.Table 2Incidence rates and adjusted risk of ESRD and deathaThere were 170 patients who had both HIV and diabetes and contributed to event rates for both groups. The multivariate hazard ratio for ESRD and death utilize interaction terms to exclude the effect of overlap between diagnoses and isolate the individual effect of HIV and diabetes, respectively.Persons (n)Time at risk (person-years)ESRD events (n)Deaths (n)Age and Sex adjusted rates of ESRD (per 1000 person-years)Multivariate hazard ratio for ESRDbAdjusted for age, race, sex, baseline estimated glomerular filtration rate, hypertension, coronary artery disease, heart failure, chronic obstructive lung disease, peripheral vascular disease, hepatitis C infection, cerebrovascular disease, and socioeconomic status.Age and sex adjusted rates of death (per 1000 person-years)Multivariate hazard ratio for deathbAdjusted for age, race, sex, baseline estimated glomerular filtration rate, hypertension, coronary artery disease, heart failure, chronic obstructive lung disease, peripheral vascular disease, hepatitis C infection, cerebrovascular disease, and socioeconomic status.White No HIV or diabetes103 692338 985206520 3667.8 (7.5–8.3)Referent35.0 (34.2–35.7)Referent HIV265863175511.3 (5.9–16.6)0.68 (0.26–1.76)70.8 (52.0–90.0)2.21 (1.57–3.13) Diabetes76 765239 224418319 31322.0 (21.2–22.8)1.97 (1.86–2.08)50.3 (49.3–51.3)1.23 (1.21–1.26)Black No HIV or diabetes10 53132 434808235427.9 (25.7–30.1)Referent49.7 (46.8–52.6)Referent HIV269674856671.1 (55.4–86.7)2.11 (1.46–3.06)120.5 (90.9–150.1)2.32 (1.70–3.18) Diabetes11 57533 6231808278159.9 (56.7–63.1)1.78 (1.63–1.93)60.4 (57.4–63.4)1.06 (1.00–1.12)ESRD, end stage renal disease; HIV, human immunodeficiency virus.Numbers in parentheses indicate 95% confidence intervals.a There were 170 patients who had both HIV and diabetes and contributed to event rates for both groups. The multivariate hazard ratio for ESRD and death utilize interaction terms to exclude the effect of overlap between diagnoses and isolate the individual effect of HIV and diabetes, respectively.b Adjusted for age, race, sex, baseline estimated glomerular filtration rate, hypertension, coronary artery disease, heart failure, chronic obstructive lung disease, peripheral vascular disease, hepatitis C infection, cerebrovascular disease, and socioeconomic status. Open table in a new tab ESRD, end stage renal disease; HIV, human immunodeficiency virus. Numbers in parentheses indicate 95% confidence intervals. Mortality rates were much higher among patients with HIV compared with all other groups (Table 2). Among black patients, the age- and sex-adjusted mortality rate (per 1000 person-years) among HIV-infected individuals, 120.5 (confidence interval (CI) 90.9–150.1), was approximately double the rate found among those with diabetes, 60.4 (CI 57.4–63.4). Among white patients, the age- and sex-adjusted incidence of death per 1000 person-years was 70.8 (CI 52.0–90.0) among HIV-infected patients, 50.3 (CI 49.3–51.3) for patients with diabetes, and 35.0 (CI 34.2–35.7) for patients with neither condition. After multivariate adjustment, a two-fold increased hazard ratio (HR) for death was also observed for HIV in both white 2.21 (CI 1.57–3.13) and black 2.32 (CI 1.70–3.18) racial groups when compared with the referent group with no HIV or diabetes, respectively. In the subgroup of individuals with age <65 years, the adjusted risk of death did not change substantially for all groups. Among black individuals, the adjusted HR for death was 2.47 (HR 1.72–3.55) for HIV and 1.14 (HR 0.97–1.33) for diabetes. The age- and sex-adjusted incidence rates of ESRD per 1000 person-years were similar between black patients with HIV and diabetes, 71.1 (95% CI 55.4–86.7) versus 59.9 (CI 56.7–63.1), as shown in Table 2. Rates in these groups were higher than those among black patients with neither condition (27.9, CI 25.7–30.1). In contrast, among white patients, the age- and sex-adjusted incidence of ESRD per 1000 person-years was much lower in patients with HIV, 11.3 (CI 5.9–16.6), than patients with diabetes, 22.0 (CI 21.2–22.8), and similar to the rate among patients with neither condition, 7.8 (CI 7.5–8.3). In multivariate Cox proportional hazard analysis, both HIV (HR 2.11, CI 1.46–3.06) and diabetes (HR 1.78, CI 1.63–1.93) were strongly associated with ESRD among black patients when compared with the referent group with neither condition. Among white patients, diabetes doubled the risk of ESRD (HR 1.97, CI 1.86–2.08), but HIV was not associated with an increased risk of ESRD (HR 0.68, CI 0.26–1.76). Among cohort members with age <65 years, the adjusted HR for ESRD was 2.08 (CI 1.44–3.00) for black patients with HIV and 1.88 (CI 1.67–2.12) for black patients with diabetes. Point estimates for rates of eGFR decline were greatest among black patients with HIV compared with other groups throughout the range of baseline eGFR (Table 3); however, these differences were not statistically significant when compared with rates among black patients with diabetes. The mean annual change in eGFR among white individuals with HIV was low, except among patients with severe CKD at baseline (eGFR of 15–29 ml/min/1.73 m2). Among black patients 1.4 mg/dl) were associated with an adjusted HR of 2.5 (1.9–3.3) for mortality.11.Gardner L.I. Holmberg S.D. Williamson J.M. et al.Development of proteinuria or elevated serum creatinine and mortality in HIV-infected women.J Acquir Immune Defic Syndr. 2003; 32: 203-209Crossref PubMed Scopus (144) Google Scholar Extending these results, an analysis from the Women's Interagency HIV Study (WIHS) found that the presence of proteinuria and elevated serum creatinine level was independently associated with an increased risk of death among HIV-infected women.10.Szczech L.A. Hoover D.R. Feldman J.G. et al.Association between renal disease and outcomes among HIV-infected women receiving or not receiving antiretroviral therapy.Clin Infect Dis. 2004; 39: 1199-1206Crossref PubMed Scopus (158) Google Scholar These studies examined a total of approximately 350 women with kidney disease at baseline and did not analyze progression to ESRD, rates of kidney function decline, or provide comparisons with HIV-negative groups. Case series of HIV-infected individuals with CKD have also established high-mortality rates in this patient group. However, these studies were limited to patients who were evaluated by kidney biopsy, and were conducted before the advent of antiretroviral therapy.3.Szczech L.A. Gange S.J. van der Horst C. et al.Predictors of proteinuria and renal failure among women with HIV infection.Kidney Int. 2002; 61: 195-202Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar, 6.Szczech L.A. Gupta S.K. Habash R. et al.The clinical epidemiology and course of the spectrum of renal diseases associated with HIV infection.Kidney Int. 2004; 66: 1145-1152Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar, 7.Atta M.G. Gallant J.E. Hafizur Rahman M. et al.Antiretroviral therapy in the treatment of HIV-associated nephropathy.Nephrol Dial Transplant. 2006; 21: 2809-2813Crossref PubMed Scopus (126) Google Scholar, 8.Estrella M. Fine D.M. Gallant J.E. et al.HIV type 1 RNA level as a clinical indicator of renal pathology in HIV-infected patients.Clin Infect Dis. 2006; 43: 377-380Crossref PubMed Scopus (59) Google Scholar, 9.Laradi A. Mallet A. Beaufils H. et al.HIV-associated nephropathy: outcome and prognosis factors. Groupe d' Etudes Nephrologiques d'Ile de France.J Am Soc Nephrol. 1998; 9: 2327-2335PubMed Google Scholar Our study builds on these findings by examining the impact of HIV in the context of a large, predominantly male, contemporary patient population with CKD. Three significant clinical outcomes, including death, ESRD, and rates of eGFR decline were analyzed, providing a broad, inclusive view of the clinical implications of CKD among HIV-infected individuals. In addition, the use of HIV-negative controls in this study allows comparison with established risk factors for ESRD such as diabetes, and illustrates areas where the care for HIV-infected patients with CKD could be improved. Finally, the large number of patients with CKD allows a detailed characterization of the interaction between CKD and race. Prior studies have recognized that CKD is an independent risk factor for mortality in the general population.12.Go A.S. Chertow G.M. Fan D. et al.Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization.N Engl J Med. 2004; 351: 1296-1305Crossref PubMed Scopus (9019) Google Scholar,13.Tonelli M. Wiebe N. Culleton B. et al.Chronic kidney disease and mortality risk: a systematic review.J Am Soc Nephrol. 2006; 17: 2034-2047Crossref PubMed Scopus (1210) Google Scholar In our study, even within the context of this high risk group, both white and black patients with HIV had increased mortality when compared with other disease states, such as diabetes. It is unclear why mortality in the setting of CKD should be magnified by HIV infection. In general, increased mortality among CKD patients has been attributed to cardiovascular disease,12.Go A.S. Chertow G.M. Fan D. et al.Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization.N Engl J Med. 2004; 351: 1296-1305Crossref PubMed Scopus (9019) Google Scholar,14.Weiner D.E. Tighiouart H. Amin M.G. et al.Chronic kidney disease as a risk factor for cardiovascular disease and all-cause mortality: a pooled analysis of community-based studies.J Am Soc Nephrol. 2004; 15: 1307-1315Crossref PubMed Scopus (1055) Google Scholar prompting recommendations for cardiovascular risk reduction as part of CKD management.15.National Kidney Foundation K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification.Am J Kidney Dis. 2002; 39: S1-S266PubMed Google Scholar In this cohort, the relatively low prevalence of cardiovascular disease among patients with HIV suggests that alternative mechanisms of mortality may be relevant to the HIV-infected CKD population. Although, some studies have found that cardiovascular disease is increased in the setting of HIV-infection compared with HIV-negative controls,16.Triant V.A. Lee H. Hadigan C. et al.Increased acute myocardial infarction rates and cardiovascular risk factors among patients with HIV disease.J Clin Endocrinol Metab. 2007Google Scholar,17.Hsue P.Y. Lo J.C. Franklin A. et al.Progression of atherosclerosis as assessed by carotid intima-media thickness in patients with HIV infection.Circulation. 2004; 109: 1603-1608Crossref PubMed Scopus (492) Google Scholar mortality rates in HIV-infected individuals included in kidney biopsy studies appear to correlate with the severity of HIV infection.9.Laradi A. Mallet A. Beaufils H. et al.HIV-associated nephropathy: outcome and prognosis factors. Groupe d' Etudes Nephrologiques d'Ile de France.J Am Soc Nephrol. 1998; 9: 2327-2335PubMed Google Scholar, 18.Cheng J.T. Anderson Jr, H.L. Markowitz G.S. et al.Hepatitis C virus-associated glomerular disease in patients with human immunodeficiency virus coinfection.J Am Soc Nephrol. 1999; 10: 1566-1574PubMed Google Scholar, 19.Carbone L. D'Agati V. Cheng J.T. et al.Course and prognosis of human immunodeficiency virus-associated nephropathy.Am J Med. 1989; 87: 389-395Abstract Full Text PDF PubMed Google Scholar Among HIV-infected women in the HERS cohort, HIV or AIDS-related causes were recorded on death certificates of 58% of patients with elevated creatinine or proteinuria. Data from the WIHS cohort suggest that elevated serum creatinine levels are a predictor for the development of the acquired immune deficiency syndrome (AIDS).10.Szczech L.A. Hoover D.R. Feldman J.G. et al.Association between renal disease and outcomes among HIV-infected women receiving or not receiving antiretroviral therapy.Clin Infect Dis. 2004; 39: 1199-1206Crossref PubMed Scopus (158) Google Scholar Collectively, these observations raise the question of whether the optimal approach to reducing mortality in HIV-infected individuals with CKD differs from the strategy used in the HIV-negative population. Further studies are needed to elucidate mechanisms for increased death in this group in the present era of antiretroviral therapy and to determine whether interventions focused on virologic suppression can improve CKD outcomes. Although both black and white HIV-infected patients in this cohort had higher death rates than their counterparts with diabetes, black patients also had much higher rates of progression to ESRD and experienced a faster mean decline in eGFR than white patients with HIV. Rates of ESRD among black patients with HIV were similar to those in the high-risk group of black patients with diabetes. These findings are consistent with the known overrepresentation of black patients in the United States Renal Data System dialysis registry1.US Renal Data System (USRDS)Annual data report. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD2001Google Scholar, 20.Ahuja T.S. Grady J. Khan S. Changing trends in the survival of dialysis patients with human immunodeficiency virus in the United States.J Am Soc Nephrol. 2002; 13: 1889-1893Crossref PubMed Scopus (118) Google Scholar, 21.Eggers P.W. Kimmel P.L. Is there an epidemic of HIV Infection in the US ESRD program?.J Am Soc Nephrol. 2004; 15: 2477-2485Crossref PubMed Scopus (95) Google Scholar and in renal biopsy series conducted in HIV-infected patients.6.Szczech L.A. Gupta S.K. Habash R. et al.The clinical epidemiology and course of the spectrum of renal diseases associated with HIV infection.Kidney Int. 2004; 66: 1145-1152Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar, 9.Laradi A. Mallet A. Beaufils H. et al.HIV-associated nephropathy: outcome and prognosis factors. Groupe d' Etudes Nephrologiques d'Ile de France.J Am Soc Nephrol. 1998; 9: 2327-2335PubMed Google Scholar, 19.Carbone L. D'Agati V. Cheng J.T. et al.Course and prognosis of human immunodeficiency virus-associated nephropathy.Am J Med. 1989; 87: 389-395Abstract Full Text PDF PubMed Google Scholar, 22.Laurinavicius A. Hurwitz S. Rennke H.G. Collapsing glomerulopathy in HIV and non-HIV patients: a clinicopathological and follow-up study.Kidney Int. 1999; 56: 2203-2213Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar, 23.Bourgoignie J.J. Meneses R. Ortiz C. et al.The clinical spectrum of renal disease associated with human immunodeficiency virus.Am J Kidney Dis. 1988; 12: 131-137Abstract Full Text PDF PubMed Scopus (133) Google Scholar In addition, black race is known to be a risk factor for the development of CKD among HIV-infected persons.3.Szczech L.A. Gange S.J. van der Horst C. et al.Predictors of proteinuria and renal failure among women with HIV infection.Kidney Int. 2002; 61: 195-202Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar,24.Gupta S.K. Mamlin B.W. Johnson C.S. et al.Prevalence of proteinuria and the development of chronic kidney disease in HIV-infected patients.Clin Nephrol. 2004; 61: 1-6Crossref PubMed Scopus (99) Google Scholar Although the racial predilection of kidney disease among HIV-infected individuals has been established, the magnitude of these differences in comparison with other high risk groups, such as those with diabetes, had previously not been well characterized. Collectively, these findings raise the question of whether the optimal approach to CKD management among HIV-infected individuals may differ according to the race of the patient. Among black individuals, early identification of CKD and interventions to slow progression of renal disease are of paramount importance. Among white patients, particularly those with only moderate reductions in eGFR, interventions focused on mortality reduction may have a greater benefit than those directed at slowing progression of renal disease. Perhaps most importantly, these striking racial differences in CKD progression among patients with HIV highlight the critical need for studies devoted to the understanding of underlying disease mechanisms for HIV-related renal disease. The strengths of our study include its large sample size, national scope, and the availability of high-quality outcome data on death and ESRD. Our study also has several limitations, which are primarily related to the use of 'real world' clinical data obtained as part of routine clinical care and obtained in a single health care system. Specifically, the cohort was limited to patients who met criteria for CKD based on having two eGFR measurements at least 3 months apart. Our sample thus excluded patients who may have had CKD but did not undergo the requisite number and spacing of creatinine measurements required for cohort entry. Although this limitation is unlikely to impact our primary finding of race differences in outcomes among patients with HIV and CKD, it may have resulted in inflated rates of ESRD among cohort members. Use of the Modification of Diet in Renal Disease (MDRD) equation to estimate GFR has several limitations. This equation may be inaccurate in the clinical setting, where creatinine measurements are not typically calibrated the MDRD laboratory at the Cleveland Clinic.25.Coresh J. Astor B.C. McQuillan G. et al.Calibration and random variation of the serum creatinine assay as critical elements of using equations to estimate glomerular filtration rate.Am J Kidney Dis. 2002; 39: 920-929Abstract Full Text Full Text PDF PubMed Scopus (619) Google Scholar In addition, the MDRD equation has not been independently validated as a measure of GFR among HIV-infected persons. It is possible that systematic differences in the accuracy of the MDRD equations among patients with and without HIV may contribute to the observed differences in outcomes. Nevertheless, the prognostic significance of eGFR among patients with HIV reported here is highly relevant to clinical practice. Estimation of GFR using the MDRD equation has been widely incorporated into routine clinical care and this method is specifically recommended by current Infectious Disease Society of America Guidelines for assessment of kidney function in the HIV-infected population.4.Gupta S.K. Eustace J.A. Winston J.A. et al.Guidelines for the management of chronic kidney disease in HIV-infected patients: recommendations of the HIV Medicine Association of the Infectious Diseases Society of America.Clin Infect Dis. 2005; 40: 1559-1585Crossref PubMed Scopus (512) Google Scholar,15.National Kidney Foundation K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification.Am J Kidney Dis. 2002; 39: S1-S266PubMed Google Scholar Our study included a national sample of predominantly male patients who were insured and received care in the Department of Veterans Affairs (VA) health-care system. Results may not be generalizable to uninsured patients, non-veteran populations, women, or other race/ethnic groups not studied here. Previous studies have shown that veterans receiving care at the VA have a higher prevalence of comorbidity when compared with non-veterans in both diabetic and non-diabetic populations.26.Reiber G.E. Koepsell T.D. Maynard C. et al.Diabetes in nonveterans, veterans, and veterans receiving Department of Veterans Affairs health care.Diabetes Care. 2004; 27: B3-B9Crossref PubMed Scopus (53) Google Scholar,27.Agha Z. Lofgren R.P. VanRuiswyk J.V. et al.Are patients at Veterans Affairs medical centers sicker? A comparative analysis of health status and medical resource use.Arch Intern Med. 2000; 160: 3252-3257Crossref PubMed Scopus (551) Google Scholar However, HIV-infected veterans receiving care in the VA appear to have less AIDS-defining conditions and higher CD4+ counts than non-veterans.28.Zingmond D.S. Kilbourne A.M. Justice A.C. et al.Differences in symptom expression in older HIV-positive patients: the veterans aging cohort 3 site study and HIV cost and service utilization study experience.J Acquir Immune Defic Syndr. 2003; 33: S84-S92Crossref PubMed Scopus (64) Google Scholar Therefore, relative differences in CKD outcomes between HIV-infected and diabetic populations may be conservative estimates when compared with settings outside of the VA health-care system. It should also be noted that although the gender composition of the veteran population studied here is mostly male, approximately 80% of HIV-infected persons in the United States are also male.29.HIV/AIDS Surveillance Report: HIV infection and AIDS in the United States and Dependent Areas, 2005. [cited August 22, 2007]; Available from:http://www.cdc.gov/hiv/topics/surveillance/resources/reports/2005report/pdf/2005SurveillanceReport.pdfGoogle Scholar Overall rates of change in eGFR per year in this cohort were relatively low.30.Zeller K. Whittaker E. Sullivan L. et al.Effect of restricting dietary protein on the progression of renal failure in patients with insulin-dependent diabetes mellitus.N Engl J Med. 1991; 324: 78-84Crossref PubMed Scopus (365) Google Scholar, 31.Hemmelgarn B.R. Zhang J. Manns B.J. et al.Progression of kidney dysfunction in the community-dwelling elderly.Kidney Int. 2006; 69: 2155-2161Abstract Full Text Full Text PDF PubMed Scopus (302) Google Scholar, 32.Wang X. Lewis J. Appel L. et al.Validation of creatinine-based estimates of GFR when evaluating risk factors in longitudinal studies of kidney disease.J Am Soc Nephrol. 2006; 17: 2900-2909Crossref PubMed Scopus (59) Google Scholar, 33.Klahr S. Levey A.S. Beck G.J. et al.The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group.N Engl J Med. 1994; 330: 877-884Crossref PubMed Scopus (2056) Google Scholar Low rates of eGFR decline may be in part reflect our study design: we excluded creatinine measurements within 90 days of death or ESRD and patients with an eGFR <15 ml/min/1.73 m2 at baseline; we included only patients receiving outpatient care and had undergone at least two creatinine measurements at least 3 months apart (i.e. those who were likely to have their kidney disease actively managed by a physician). It is also possible that low observed rates of eGFR decline may reflect the advanced age of the group studied. Repeated measures analysis may also be prone to regression to the mean, which may cause rates to appear lower than expected.34.Levey A.S. Gassman J.J. Hall P.M. et al.Assessing the progression of renal disease in clinical studies: effects of duration of follow-up and regression to the mean. Modification of Diet in Renal Disease (MDRD) Study Group.J Am Soc Nephrol. 1991; 1: 1087-1094PubMed Google Scholar,35.Barnett A.G. van der Pols J.C. Dobson A.J. Regression to the mean: what it is and how to deal with it.Int J Epidemiol. 2005; 34: 215-220Crossref PubMed Scopus (1145) Google Scholar Despite adjusting our analyses for a large number of comorbid conditions and sociodemographic characteristics, the possibility of residual confounding by factors not included in the analysis (e.g. proteinuria, body mass index, diet) or by differences in disease severity (e.g. stage of heart failure or severity of diabetes) that could not be defined by the data sources available to us cannot be ruled out. We also relied on ICD-9 codes to identify patients with diabetes, which may have lead to some patients being misclassified. However, it is reassuring that incidence rates for ESRD and mortality are of similar magnitude with previously published estimates.36.Jones C.A. Krolewski A.S. Rogus J. et al.Epidemic of end-stage renal disease in people with diabetes in the United States population: do we know the cause?.Kidney Int. 2005; 67: 1684-1691Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar, 37.Karter A.J. Ferrara A. Liu J.Y. et al.Ethnic disparities in diabetic complications in an insured population.JAMA. 2002; 287: 2519-2527Crossref PubMed Scopus (694) Google Scholar, 38.Patel U.D. Young E.W. Ojo A.O. et al.CKD progression and mortality among older patients with diabetes.Am J Kidney Dis. 2005; 46: 406-414Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar HIV-infection has important clinical implications among patients with CKD. Although HIV is a strong risk factor for mortality in both white and black CKD patients, rates of death, ESRD, and renal function decline differ greatly between HIV-infected patients of white or black race. These differences raise the question of whether race should be a consideration in the management of patients with HIV and CKD and highlight the importance of future investigations into causes of death and mechanisms underlying progression of kidney disease in this population.
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