In the current study, the prevalence of proteinuria among HIV-infected adolescents who participated in the REACH cohort was 19.1%, almost 2 times the prevalence in healthy US adolescents.33 Logistic regression analyses revealed age, race/ethnicity, BMI category, and low CD4+ T-cell count as significant predictors of proteinuria; in the linear regression with the natural log-transformed UP/Cr ratio as the dependent variable, there was an inverse relationship between both BMI category and CD4+ T-cell count category with UP/Cr. The association with risk factors such as severity of HIV-infection and nutrition status inferred by these relationships is similar to what other studies have demonstrated in different HIV-infected adult populations.34,35 Diabetes and hypertension are known cardiovascular and kidney disease risk factors associated with proteinuria in the general population and among those who are HIV-infected.36,37 In the US, the prevalence of diabetes and hypertension in adolescents is <2%38; consequently, although these data were not available, hypertension and diabetes are expected to be minimal among the adolescents in this cohort. Other factors, such as the metabolic syndrome, exposure to multiple medications over time, or myopathic disorders related to HIV, may also play a role in the development of proteinuria and subsequent kidney dysfunction.23,39
Classification of the REACH cohort by proteinuria status demonstrated a significant difference between mean CysC (P = 0.01) of 0.77 mg/L in those with proteinuria versus 0.71 mg/L in those with normal urinary protein excretion, respectively. The values obtained for serum creatinine and cystatin C were both slightly lower than those reported from NHANES III, including non-Hispanic blacks with values reported as 0.76 mg/dL for serum creatinine and 0.80 mg/L for CysC, respectively.49 This difference may be due to the differences in study populations as the mean age of our cohort was 18 years compared with 15 years in NHANES III. Additionally, there have been changes in calibration and sensitivity of the methods during the past 5 years50; however, this should not result in differential misclassification.
Our final model in logistic regression analyses revealed a greater likelihood of an eCysC among participants who were obese, nonblack, male gender, and had an elevated VL. In contrast to the logistic regression results for proteinuria, in which a low CD4+ T-cell count (<200 cells/mm3) was found to be a strong predictor, participants with medium CD4+ T-lymphocyte counts (200–499 cells/mm3) were most likely to have an eCysC. In linear regression models with CysC as the dependent variable, least square mean comparisons demonstrated similar findings. Participants with both low and medium CD4+ T-cell counts demonstrated significantly higher CysC concentrations than those with high CD4+ T-cell counts. CysC-derived GFR estimating equations have not been validated in healthy children and adolescent populations; however, they have shown greater sensitivity and accuracy in those with kidney dysfunction, particularly in those with a GFR <90 mL/min per 1.73 m2.51 In this study, estimated glomerular filtration rate (eGFRs) were calculated using different equations.52–55 At higher GFRs, serum creatinine estimates are less precise and cystatin C provides more valid estimation.56 GFR estimates as calculated from serum creatinine and/or CysC are known to be unreliable for values >60 mL/min per 1.73 m2; thus, those that are calculated to be >60 mL/min per 1.73 m2 are generally reported as such in clinical laboratory reports. The majority of participants in the REACH cohort had an eGFR over 60 mL/min per 1.73 m2. Therefore, we selected to report CysC values rather than an eGFR calculated from CysC. The eCysC is associated with many of the abnormalities present in moderate to advanced CKD.56 Recent data presented by the Chronic Kidney Disease Epidemiology Collaboration suggest that cystatin C should not replace creatinine for GFR estimation in general practice; however, it may be useful in specific cases, such as confirmation of the diagnosis of CKD in patients with a decreased GFR as estimated from serum creatinine and more accurate estimation of GFR in patients with muscle wasting or chronic illness.57 Studies have shown that CysC is higher in those who are HIV infected when compared with uninfected individuals and that there is a correlation with VL,58 as found in our analyses, and inflammatory markers.23 It is unclear if the biological associations of CysC are with HIV infection or kidney disease. Although the finding should be cautiously interpreted, it is possible that these are potential kidney disease progression indicators in HIV-infected adolescents.
The current study has potential limitations. We were unable to assess causality because of the study's observational cross-sectional design. In addition, the assessment of proteinuria was determined from spot urine samples as opposed to a timed or 24-hour urine collection; however, spot urine measurement has been shown to perform well at detecting abnormal urinary protein excretion in those with HIV, and the one time collection avoids error introduced by inadequate collections over time.57 Another limitation is that proteinuria was measured at only one time point. This may lead to misclassification of some individuals with regard to proteinuria status as the KDOQI of the NKF guidelines recommend a second measurement to confirm the persistence of proteinuria.63 Additionally, the study population was primarily composed of women and our results may not be generalizable to a broader population. In support of the study's internal validity, evaluation of participant descriptors for those not included in the study demonstrated similar characteristics as the majority of the missing individuals were normal weight (44.8%), non-Hispanic black females (72.4%) with a mean age of 17 years. In addition, REACH participants not included in the study presented with an average CD4+ T-cell count of 532 ± 273 cells/mm3 and 41.4% were on cART. Despite study limitations, the REACH Cohort has several notable strengths, including being a representative sample of urban HIV-infected adolescents in the US. In addition, serum and urine measurements in this study were conducted at a central laboratory following standardized procedures.
In conclusion, in the current study, kidney disease as indicated by proteinuria was present in 19.1% of the HIV-infected adolescents participating in REACH. HIV-infected adolescents in the REACH cohort with a low CD4+ T-cell count and low BMI were more likely to be diagnosed with proteinuria. In REACH, there were significant correlations with increasing CysC concentration, including low and medium CD4+ T-cell counts and a high BMI. With the level of current evidence, the added value of CysC in assessment of kidney dysfunction in HIV-infected adolescents will have to be both clinically useful and economically acceptable for its widespread adoption.20 Early detection of kidney disease in HIV-infected adolescents would allow for appropriate evaluation and treatment, as well as modification of medication regimens to avoid systemic toxicity and worsening kidney function. Further studies investigating earlier markers of kidney damage and systemic therapies targeting kidney disease risk in this vulnerable population are warranted.
The study was scientifically reviewed by the ATN's Therapeutic Leadership Group. Network, scientific, and logistical support was provided by the ATN Coordinating Center (C. Wilson, C. Partlow) at the University of Alabama at Birmingham. We thank the REACH investigators, staff, and participants for their valuable contributions (listed in J Adolescent Health 2001; 29: S5–S6). The parent study and this substudy conformed to the procedures for informed consent (parental permission was obtained wherever required) approved by institutional review boards at all sponsoring organizations and to human experimentation guidelines set forth by the United States Department of Health and Human Services.
1. Seal PS, Jackson DA, Chamot E, et al.. Temporal trends in presentation for outpatient HIV medical care 2000-2010: implications for short-term mortality. J Gen Intern Med. 2011;26:745–750.
2. Centers for Disease Control and Prevention (CDC). HIV surveillance—United States, 1981-2008. MMWR Morb Mortal Wkly Rep. 2011;60:689–693.
3. Gupta SK, Eustace JA, Winston JA, 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;40:1559–1585.
4. Fernando SK, Finkelstein FO, Moore BA, et al.. Prevalence of chronic kidney disease in an urban HIV infected population. Am J Med Sci. 2008;335:89–94.
5. Szczech LA, Hoover DR, Feldman JG, et al.. Association between renal disease and outcomes among HIV-infected women receiving or not receiving antiretroviral therapy. Clin Infect Dis. 2004;39:1199–1206.
6. Wyatt CM, Hoover DR, Shi Q, et al.. Microalbuminuria is associated with all-cause and AIDS mortality in women with HIV infection. J Acquir Immune Defic Syndr. 2010;55:73.
7. Winston JA. HIV and CKD epidemiology. Adv Chronic Kidney Dis. 2010;17:19–25.
8. Lucas GM, Eustace JA, Sozio S, et al.. Highly active antiretroviral therapy and the incidence of HIV-1-associated nephropathy: a 12-year cohort study. AIDS. 2004;18:541–546.
9. Lescure FX, Flateau C, Pacanowski J, et al.. HIV-associated kidney glomerular diseases: changes with time and HAART. Nephrol Dial Transplant. 2012;27:2349–2355.
10. Kalyesubula R, Perazella MA. Nephrotoxicity of HAART. AIDS Res Treat. 2011;2011:562790.
11. Daugas E, Rougier JP, Hill G. HAART-related nephropathies in HIV-infected patients. Kidney Int. 2005;67:393–403.
12. Maggi P, Bartolozzi D, Bonfanti P, et al.. Renal complications in HIV disease: between present and future. AIDS Rev. 2012;14:37.
13. Stoycheff N, Pandya K, Okparavero A, et al.. Early change in proteinuria as a surrogate outcome in kidney disease progression: a systematic review of previous analyses and creation of a patient-level pooled dataset. Nephrol Dial Transplant. 2011;26:848–857.
14. Garg AX, Kiberd BA, Clark WF, et al.. Albuminuria and renal insufficiency prevalence guides population screening: results from the NHANES III. Kidney Int. 2002;61:2165–2175.
15. Coresh J, Selvin E, Stevens LA, et al.. Prevalence of chronic kidney disease in the United States. JAMA. 2007;298:2038–2047.
16. Estrella MM, Parekh RS, Astor BC, et al.. Chronic kidney disease and estimates of kidney function in HIV infection: a cross-sectional study in the multicenter AIDS cohort study. J Acquir Immune Defic Syndr. 2011;57:380–386.
17. Yanik EL, Lucas GM, Vlahov D, et al.. HIV and proteinuria in an injection drug user population. Clin J Am Soc Nephrol. 2010;5:1836–1843.
18. Chaparro AI, Mitchell CD, Abitbol CL, et al.. Proteinuria in children infected with the human immunodeficiency virus. J Pediatr. 2008;152:844–849.
19. Esezobor CI, Iroha E, Onifade E, et al.. Prevalence of proteinuria among HIV-infected children attending a tertiary hospital in Lagos, Nigeria. J Trop Pediatr. 2010;56:187–190.
20. Gagneux-Brunon A, Mariat C, Delanaye P. Cystatin C in HIV-infected patients: promising but not yet ready for prime time. Nephrol Dial Transplant. 2012;27:1305–1313.
21. Choi A, Scherzer R, Bacchetti P, et al.. Cystatin C, albuminuria, and 5-year all-cause mortality in HIV-infected persons. Am J Kidney Dis. 2010;56:872–882.
22. Overton ET, Patel P, Mondy K, et al.. Cystatin C and Baseline Renal Function Among HIV-Infected Persons in the SUN Study. AIDS Research and Human Retroviruses. 2012;28:148–155.
23. Neuhaus J, Jacobs DR Jr, Baker JV, et al.. Markers of inflammation, coagulation, and renal function are elevated in adults with HIV infection. J Infect Dis. 2010;201:1788–1795.
24. Wyatt CM, Klotman PE. HIV-1 and HIV-associated nephropathy 25 years later. Clin J Am Soc Nephrol. 2007;2(suppl 1):S20–S24.
25. Purswani MU, Chernoff MC, Mitchell CD, et al.. Chronic kidney disease associated with perinatal HIV infection in children and adolescents. Pediatric Nephrology. 2012;27:981–989.
26. Wilson CM, Houser J, Partlow C, et al.; Adolescent Medicine HIVARN. The REACH (Reaching for Excellence in Adolescent Care and Health) project: study design, methods, and population profile. J Adolesc Health. 2001;29(3 suppl):8–18.
27. Rogers AS, Futterman DK, Moscicki AB, et al.. The REACH Project of the Adolescent Medicine HIV/AIDS Research Network: design, methods, and selected characteristics of participants. J Adolesc Health. 1998;22:300–311.
28. Wilson CM, Ellenberg JH, Douglas SD, et al.; Reach Project Of The Adolescent Medicine HIVARN. CD8+CD38+ T cells but not HIV type 1 RNA viral load predict CD4+ T cell loss in a predominantly minority female HIV+ adolescent population. AIDS Res Hum Retroviruses. 2004;20:263–269.
29. Douglas SD, Rudy B, Muenz L, et al.. T-lymphocyte subsets in HIV-infected and high-risk HIV-uninfected adolescents: retention of naive T lymphocytes in HIV-infected adolescents. The Adolescent Medicine HIV/AIDS Research Network. Arch Pediatr Adolesc Med. 2000;154:375–380.
30. Dodder NG, Tai SS, Sniegoski LT, et al.. Certification of creatinine in a human serum reference material by GC-MS and LC-MS. Clin Chem. 2007;53:1694–1699.
31. Myers GL, Miller WG, Coresh J, et al.; National Kidney Disease Education Program Laboratory Working G. Recommendations for improving serum creatinine measurement: a report from the Laboratory Working Group of the National Kidney Disease Education Program. Clin Chem. 2006;52:5–18.
32. Levey AS, Coresh J, Balk E, et al.; National Kidney F. National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Int Med. 2003;139:137–147.
33. Hogg RJ, Furth S, Lemley KV, et al.; National Kidney Foundation's Kidney Disease Outcomes Quality I. National Kidney Foundation's Kidney Disease Outcomes Quality Initiative clinical practice guidelines for chronic kidney disease in children and adolescents: evaluation, classification, and stratification. Pediatrics. 2003;111(6 pt 1):1416–1421.
34. Msango L, Downs JA, Kalluvya SE, et al.. Renal dysfunction among HIV-infected patients starting antiretroviral therapy. AIDS. 2011;25:1421–1425.
35. Emem CP, Arogundade F, Sanusi A, et al.. Renal disease in HIV-seropositive patients in Nigeria: an assessment of prevalence, clinical features and risk factors. Nephrol Dial Transplant. 2008;23:741–746.
36. de Zeeuw D, Parving HH, Henning RH. Microalbuminuria as an early marker for cardiovascular disease. J Am Soc Nephrol. 2006;17:2100–2105.
37. Jotwani V, Li Y, Grunfeld C, Choi AI, et al.. Risk Factors for ESRD in HIV-Infected Individuals: Traditional and HIV-Related Factors. Am J Kidney Dis. 2011;59:628–635.
38. Chavers BM, Rheault MN, Foley RN. Kidney function reference values in US adolescents: National Health And Nutrition Examination Survey 1999-2008. Clin J Am Soc Nephrol. 2011;6:1956–1962.
39. Tien PC, Choi AI, Zolopa AR, et al.. Inflammation and mortality in HIV-infected adults: analysis of the FRAM study cohort. J Acquir Immune Defic Syndr. 2010;55:316–322.
40. Fulop T, Olivier J, Meador RS, et al.. Screening for chronic kidney disease in the ambulatory HIV population. Clin Nephrol. 2010;73:190–196.
41. Gupta SK, Smurzynski M, Franceschini N, et al.. The effects of HIV type-1 viral suppression and non-viral factors on quantitative proteinuria in the highly active antiretroviral therapy era. Antivir Ther. 2009;14:543–549.
42. Szczech LA, Gange SJ, van der Horst C, et al.. Predictors of proteinuria and renal failure among women with HIV infection. Kidney Int. 2002;61:195–202.
43. de Jong PE, Verhave JC, Pinto-Sietsma SJ, et al.; group Ps. Obesity and target organ damage: the kidney. Int J Obes Relat Metab Disord. 2002;26(suppl 4):S21–S24.
44. Chen J, Muntner P, Hamm LL, et al.. The metabolic syndrome and chronic kidney disease in U.S. adults. Ann Int Med. 2004;140:167–174.
45. Deti EK, Thiebaut R, Bonnet F, et al.; Groupe d'Epidemiologie Clinique du SeA. Prevalence and factors associated with renal impairment in HIV-infected patients, ANRS C03 Aquitaine Cohort, France. HIV Med. 2010;11:308–317.
46. Menezes AM, Torelly J Jr, Real L, et al.. Prevalence and risk factors associated to chronic kidney disease in HIV-infected patients on HAART and undetectable viral load in Brazil. PloS One. 2011;6:e26042.
47. Lindsey JC, Jacobson DL, Li H, et al.. Using cluster heat maps to investigate relationships between body composition and laboratory measurements in HIV-infected and HIV-uninfected children and young adults. J Acquir Immune Defic Syndr. 2012;59:325–328.
48. Jacobson DL, Patel K, Siberry GK, et al.. Body fat distribution in perinatally HIV-infected and HIV-exposed but uninfected children in the era of highly active antiretroviral therapy: outcomes from the Pediatric HIV/AIDS Cohort Study. Am J Clin Nutr. 2011;94:1485–1495.
49. Groesbeck D, Kottgen A, Parekh R, et al.. Age, gender, and race effects on cystatin C levels in US adolescents. Clin J Am Soc Nephrol. 2008;3:1777–1785.
50. Larsson A, Hansson LO, Flodin M, et al.. Calibration of the Siemens cystatin C immunoassay has changed over time. Clin Chem. 2011;57:777.
51. Zappitelli M, Parvex P, Joseph L, et al.. Derivation and validation of cystatin C-based prediction equations for GFR in children. Am J Kidney Dis. 2006;48:221–230.
52. Levey AS, Coresh J, Greene T, et al.; Chronic Kidney Disease Epidemiology C. Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med. 2006;145:247–254.
53. Schwartz GJ, Haycock GB, Edelmann CM Jr, et al.. A simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine. Pediatrics. 1976;58:259–263.
54. Schwartz GJ, Work DF. Measurement and estimation of GFR in children and adolescents. Clin J Am Soc Nephrol. 2009;4:1832–1843.
55. Stevens LA, Coresh J, Schmid CH, et al.. Estimating GFR using serum cystatin C alone and in combination with serum creatinine: a pooled analysis of 3,418 individuals with CKD. Am J Kidney Dis. 2008;51:395–406.
56. Muntner P, Vupputuri S, Coresh J, et al.. Metabolic abnormalities are present in adults with elevated serum cystatin C. Kidney Int. 2009;76:81–88.
57. Inker LA, Schmid CH, Tighiouart H, et al.. Estimating Glomerular Filtration Rate from Serum Creatinine and Cystatin C. N Engl J Med. 2012;367:20–29.
58. Jaroszewicz J, Wiercinska-Drapalo A, Lapinski TW, et al.. Short communication Does HAART improve renal function? An association between serum cystatin C concentration, HIV viral load and HAART duration. Antivir Ther. 2006;11:641–645.
59. Gupta SK, Komarow L, Gulick RM, et al.. Proteinuria, creatinine clearance, and immune activation in antiretroviral-naive HIV-infected subjects. J Infect Dis. 2009;200:614–618.
60. Choi AI, Shlipak MG, Hunt PW, et al.. HIV-infected persons continue to lose kidney function despite successful antiretroviral therapy. AIDS. 2009;23:2143–2149.
61. Baker JV, Peng G, Rapkin J, et al.; Terry Beirn Community Programs for Clinical Research on AIDS. CD4+ count and risk of non-AIDS diseases following initial treatment for HIV infection. AIDS. 2008;22:841–848.
62. Atta MG, Deray G, Lucas GM. Antiretroviral nephrotoxicities. Semin Nephrol. 2008;28:563–575.
63. Coresh J, Astor BC, 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;39:920–929.