Urinary biomarkers of kidney injury are associated with all-cause mortality in the Women's Interagency HIV Study (WIHS).

OBJECTIVES: Chronic kidney disease (CKD) is common in HIV-infected individuals, and is associated with mortality in both the HIV-infected and general populations. Urinary markers of tubular injury have been associated with future kidney disease risk, but associations with mortality are unknown. METHODS: We evaluated the associations of urinary interleukin-18 (IL-18), liver fatty acid binding protein (L-FABP), kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL) and the albumin-to-creatinine ratio (ACR) with 10-year, all-cause death in 908 HIV-infected women. Serum cystatin C was used to estimate the glomerular filtration rate (eGFRcys). RESULTS: There were 201 deaths during 9269 person-years of follow-up. After demographic adjustment, compared with the lowest tertile, the highest tertiles of IL-18 [hazard ratio (HR) 2.54; 95% confidence interval (CI) 1.75-3.68], KIM-1 (HR 2.04; 95% CI 1.44-2.89), NGAL (HR 1.50; 95% CI 1.05-2.14) and ACR (HR 1.63; 95% CI 1.13-2.36) were associated with higher mortality. After multivariable adjustment including adjustment for eGFRcys, only the highest tertiles of IL-18 (HR 1.88; 95% CI 1.29-2.74) and ACR (HR 1.46; 95% CI 1.01-2.12) remained independently associated with mortality. Findings for KIM-1 were borderline (HR 1.41; 95% CI 0.99-2.02). We found a J-shaped association between L-FABP and mortality. Compared with persons in the lowest tertile, the HR for the middle tertile of L-FABP was 0.67 (95% CI 0.46-0.98) after adjustment. Associations were stronger when IL-18, ACR and L-FABP were simultaneously included in models. CONCLUSIONS: Among HIV-infected women, some urinary markers of tubular injury are associated with mortality risk, independently of eGFRcys and ACR. These markers represent potential tools with which to identify early kidney injury in persons with HIV infection.

Urinary NGAL is a useful clinical biomarker of HIV-associated nephropathy.

BACKGROUND: Urinary neutrophil gelatinase-associated lipocalin (uNGAL) is expressed by kidney tubules that are acutely damaged, but few studies have investigated the association of neutrophil gelatinase-associated lipocalin (NGAL) with different forms of chronic kidney disease (CKD). HIV-associated nephropathy (HIVAN) is a progressive form of CKD characterized by collapsing focal segmental glomerulosclerosis and microcytic tubular dilatation that typically leads to end-stage renal disease (ESRD). METHODS: Previously, we reported that microcystic tubular dilatations specifically expressed NGAL RNA, implying that the detection of uNGAL protein could mark advanced HIVAN. To test this idea, we performed a comparative study of diverse proteinuric glomerulopathies in 25 patients who were HIV positive. RESULTS: Eighteen patients had HIVAN and seven had other glomerulopathies (four membranoproliferative glomerulonephritis, one membranous glomerulonephritis, one amyloid and one malarial GN). HIVAN and non-HIVAN patients did not differ with respect to age, ethnicity, serum creatinine, estimated GFR, proteinuria or the prevalence of hypocomplementemia (6 versus 29%, P = 0.18), but HIVAN patients were less likely to have HCV infections. HIVAN patients expressed 4-fold higher levels of uNGAL than the patients with other glomerulopathies [387 ± 338 versus 94 ± 101 µg/g urine creatinine (uCr), P = 0.02]. A cutpoint of 121.5 µg uNGAL/g uCr demonstrated 94% sensitivity and 71% specificity for the diagnosis of HIVAN, with an area under the receiver operator characteristic curve of 0.88. CONCLUSION: In summary, while HIVAN disease is currently diagnosed only by kidney biopsy, uNGAL can distinguish HIVAN from other proteinuric glomerulopathies in the HIV-infected patient, likely because of its specific expression from characteristic microcysts.

Urinary NGAL marks cystic disease in HIV-associated nephropathy.

Nephrosis and a rapid decline in kidney function characterize HIV-associated nephropathy (HIVAN). Histologically, HIVAN is a collapsing focal segmental glomerulosclerosis with prominent tubular damage. We explored the expression of neutrophil gelatinase-associated lipocalin (NGAL), a marker of tubular injury, to determine whether this protein has the potential to aid in the noninvasive diagnosis of HIVAN. We found that expression of urinary NGAL was much higher in patients with biopsy-proven HIVAN than in HIV-positive and HIV-negative patients with other forms of chronic kidney disease. In the HIV-transgenic mouse model of HIVAN, NGAL mRNA was abundant in dilated, microcystic segments of the nephron. In contrast, urinary NGAL did not correlate with proteinuria in human or in mouse models. These data show that marked upregulation of NGAL accompanies HIVAN and support further study of uNGAL levels in large cohorts to aid in the noninvasive diagnosis of HIVAN and screen for HIVAN-related tubular damage.

A urinary biomarker profile for children with HIV-associated renal diseases.

Human immunodeficiency virus (HIV)-infected children are at risk of developing several types of renal diseases, including HIV-associated nephropathy (HIVAN), which is usually seen during late stages of infection in children with a high viral load. This disease is defined by the presence of proteinuria associated with mesangial hyperplasia and/or global-focal segmental glomerulosclerosis combined with microcystic transformation of the renal tubules. Because HIVAN can have an insidious clinical onset, renal biopsy is the only definitive way of establishing a diagnosis. Given the risk of performing this procedure in HIV-infected children with other AIDS-defining illness, we sought to identify informative biomarkers such as growth factors in the urine of 55 HIV-infected children that might be predictive of the extent and activity of the renal lesions characteristic of HIVAN. We found that the levels of epidermal growth factor were lower in the urine of children with renal disease, whereas levels of fibroblast growth factor-2 and metalloproteinase-2 were higher as compared with those levels in infected children without renal disease. Similar changes were observed in HIV-Tg26 mice correlating with the progression of renal disease in this model of HIVAN. Our findings suggest that this urinary growth factor profile may be useful in facilitating the diagnosis of HIV-infected children at risk of developing HIVAN when interpreted in the appropriate clinical setting.

Podocytes in HIV-associated nephropathy.

HIV-associated nephropathy (HIVAN) is the leading cause of end-stage renal failure in HIV-1 seropositive patients. The pathologic findings include collapsing focal segmental glomerulosclerosis with proliferation of epithelial cells in Bowman's space. Anatomically, these cells correspond to podocytes and exhibit a unique phenotype with loss of many differentiation markers including synaptopodin and dysregulation of the cell cycle markers consistent with proliferation. Podocyte dysfunction appears to be a direct result of HIV-1 protein expression, specifically Nef and Vpr as well as specific host factors that have yet to be elucidated. The mechanism by which Nef induces podocyte proliferation and dedifferentiation has been traced to its ability to activate several signaling pathways including Src-Stat3 and ras-raf-MAPK1, 2. Activation of the cAMP/PKA pathway with all-trans-retinoic acid appears to modulate these changes and returns podocytes to a differentiated, nonproliferating phenotype.

Urinary protein-to-creatinine ratio versus 24-h proteinuria in the screening for nephropathy in HIV patients.

To determine the correlation between protein-to-creatinine ratio and 24-h urinary protein, proteinuria was measured in 45 patients attending a public HIV clinic in Porto Alegre, Brazil, using 24-h urinary protein excretion (24hUP) and urinary protein-to-creatinine ratio. Spearman's correlation test was done to evaluate the association between spot protein-to-creatinine ratio and 24hUP. The limits of agreement between the two methods were analysed by the Bland-Altman method. For protein excretion <1 g/day, limits (95%) of agreement of protein-to-creatinine ratio and 24hUP were +0.112 and -0.097 g/day. A strong correlation (r = 0.957) was found between protein-to-creatinine ratio and 24hUP excretion. The conclusion is that the protein-to-creatinine ratio in spot urine specimens is an accurate, convenient and reliable screening method to estimate the urinary protein excretion in HIV patients to detect abnormal urinary protein loss. Further studies are required to evaluate renal disease in HIV patients with chronic renal disease and higher urinary protein excretion.

Urine alpha1-microglobulin is a better marker for early tubular dysfunction than beta2-microglobulin among tenofovir-exposed human immunodeficiency virus-infected men who have sex with men.

OBJECTIVES: Men who have sex with men are at risk of tenofovir nephrotoxicity due to its wide use in both treatment and prophylaxis for human immunodeficiency virus infection, but little is known about the urinary biomarkers of early renal dysfunction in this population. This study aims to identify useful biomarkers of early renal dysfunction among human immunodeficiency virus-infected men who have sex with men exposed to tenofovir. METHODS: In a cross-sectional study urinary alpha1-microglobulin, beta2-microglobulin, N-acetyl-ß-d-glucosaminidase and albumin were measured and expressed as the ratio-to-creatinine in 239 human immunodeficiency virus-infected men who have sex with men who were treatment naïve or receiving antiretroviral therapy with tenofovir-containing or non-tenofovir-containing regimens. Additionally, 56 patients in the non-antiretroviral therapy group started a tenofovir-containing regimen and were assessed after 3 and 6 months on antiretroviral therapy. RESULTS: Both the frequency of alpha1-microglobulin proteinuria (alpha1-microglobulin-creatinine ratio >25.8mg/g) and the median urinary alpha1-microglobulin-creatinine ratio were higher in the tenofovir disoproxil fumarate group than the other two groups (all p<0.05). A higher frequency of beta2-microglobulin proteinuria (beta2-microglobulin-creatinine ratio >0.68mg/g) was also observed in the tenofovir group (28.9%) compared to the non-tenofovir group (13.6%, p=0.024). There were no significant differences between groups for N-acetyl-ß-d-glucosaminidase and albumin. In the longitudinal study, the median urinary alpha1-microglobulin-creatinine ratio after 3 and 6 months on tenofovir-containing therapy (16.8 and 17.3mg/g) was higher than baseline (12.3mg/g, p=0.023 and 0.011, respectively), while no statistically important changes were observed in urinary beta2-microglobulin-creatinine ratio or in the other biomarkers after 3 and 6 months on antiretroviral therapy (all p>0.05). CONCLUSION: Urinary alpha1-microglobulin seems to be a more sensitive and stable indicator of tubular dysfunction than urinary beta2-microglobulin for assessing tenofovir-related nephrotoxicity and can be significantly altered after tenofovir exposure.

Association of urine α1-microglobulin with kidney function decline and mortality in HIV-infected women.

BACKGROUND AND OBJECTIVES: Despite advances in therapy, HIV-infected individuals remain at higher risk for kidney dysfunction than uninfected individuals. It was hypothesized that urine levels of α1-microglobulin, a biomarker of proximal tubular dysfunction, would predict kidney function decline and mortality risk in HIV-infected and uninfected women. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In the Women's Interagency HIV Study, urine α1-microglobulin and creatinine concentrations were measured in 903 HIV-infected and 287 uninfected women using stored urine from 1999 to 2000, when prevalence of tenofovir use was <1%. Participants were categorized into three categories by level of α1-microglobulin-to-creatinine ratio, and associations with kidney decline and all-cause mortality over 8 years were evaluated. RESULTS: Urine α1-microglobulin was detectable in 60% of HIV-infected and 40% of uninfected women (P<0.001). Among HIV-infected women, there were 177 (22%), 61 (7%), and 128 (14%) patients with incident CKD, with 10% annual eGFR decline, and who died, respectively. Compared with HIV-infected women in the lowest α1-microglobulin category, HIV-infected women in the highest α1-microglobulin category had a 2.1-fold risk of incident CKD (95% confidence interval, 1.3 to 3.4), 2.7-fold risk of 10% annual eGFR decline (95% confidence interval, 1.2 to 5.9), and 1.6-fold mortality risk (95% confidence interval, 1.0 to 2.6) in models adjusting for kidney risk factors, baseline eGFR, and albuminuria. Among uninfected women, the highest α1-microglobulin category was associated with 3% (relative risk, 2.2; 95% confidence interval, 1.4 to 3.5) and 5% (relative risk, 2.2; 95% confidence interval, 1.1 to 4.3) annual eGFR decline relative to the lowest α1-microglobulin category. CONCLUSIONS: Proximal tubular dysfunction, indicated by urine α1-microglobulin, was independently associated with kidney function decline in HIV-infected and uninfected women and mortality risk among HIV-infected women.

Incidence of microalbuminuria in ambulatory patients with acquired immunodeficiency syndrome.

Nephropathies associated with human immunodeficiency syndrome (HIVAN) are characterized by gross proteinuria, lack of change in blood pressure, and various histologic lesions. The present study prospectively measured microalbuminuria in 72 HIV-seropositive patients (3 asymptomatic, 32 AIDS-related complex, 37 AIDS) screened for Phase I clinical pharmacology studies. There were 14 patients (19.4%) that had abnormal urinary levels of microalbumin; 7 of these patients (50%) had proteinuria similar to those values found in diabetic nephrotic syndrome. Microalbumin levels were not correlated with race, sex, risk factors of AIDS, disease history, or concurrent drug therapy. In contrast, urinary microalbumin levels were correlated with CD 4 T-cell and WBC counts, tumor necrosis factor alpha and beta 2-microglobulin levels, suggesting an association between AIDS progression and microalbuminuria. By monitoring urinary microalbumin levels, those patients susceptible to the development of nephrotic syndrome could be identified and prophylactic measures initiated.

Urinary markers of kidney injury and kidney function decline in HIV-infected women.

OBJECTIVE: HIV-infected persons have substantially higher risk of kidney failure than persons without HIV, but serum creatinine levels are insensitive for detecting declining kidney function. We hypothesized that urine markers of kidney injury would be associated with declining kidney function among HIV-infected women. METHODS: In the Women's Interagency HIV Study, we measured concentrations of albumin-to-creatinine ratio, interleukin-18 (IL-18), kidney injury marker-1 (KIM-1), and neutrophil gelatinase-associated lipocalin from stored urine among 908 HIV-infected and 289 HIV-uninfected participants. Primary analyses used cystatin C-based estimated glomerular filtration rate (CKD-EPI eGFRcys) as the outcome, measured at baseline and 2 follow-up visits over 8 years; secondary analyses used creatinine (CKD-EPI eGFRcr). Each urine biomarker was categorized into tertiles, and kidney decline was modeled with both continuous and dichotomized outcomes. RESULTS: Compared with the lowest tertiles, the highest tertiles of albumin-to-creatinine ratio (-0.15 mL/min per 1.73 m, P < 0.0001), IL-18 (-0.09 mL/min per 1.73 m, P < 0.0001) and KIM-1 (-0.06 mL/min per 1.73 m, P < 0.001) were independently associated with faster eGFRcys decline after multivariate adjustment including all 3 biomarkers among HIV-infected women. Among these biomarkers, only IL-18 was associated with each dichotomized eGFRcys outcome: ≥3% (relative risk = 1.40; 95% confidence interval: 1.04 to 1.89); ≥5% (1.88; 1.30 to 2.71); and ≥10% (2.16; 1.20 to 3.88) for the highest versus lowest tertile. In alternative models using eGFRcr, the high tertile of KIM-1 had independent associations with 5% (1.71; 1.25 to 2.33) and 10% (1.78; 1.07 to 2.96) decline, and the high IL-18 tertile with 10% decline (1.97; 1.00 to 3.87). CONCLUSIONS: Among HIV-infected women in the Women's Interagency HIV Study cohort, novel urine markers of kidney injury detect risk for subsequent declines in kidney function.

The prevalence of renal impairment among adults with early HIV disease in Blantyre, Malawi.

We determined the prevalence of renal impairment and possible HIV-associated nephropathy (HIVAN) in adults with World Health Organization (WHO) stages I or II HIV, presenting to the antiretroviral therapy (ART) clinic in a central hospital in Malawi. We enrolled 526 ART-naïve subjects, 67% women, median age 34 (17-73) years and mean CD4 count 305 (3-993) cells/µL. Blood pressure, weight, urine dipstick and microscopy, CD4 cell count and serum creatinine were measured. Creatinine clearance (CrCL) was estimated using the Cockcroft-Gault equation. Possible HIVAN was diagnosed based on levels of proteinuria and CrCl. In all, 23.3% had proteinuria (≥ 1+). 57.4% had reduced CrCl (< 90 mL/minute): 18.8% had moderate (CrCl 30-59 mL/minute) and 2.2% severe (CrCl <30 mL/minute) renal dysfunction. Extrapolating from renal biopsy studies that confirmed HIVAN, the proportion of patients with HIVAN in our clinic ranges from 1.8-21.2%. We conclude that renal impairment was common, though rarely severe, among HIV-infected adults with clinically non-advanced HIV disease. Renal dysfunction has been demonstrated to be a risk factor for (early) mortality. These results are relevant for ART programmes, such as those in Malawi, where renal function is not routinely assessed.

Urine alpha1-microglobulin is a better marker for early tubular dysfunction than beta2-microglobulin among tenofovir-exposed human immunodeficiency virus-infected men who have sex with men

Objectives: Men who have sex with men are at risk of tenofovir nephrotoxicity due to its wide use in both treatment and prophylaxis for human immunodeficiency virus infection, but little is known about the urinary biomarkers of early renal dysfunction in this population. This study aims to identify useful biomarkers of early renal dysfunction among human immunodeficiency virus-infected men who have sex with men exposed to tenofovir.Methods: In a cross-sectional study urinary alpha1-microglobulin, beta2-microglobulin, N-acetyl-B-n-glucosaminidase and albumin were measured and expressed as the ratio-to-creatinine in 239 human immunodeficiency virus-infected men who have sex with men who were treatment naïve or receiving antiretroviral therapy with tenofovir-containing or non-tenofovir-containing regimens. Additionally, 56 patients in the non-antiretroviral therapy group started a tenofovir-containing regimen and were assessed after 3 and 6 months on antiretroviral therapy.Results: Both the frequency of alpha1-microglobulin proteinuria (alpha1-microglobulin-creatinine ratio >25.8 mg/g) and the median urinary alpha1-microglobulin-creatinine ratio were higher in the tenofovir disoproxil fumarate group than the other two groups (all p< 0.05). A higher frequency of beta2-microglobulin proteinuria (beta2-microglobulin-creatinine ratio >0.68 mg/g) was also observed in the tenofovir group (28.9%) compared to the non-tenofovir group (13.6%, p= 0.024). There were no significant differences between groups for N-acetyl-β-n-glucosaminidase and albumin. In the longitudinal study, the median urinary alphat-microglobulin-creatinine ratio after 3 and 6 months on tenofovir-containing therapy (16.8 and 17.3 mg/g) was higher than baseline (12.3 mg/g, p= 0.023 and 0.011, respectively), while no statistically important changes were observed in urinary beta2-microglobulin-creatinine ratio or in the other biomarkers after 3 and 6 months on antiretroviral therapy (all p> 0.05).Conclusion: Urinary alphat-microglobulin seems to be a more sensitive and stable indicator of tubular dysfunction than urinary beta2-microglobulin for assessing tenofovir-related nephrotoxicity and can be significantly altered after tenofovir exposure.

Iron-related proteins: candidate urine biomarkers in childhood HIV-associated renal diseases.

BACKGROUND: Because of the risk of performing renal biopsies in children with co-morbid conditions, we carried out this study to identify candidate protein biomarkers in the urine of HIV-infected children with renal disease. DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS: Urine samples from HIV-infected children with biopsy proven HIV-nephropathy (HIVAN; n = 4), HIV-associated Hemolytic Uremic Syndrome (HIV-HUS; n = 2), or no renal disease (n = 3) were analyzed by two-dimensional electrophoresis (2-DE) and proteomic methods. Positive findings were confirmed in HIV-infected children with (n = 20) and without (n = 10) proteinuria using commercially available assays. RESULTS: By 2-DE analysis, a single urine marker was not sufficient to distinguish children with HIVAN from the others. High urine levels of beta(2)-microglobulin and retinol-binding protein (RBP) suggested the presence of tubular injury. In addition, we found elevated urine levels of iron and the iron-related proteins, transferrin, hemopexin, haptoglobin, lactoferrin, and neutrophil gelatinase-associated lipocalin (NGAL), in children with HIVAN and HIV-HUS. Furthermore, we detected a significant accumulation of iron in the urine and kidneys of HIV-transgenic (Tg) rats with renal disease. CONCLUSION: These findings suggest that iron and iron-related proteins might be promising candidate urine biomarkers to identify HIV-infected children at risk of developing HIVAN and HIV-HUS. Moreover, based on the results of previous studies, we speculate that the release or accumulation of iron in the kidney of HIV-infected children may contribute to the rapid progression of their renal disease, and could become a new therapeutic target against HIVAN and HIV-HUS.

Low molecular weight proteinuria in human immunodeficiency virus-infected patients.

To determine whether human immunodeficiency virus (HIV) infection is associated with incipient tubular or glomerular defects, we determined the urinary excretion of four low molecular weight proteins (LMWP); beta2-microglobulin (U-beta2-m), cystatin C (U-cyst C), Clara cell protein (U-CC16), and retinol-binding protein (U-RBP), the markers of tubular dysfunction, the excretion of albumin (U-Alb), a marker of glomerular defect, and the excretion of N-acetyl-beta-D-glucosaminidase (U-NAG), a marker of structural damage of the proximal tubular epithelium. Their determinants have been assessed by stepwise regression analysis using as possible predictors age, sex, serum-beta2-m (S-beta2-m), CD4 lymphocyte count, or HIV infection stage and therapy. The study involved 76 HIV-infected patients without renal disease, 56 with S-beta2-m < 5 mg/L (Group B1), 20 with S-beta2-m > or = 5 mg/L (Group B2), and 30 HIV-negative controls. Fourteen patients (18.4%) had no abnormal urinary protein loss, and 62 (81.6%) had elevated urinary excretion of at least one protein (Alb, LMWP, or NAG). A single urinary protein was abnormal in 21 patients (U-beta2-m, n = 9; U-RBP, n = 2; U-CC16, n = 4; and U-Alb, n = 6). At least two LMWP were abnormal without increased U-Alb in 23 patients (12 with increased and 11 with normal U-NAG). Ten patients had an increased urinary excretion of at least one LMWP together with U-Alb (5 with increased and 5 with normal U-NAG). An increased urinary excretion of all proteins was observed in the last 8 patients. The average urinary excretion of all proteins (except cyst C) was significantly higher in HIV than in the control group. As expected, U-beta2-m and the prevalence of abnormal U-beta2-m values were higher in the B2 than in the B1 group (P = 0.0001), whereas the average urinary excretion and the prevalence of elevated values of Alb, LMWP (except beta2-m) or NAG were the same in both HIV groups. By stepwise regression analysis, age emerged as a significant determinant of urinary excretion of beta2-m and CC16, whereas male sex was associated with increased U-CC16. S-beta2-m, CD4-lymphocyte count, or HIV infection stage emerged as significant determinants only for U-beta2-m as a consequence of a close correlation between S-beta2-m and either HIV infection stage (r = -0.52, P = 0.0001), or CD4 count (r = -0.45, P = 0.0002). Over 80% of HIV-infected patients without overt renal disease have evidence of glomerular permeability defects or tubular dysfunction, whatever the stage of the disease. U-Alb, RBP, and CC16 appear as the most sensitive and reliable early markers of these abnormalities. Their cause and prognostic value remain to be determined.

Oncotic pressure and edema formation in hypoalbuminemic HIV-infected patients with proteinuria.

Human immunodeficiency virus nephropathy (HIVN) continues to challenge nephrologic consultative services at major urban institutions. Although noted in the literature, the decreased incidence of peripheral edema in HIVN has been unexplained to date. In HIV patients, total proteins frequently are found to be elevated due to an elevated globulin fraction. The impact that plasma proteins, specifically globulins, have on the total oncotic pressure has not been reported in HIVN, but may play a role in the paucity of edema noted in this proteinuric population. To evaluate the contributions of serum globulin to the total oncotic pressure and the presence or absence of edema in HIVN, we randomly selected 27 patients with proteinuria greater than 2.5 g/24 hr and serum albumin less than 3.1 g/dL from patients presenting to the nephrology outpatient clinic at the University of Miami/Jackson Memorial Hospital. Seventeen of the patients (63%) had a known diagnosis of HIV infection (group 1). These patients were subdivided into two subgroups: those presenting with clinically evident edema on physical examination (n = 7 [41%]; group 1A) and those who had an absence of edema (n = 10 [59%]; group 1B). Conversely, group 2 comprised 10 patients without known HIV infection, of whom six (60%) had edema (group 2A) and four (40%) did not (group 2B). Blood pressures were noted, and mean arterial pressure was calculated using standard formulas. Serum albumin, serum total proteins, and urine total proteins were measured using standard laboratory methods. Oncotic pressures for albumin (alpha), globulin (beta), and total protein (c) were calculated using the following formula: COPpl = alpha(2.8c + 0.18c2 + 0.012c3) + beta(0.9c + 0.12c2 + 0.004c3). We used Student's t-test to analyze the data. There is no significant difference between the albumin concentrations of HIV patients without edema (group 1B) and non-HIV patients with edema (group 2A), with mean concentrations of 2.3 +/- 0.1 g/dL versus 2.3 +/- 0.15 g/dL, respectively (P = NS). Group 1B, however, has a total oncotic pressure of 17.1 +/- 1.5 mm Hg, whereas both groups with edema (groups 1A and 2A) have statistically significant lower total oncotic pressures (12.1 +/- 2.3 mm Hg and 12.9 +/- 1.1 mm Hg, respectively; P < 0.05). The globulin oncotic pressures may account for some of the differences in total oncotic pressures, being significantly higher for those patients without edema in group 1B compared with group 2A (7.1 +/- 0.9 mm Hg v 3.9 +/- 0.4 mm Hg, respectively; P < 0.05). In patients with HIV, however, the presence or absence of edema is mandated by albumin concentration because both groups have similar globulin concentrations (group 1A 3.1 +/- 0.1 g/dL v group 1B 3.8 +/- 0.3 g/dL; P = NS). Mean arterial pressure does not play a role in edema formation in this study because the HIV patients without edema had the higher blood pressures (group 1B 97.8 +/- 4.7 mm Hg v group 2A 84.7 +/- 5.5 mm Hg; P < 0.05). We conclude that globulins play an important role in maintaining oncotic pressure in low albumin states. HIVN patients with increased serum immune globulin may benefit from higher globulin oncotic pressure, delaying the onset of clinical edema in the setting of proteinuria.