Proteinuria has been consistently associated with higher risk of kidney disease progression, cardiovascular disease, and mortality, independent of kidney function level in the general population and in HIV-infected individuals [1,2]. HIV-infected persons and at-risk injection drug users (IDUs) are at high risk of developing kidney disease. Nearly one-third of IDUs have proteinuria, and those who are HIV-infected have a three-fold greater risk for proteinuria [3,4].
Proteinuria in this patient population likely results from the culmination of several risk factors for kidney disease including diabetes, hepatitis C virus (HCV) infection, and hypertension. In addition to these well known risk factors, vitamin D deficiency, which is highly prevalent in HIV-infected persons [5,6], may play a role in the development of proteinuria. Vitamin D deficiency may augment renin–angiotensin system (RAS) activity and exacerbate insulin resistance [7,8]. Moreover, vitamin D deficiency has been linked to greater inflammation and fibrosis in the kidney, which in turn, may exacerbate proteinuria [9–11].
Previous studies in the general population have demonstrated that higher levels of 25 hydroxy (OH)-vitamin D are associated with lower risk of albuminuria and end-stage renal disease [12,13]. More importantly, results from small clinical trials of individuals with chronic kidney disease (CKD) suggest that repletion of vitamin D may lower proteinuria [14,15]. No study, however, has evaluated the association of vitamin D deficiency with proteinuria among IDUs, a patient population at high risk for both vitamin D deficiency and proteinuria and who have risk factors for proteinuria and CKD beyond traditional risk factors. To this end, we conducted a cross-sectional study in the AIDS Linked to the IntraVenous Experience (ALIVE) cohort to evaluate whether vitamin D deficiency was associated with urinary protein excretion and persistent proteinuria among HIV-infected and uninfected IDUs.
A detailed description of the ALIVE study has been reported previously . Briefly, the original focus of the ALIVE study was to investigate the incidence and natural history of HIV infection among IDUs in a community-based observational cohort in Baltimore, Maryland. Participants were initially enrolled in 1988–1989 with subsequent enrollments in 1994–1995, 1998, 2000, and 2005–2008. Of 4376 total IDUs recruited, 1065 were HIV-infected and another 340 seroconverted during follow-up.
The study sample for this analysis was selected from IDUs who were actively followed in 2007 through 2008. For inclusion, individuals had to have stored serum available concurrent with previously obtained serum creatinine and urine protein quantification. In total, 898 participants had serum creatinine and at least one urine protein-to-creatinine ratio available. Stored serum samples for 25(OH)-vitamin D measurement were available in 882 individuals. All participants provided informed consent, and the Johns Hopkins School of Public Health Institutional Review Board approved the study.
During biannual in-person visits, participants completed standardized questionnaires and collection of blood and urine; a subset also completed a physical examination. Questions asked by trained interviewers focused on the participant's medical and social history and current medications. Questions regarding sensitive risk behaviors were conducted via a computer privately.
The primary outcome of interest was urinary protein excretion, estimated by a spot urine protein-to-creatinine ratio on samples collected concurrently with sera for vitamin D levels. Among individuals with at least two urine samples available (n = 737), we also examined persistent proteinuria, defined as a random urine protein-to-creatinine ratio greater than 200 mg/g on two occasions, the clinical definition of proteinuria recommended by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative . The median time elapsed between the two urinary protein quantifications was 1.01 years [interquartile range (IQR) 0.99–1.08 years].
The primary predictor of interest was 25(OH)-vitamin D which was measured at the Tufts Medical Center Core Laboratory using radioimmunoassay (Diasorin, Stillwater, Minnesota, USA), the method on which clinical cut-offs have been based [18,19]. One participant whose vitamin D result exceeded the maximum limit of detection for the assay was excluded. Because the distribution of 25(OH)-vitamin D in the study population was skewed, values were log-transformed. Vitamin D levels were examined continuously and categorically, with vitamin D deficiency defined as a level below 10 ng/ml .
Data on potential confounders were obtained through the questionnaire or through clinical and laboratory testing performed at study visits . Hypertension was defined as a self-reported physician diagnosis of high blood pressure, systolic measurement of 140 mmHg or greater, or a diastolic measurement of 90 mmHg or higher. Diabetes was defined as a self-reported physician diagnosis of this condition. HCV infection was defined based on a positive third-generation antibody test result. HIV-uninfected participants underwent HIV antibody testing, whereas HIV-infected individuals underwent HIV-1 RNA and CD4+ cell count measurements after each visit. Estimated glomerular filtration rate (eGFR) was calculated based on serum creatinine using the Modification of Diet in Renal Disease equation . An eGFR less than 60 ml/min per 1.73 m2 defined impaired kidney function.
Initial descriptive analyses utilized Student t-tests or Wilcoxon rank-sum tests for continuous variables and X2 test for categorical variables. Unadjusted and adjusted linear regression models were constructed to evaluate the association between vitamin D deficiency and urinary protein excretion values from visits concurrent with vitamin D samples. We adjusted for sociodemographic and clinical characteristics associated with both vitamin D deficiency and proteinuria [HCV and HIV infection, diabetes, hypertension, body mass index (BMI), and impaired kidney function]. The final model included covariates with P values less than 0.05 in the unadjusted model. We assessed potential effect modification of the association between vitamin D deficiency and urinary protein excretion by HIV infection, diabetes, and impaired kidney function by inclusion of interaction terms in the linear model and by stratified analyses.
The odds of persistent proteinuria associated with vitamin D deficiency was evaluated with logistic regression models. As in the linear regression models, we adjusted for demographic characteristics, comorbid conditions, BMI, and impaired kidney function, with the final model including covariates with P values less than 0.05 in the unadjusted model. Effect modification of the association between vitamin D deficiency and persistent proteinuria by HIV infection, diabetes, and impaired kidney function was evaluated using similar approaches as the linear regression models. Sensitivity analyses in which vitamin D was modeled continuously and categorically with a cut-off of at least 20 and less than 20 ng/ml were also performed.
Table 1 describes the sociodemographic and clinical characteristics of participants. The majority of participants were African American (92%), cigarette smokers (83%), and HCV seropositive (86%). Nearly one-third had used injection drugs within the prior 6 months. In addition, 27% were taking multivitamins. Half of participants self-reported a prior physician diagnosis of hypertension; whereas 11% had prior diabetes diagnosis. Fifty-four percent of participants had a BMI of 25 kg/m2 or greater, of whom 48% were obese (BMI ≥30 kg/m2). Of the 268 HIV-infected participants, 55% had recently been on highly active antiretroviral therapy (HAART), 40% had HIV-1 RNA levels less than 50 copies/ml, and 66% had CD4+ cell counts above 200 cells/μl.
A total of 218 (25%) and 193 (26%) participants had a urinary protein excretion exceeding 200 mg/g on the first and second samples, respectively. Among the 737 participants who had both first and second urine samples available, the prevalence of persistent proteinuria was 18%. Only 6% of participants had an estimated GFR less than 60 ml/min|1.73 m2. The median vitamin D level for the overall population was 13.3 ng/ml (IQR 8.99–20.33 ng/ml), with 30% having vitamin D levels below 10 ng/ml. The majority of samples were collected during the fall or winter seasons (77%).
Association between vitamin D deficiency and urinary protein excretion
In the unadjusted linear regression models, vitamin D levels below 10 ng/ml were significantly associated with 103.26 mg/g greater urinary protein excretion compared to higher vitamin D levels [95% confidence interval (CI) 6.27, 200.25] (Table 2). This association was attenuated after adjustment for sociodemographic factors, comorbid conditions, BMI, and impaired kidney function (β-coefficient = 90.17 mg/g, 95% CI −0.0004, 180.33). HIV infection and diabetes modified the association between vitamin D deficiency and urinary protein excretion (P-interaction <0.05 for both) (Fig. 1). The association between vitamin D deficiency and urinary protein excretion was not statistically significant among HIV-uninfected and nondiabetic participants. In contrast, vitamin D deficiency was associated with a 231.24 mg/g higher urinary protein excretion (95% CI 28.15, 434.33) among HIV-infected participants. Similarly among diabetic participants, vitamin D deficiency was associated with significantly higher levels of urinary protein excretion (β-coefficient = 722.48 mg/g, 95% CI 313.40, 1131.56) compared to vitamin D levels above10 ng/ml. Whereas impaired kidney function also modified the association between vitamin D deficiency and urinary protein excretion (P-interaction <0.001), vitamin D deficiency was not significantly associated with urinary protein excretion in the adjusted models stratified by kidney function. Inferences from this analysis, however, were limited by the small number of participants with impaired kidney function.
Association of vitamin D deficiency and persistent proteinuria
Vitamin D deficiency was not associated with persistent proteinuria in the unadjusted models (Table 3). Similar findings were observed after adjustment for sociodemographic characteristics, comorbid conditions, BMI, and impaired kidney function [odds ratio (OR) 1.37, 95% CI 0.86, 2.18]. Diabetes, however, modified the association between vitamin D deficiency and persistent proteinuria (P-interaction = 0.008). Vitamin D deficiency was not associated with persistent proteinuria among nondiabetic participants (OR 1.06, 95% CI 0.64, 1.76). In contrast, vitamin D levels below 10 ng/ml were associated with more than a six-fold greater odds of persistent proteinuria among diabetic participants (OR 6.29, 95% CI 1.54, 25.69) compared to those with higher vitamin D levels in fully adjusted models; ORs for persistent proteinuria among diabetic patients remained increased in the range of 3–6 irrespective of adjustment factors (Table 3). Neither HIV infection nor impaired kidney function modified the association between vitamin D deficiency and persistent proteinuria. Other independent predictors of persistent proteinuria in the multivariable model included HIV infection (OR 5.02, 95% CI 3.21, 8.32), HCV seropositivity (OR 7.15, 95% CI 1.68, 30.41), hypertension (OR 2.00, 95% CI 1.22, 3.25), and BMI (OR 0.91 per kg/m2, 95% CI 0.87, 0.96). When modeled continuously, lower vitamin D levels were associated with higher odds of proteinuria among diabetic (OR 5.01 per 10% lower vitamin D, 95% CI 1.47, 17.00) but not among nondiabetic participants (OR 1.09 per 10% lower vitamin D, 95% CI 0.75, 1.59). Similar findings were observed in multivariable analyses using a cut-off of less than 20 ng/ml to define vitamin D deficiency, with no association observed in nondiabetic participants (OR 0.99, 95% CI 0.59, 1.67) but with the odds of persistent proteinuria associated with vitamin D deficiency attenuated among diabetic participants (OR 3.57, 95% CI 0.82, 15.42).
In this study of well characterized HIV-infected and uninfected IDUs, vitamin D deficiency was associated with higher levels of urinary protein excretion independent of potential confounders such as sociodemographic factors and BMI. This association was modified by HIV infection, diabetes, and impaired kidney function, with substantially higher urinary protein excretion associated with vitamin D deficiency in participants with any of these conditions. Moreover, among diabetic individuals, severe vitamin D deficiency was associated with a more than six-fold higher risk of persistent proteinuria independent of the same potential confounders. These observations are important because severe vitamin D deficiency and proteinuria are common among IDUs and have been associated with adverse outcomes. In addition, vitamin D deficiency is a modifiable factor.
Kidney dysfunction and albuminuria are associated with greater risk of cardiovascular complications and mortality in the general and HIV-infected populations [1,2,23,24]. Although the incidence of HIV-associated nephropathy is declining in the context of effective antiretroviral therapy, the prevalence of kidney disease continues to increase among HIV-infected individuals [25,26]. As this patient population ages, more traditional risk factors for kidney disease such as diabetes and hypertension play a greater role in kidney disease pathogenesis and progression. Understanding the complex interplay among these risk factors, including the contribution of vitamin D, will allow appropriate interventions and management to be determined.
Our results are consistent with recent findings from the general US population and among HIV-uninfected individuals with CKD. Among 15 068 participants in the Third National Health and Nutrition Examination Survey, de Boer et al. demonstrated a linear inverse association between vitamin D levels and albuminuria. Among 1847 individuals with impaired kidney function, low levels of 25(OH)-vitamin D and 1,25(diOH)-vitamin D were both independently associated with a 2–3-fold higher risk of albuminuria . The association between vitamin D and proteinuria observed in our study are further supported by small short-term clinical trials in individuals with CKD who received paricalcitol, an analog of active vitamin D. In 61 HIV-uninfected individuals with CKD and proteinuria above 400 mg/day, Fishbane et al. showed that participants who received paricalcitol experienced an 18% decline in proteinuria from baseline to 6 months compared to a 3% increase in individuals who received placebo .
Our findings, however, suggest that vitamin D deficiency's role in kidney disease is important primarily among diabetic individuals. Results from prior studies of diabetic mouse models and humans with diabetic nephropathy support the important role of vitamin D deficiency in the pathogenesis and progression of diabetic nephropathy. In a series of experiments by Zhang et al., the combined administration of losartan and paricalcitol prevented albuminuria and restored hyperglycemia-induced glomerular structural changes to a greater degree than either drug alone in murine models of type 1 diabetes. A subsequent study confirmed the favorable effect of losartan and vitamin D on kidney disease in a model of type 2 diabetes . A more recent clinical trial evaluated the effect of paricalcitol on albuminuria among 281 type 2 diabetic individuals with impaired kidney function (median eGFR 39–42 ml/min|1.73 m2) and persistent albuminuria despite RAS blockade . Participants who received 2 μg of paricalcitol had an average decline in 24-h urinary albuminuria of 34% from baseline. There was a trend, however, for increasing urinary albumin excretion 60 days after paricalcitol cessation. Individuals who received placebo had no significant change in albuminuria.
Several mechanisms by which vitamin D deficiency may be associated with proteinuria have been proposed. First, vitamin D is a known negative regulator of the RAS which plays a key role in the development of diabetic nephropathy through angiotensin II-induced glomerular injury [29,30]. In a series of experiments, Li et al. showed that mice lacking the vitamin D receptor had elevated renin and angiotensin II levels and developed hypertension. Whereas blockade of the RAS with angiotensin-converting enzyme (ACE)-inhibitors or angiotensin-receptor blockers retards diabetic nephropathy progression [31,32], it also leads to compensatory elevations in renin which may cause renal injury independent of angiotensin II . Li et al. also demonstrated, however, that vitamin D repletion of vitamin D-deficient mice decreases renin synthesis. Second, vitamin D deficiency may exacerbate insulin resistance which in turn may cause or worsen albuminuria . Murine studies suggest that insulin activation of the podocyte insulin receptors is important in maintaining the podocyte cytoskeleton and function . Moreover, 1,25(diOH)-vitamin D administration lessens podocyte loss and inhibits hypertrophy after injury . In a meta-analysis of the association between vitamin D and type 2 diabetes, insulin resistance improved with vitamin D repletion among individuals with existing glucose intolerance . Vitamin D may also influence urinary protein excretion through its immunomodulatory effects. Among individuals with kidney disease, vitamin D levels inversely correlated with urinary levels of the pro-inflammatory chemokine, monocyte chemoattractant protein-1 (MCP-1) . In addition, vitamin D may play a role in epithelial mesenchymal transition, the process by which tubular interstitial fibrosis ensues and a mechanism though to contribute to HIV-associated nephropathy [39,40].
The study has several limitations to consider. First, the cross-sectional design precludes establishing temporality between vitamin D deficiency and proteinuria. Although animal studies and small clinical trials support a causal relationship between vitamin D deficiency and proteinuria especially among diabetic patients, we could not evaluate whether vitamin D deficiency preceded proteinuria. Due to the observational nature of this study, there may be residual confounding by unknown factors. The majority of study participants were African Americans who are known to have lower vitamin D levels than other ethnic groups. Therefore, our findings may not be generalizable to IDUs of different ethnic background. We evaluated vitamin D continuously, however, so as to not impose conventional cut-offs which may not be physiologically relevant in African Americans. In addition, we utilized a stringent cut-off to define vitamin D deficiency to avoid misclassification of individuals as being vitamin D-deficient. Our findings were significant mainly among diabetic individuals; however, we did not have renal biopsy specimens to confirm the underlying cause of their kidney disease. As the ALIVE study was initially aimed at understanding the natural history of HIV infection among IDUs, data on other factors which may impact proteinuria, such as use of ACE-inhibitors or angiotensin-receptor blockers, were not collected. Despite these limitations, the ALIVE study consists of a well characterized cohort of HIV-infected and uninfected IDUs allowing adjustment for several relevant potential confounders. Our study represents the first study of the association between vitamin D deficiency and persistent proteinuria among IDUs, a population at great risk for both conditions.
In conclusion, vitamin D deficiency was associated with higher urinary protein excretion among IDUs with HIV infection and diabetes. Furthermore, vitamin D deficiency was strongly associated with increased risk of persistent proteinuria among diabetic IDUs. Additional studies are needed to further elucidate the mechanisms by which vitamin D deficiency may promote proteinuria. Vitamin D repletion may improve proteinuria in this patient population. Results from previous small clinical trials, however, are unlikely to be generalizable to IDUs who have additional risk factors for proteinuria apart from traditional risk factors. Therefore, a well powered clinical trial to validate the observed association between vitamin D deficiency and persistent proteinuria among HIV-infected and uninfected diabetic IDUs is still needed.
The study concept and design was conducted by M.M.E., G.D.K., T.T.B., and G.M.L. The statistical analysis and drafting of the manuscript was performed by M.M.E. Critical revision of the manuscript for important intellectual content was performed by all authors.
Support: This study was supported by NIH-NIDA grant P30 DA13868, Tufts University Nutrition Collaborative, a Center for Drug Abuse and AIDS Research. M.M.E. is supported by the NIH-NIDDK-sponsored grant K23DK081317. G.M.L. is supported by NIH-NIAID grant R01DA026770. The ALIVE study was supported by NIH-NIDA grants R01DA12568 and R01DA04334 and by NIH-NIAID grant RC1AI086053.
Conflicts of interest
There are no conflicts of interest.
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Keywords:© 2012 Lippincott Williams & Wilkins, Inc.
diabetes; HIV; injection drug use; proteinuria; vitamin D deficiency