Secondary Logo

Journal Logo

Osteoprotegrin and Soluble Tumor Necrosis Factor Receptor 1 Are Associated With Microalbuminuria in Nontreated HIV-Infected Patients

Bækken, Morten MD*; Manner, Ingjerd MD; Ueland, Thor PhD; Frøland, Stig S MD, PhD§; Os, Ingrid MD, PhD; Aukrust, Pål MD, PhD; Øktedalen, Olav MD, PhD**; Damås, Jan K MD, PhD††

JAIDS Journal of Acquired Immune Deficiency Syndromes: March 1st, 2010 - Volume 53 - Issue 3 - p 419-420
doi: 10.1097/QAI.0b013e3181ba4101
Letter to the Editor
Free

*Departments of Infectious Diseases and Nephrology, Ullevaal University Hospital, Ullevaal, Norway; †Department of Nephrology, Ullevaal University Hospital, Ullevaal, Norway; ‡Research Institute for Internal Medicine and Section of Endocrinology, Rikshospitalet Medical Center, Rikshospitalet, Norway; §Research Institute for Internal Medicine and Section of Clinical Immunology and Infectious Diseases, Rikshospitalet Medical Center, Rikshospitalet, Norway; and Faculty of Medicine, University of Oslo, Oslo, Norway; ¶Department of Nephrology, Ullevaal University Hospital, Ullevaal, Norway; and Faculty of Medicine, University of Oslo, Oslo, Norway; ‖Research Institute for Internal Medicine and Section of Clinical Immunology and Infectious Diseases, Rikshospitalet Medical Center, Rikshospitalet, Norway; and Faculty of Medicine, University of Oslo, Oslo, Norway; **Department of Infectious Diseases, Ullevaal University Hospital, Ullevaal, Norway; ††Research Institute for Internal Medicine and Section of Clinical Immunology and Infectious Diseases, Rikshospitalet Medical Center, Rikshospitalet, Norway; and Department of Infectious Diseases, St. Olavs Hospital, Trondheim, Norway

To the Editors:

Because HIV-infected patients live longer after the introduction of highly active antiretroviral therapy (HAART), cardiovascular and renal diseases have emerged as significant causes of morbidity and mortality in this population.1 The mechanisms of HIV-induced renal affection has still not been fully evaluated, but the influence of viral replication, hypertension, and drug toxicity of HAART has been discussed.1,2 Also, systemic inflammation may contribute to renal and cardiovascular abnormalities in HIV infection independent of ongoing HAART.3 Members of the tumor necrosis factor (TNF) superfamily may be of importance for eliciting immune-mediated injury in various kidney and cardiovascular disorders.4,5 We therefore examined plasma levels of soluble TNF receptor type 1 (sTNFR1), osteoprotegerin (OPG), and soluble CD40 ligand (sCD40L) in HIV-infected patients and their relation to albumin excretion and blood pressure.

The present study is a substudy of the Microalbuminuria in a HIV-positive population in Oslo (MAHO) study,2 including 221 HIV-infected patients (187 males and 34 females, 46 ± 11 years); 148 received HAART (CD4+ T cell count, 0.45 ± 0.31 × 106/L; HIV RNA level, 44 ± 216 × 103 copies/mL plasma) and 73 were without treatment (CD4+ T cell count, 0.48 ± 0.29 × 106/L; HIV RNA level, 112 ± 159 × 103 copies/mL plasma). According to the albumin/creatinine ratio (ACR), patients were categorized as having normoalbuminuria (less than 2.5 mg/mmol) or microalbuminuria (2.5-30 mg/mmol). Hypertension was defined as previously described.2 Data on blood pressure, creatinine, glomerular filtration rate, β-2-microglobulin (β2MG), lipids, and glycosylated hemoglobulin (HbA1c) were obtained as previously reported.2

Concentrations of OPG and sTNFR1 (R&D Systems, Minneapolis, MN) and sCD40L (Bender MedSystems, Vienna, Austria) were measured by enzyme immunoassays. For cytokine analyses, 30 sex- and age-matched healthy individuals served as control subjects. The study was approved by the regional ethical committee. For statistical comparisons, the Kruskal-Wallis test, the Mann-Whitney U test, and the Spearman rank test were used as appropriate. Probability are two-sided and considered to be significant when P < 0.05.

HIV-infected patients (n = 221) had significantly raised serum levels of OPG, sTNFR1, and sCD40L as compared with healthy control subjects (n = 30) independent on ongoing HAART (Fig. 1A). There was no association between inflammatory parameters and CD4+ T cell counts, but sTNFR1 was significantly correlated with HIV RNA levels (r = 0.24, P < 0.005), particularly in patients on HAART (r = 0.39, P < 0.001). TNFα has previously been related to HIV replication,6 and our finding suggests that such mechanisms may also be operating during HAART.

FIGURE 1

FIGURE 1

OPG and sTNFR1 were significantly correlated to ACR in HIV-infected patients without treatment (r = 0.36, P < 0.01 and r = 0.29, P < 0.05, respectively), but not in those on HAART. Also, when patients were dichotomized with regard to absence/presence of microalbuminuria, we found significantly higher OPG and sTNFR1 levels in relation to the presence of microalbuminuria in untreated patients, but not during HAART (Fig. 1B). β2MG, reflecting impaired glomerular filtration and/or tubular reabsorption as well as lymphocyte activation, was significantly associated with OPG (r = 0.26, P < 0.001) and sTNFR1 (r = 0.53, P < 0.001) in HIV-infected patients, particularly in patients with elevated ACR (Fig. 1C) independent of ongoing HAART.

We found no association between any of the TNF superfamiliy members and blood pressure, creatinine/glomerular filtration rate levels, lipid parameters, or HbA1c in HIV-infected patients independent of ongoing HAART.

We show a significant association between sTNFR1 and OPG and microalbuminuria in HIV-infected patients and for sTNFR1, also with increased ACR, further suggesting a role for systemic inflammation in the pathogenesis of glomerular injury in HIV infection. However, although HIV-infected patients on HAART had similar levels of systemic inflammation as compared with untreated patients, reflecting that most of the untreated patients had normal CD4+ T cell counts, there was no association between OPG or sTNFR1 and ACR or the presence of microalbuminuria during HAART. Although the strong correlation between OPG/sTNFR1 and β2MG in relation to increased ACR was independent of ongoing HAART, suggesting some involvement of inflammation in the pathogenesis of glomerular injury also during HAART, our findings may suggest that other factors (eg, drug toxicity) could be of more importance.

An increased urinary albumin excretion rate is an independent risk factor for cardiovascular disease.7 Similarly, several studies have shown that enhanced inflammation, including TNF superfamily members, may predict mortality and cardiovascular events.5 Thus, the combination of increased ACR and low-grade systemic inflammation could represent a risk factor for cardiovascular events in HIV-infected individuals. However, the clinical significance of increased ACR in combination with systemic inflammation in HIV infection will have to be further investigated in prospective studies.

Morten Bækken, MD*

Ingjerd Manner, MD†

Thor Ueland, PhD‡

Stig S. Frøland, MD, PhD§

Ingrid Os, MD, PhD∥

Pål Aukrust, MD, PhD¶

Olav Øktedalen, MD, PhD**

Jan K. Damås, MD, PhD††

*Departments of Infectious Diseases and Nephrology, Ullevaal University Hospital, Ullevaal, Norway

†Department of Nephrology, Ullevaal University Hospital, Ullevaal, Norway

‡Research Institute for Internal Medicine and Section of Endocrinology, Rikshospitalet Medical Center, Rikshospitalet, Norway

§Research Institute for Internal Medicine and Section of Clinical Immunology and Infectious Diseases, Rikshospitalet Medical Center, Rikshospitalet, Norway; and Faculty of Medicine, University of Oslo, Oslo, Norway

∥Department of Nephrology, Ullevaal University Hospital, Ullevaal, Norway; and Faculty of Medicine, University of Oslo, Oslo, Norway

¶Research Institute for Internal Medicine and Section of Clinical Immunology and Infectious Diseases, Rikshospitalet Medical Center, Rikshospitalet, Norway; and Faculty of Medicine, University of Oslo, Oslo, Norway

**Department of Infectious Diseases, Ullevaal University Hospital, Ullevaal, Norway

††Research Institute for Internal Medicine and Section of Clinical Immunology and Infectious Diseases, Rikshospitalet Medical Center, Rikshospitalet, Norway; and Department of Infectious Diseases, St. Olavs Hospital, Trondheim, Norway

Back to Top | Article Outline

REFERENCES

1. Kotler DP. HIV and antiretroviral therapy: lipid abnormalities and associated cardiovascular risk in HIV-infected patients. J Acquir Immune Defic Syndr. 2008;49(Suppl 2):S79-85.
2. Baekken M, Os I, Sandvik L, et al. Microalbuminuria associated with indicators of inflammatory activity in an HIV-positive population. Nephrol Dial Transplant. 2008;23:3130-3137.
3. Kuller LH, Tracy R, Belloso W, et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med. 2008;5:e203.
4. Sanz AB, Moreno JA, Sanchez-Nino MD, et al. Tweaking renal injury. Front Biosci. 2008;13:580-589.
5. Kiechl S, Schett G, Schwaiger J, et al. Soluble receptor activator of nuclear factor-kappa B ligand and risk for cardiovascular disease. Circulation. 2007;116:385-391.
6. Aukrust P, Müller F, Lien E, et al. Tumor necrosis factor (TNF) system in human immunodeficiency virus-infected patients during highly active antiretroviral therapy (HAART): persistent TNF activation is associated with virologic and immunologic treatment failure. J Infect Dis. 1999;179:74-82.
7. Klausen K, Borch-Johnsen K, Feldt-Rasmussen B, et al. Very low levels of microalbuminuria are associated with increased risk of coronary heart disease and death independently of renal function, hypertension, and diabetes. Circulation. 2004;110:32-35.
© 2010 Lippincott Williams & Wilkins, Inc.