Tubular and glomerular proteinuria in HIV-infected adults with estimated glomerular filtration rate ≥60 ml/min per 1.73 m2
Reynes, Jacquesa,b; Cournil, Amandineb; Peyriere, Hélèneb; Psomas, Christinaa; Guiller, Elsaa; Chatron, Marlènec; Cristol, Jean-Paulc,d; Badiou, Stéphaniec,d
aDepartment of Infectious Diseases, Montpellier University Hospital
bInstitut de Recherche pour le Développement (IRD), Université Montpellier I
cDepartment of Biochemistry, Montpellier University Hospital
dUMR 204 NUTRIPASS, Universités Montpellier I/II, Montpellier, France.
Correspondence to Professor Jacques Reynes, Department of Infectious Diseases, Gui de Chauliac Hospital, F34295 Montpellier, France. Fax: +33 0 4 67 33 77 60; e-mail: firstname.lastname@example.org
Received 30 November, 2012
Revised 28 January, 2013
Accepted 31 January, 2013
Objective: To assess the frequency of glomerular and tubular proteinuria in a cohort of HIV-infected patients, and to determine the factors associated with each type of injury.
Design: Cross-sectional study of 1210 consecutive HIV-infected adults followed in HIV outpatient unit (Montpellier/France).
Methods: Spot urine protein to creatinine (uPCR), albumin to creatinine (uACR) and albumin to protein (uAPR) ratios were assessed. Glomerular injury was defined as uACR at least 30 mg/g or uPCR at least 200 mg/g with uAPR at least 0.4. Tubular injury was defined as uPCR 200 mg/g or more with uAPR less than 0.4. Multivariate logistic regression identified independent factors of each type of proteinuria, in the 1158 patients with estimated glomerular filtration rate (eGFR) at least 60 ml/min per 1.73 m2, using re-expressed modification of diet in renal disease equation.
Results: Frequency of proteinuria was 18.2% among patients with eGFR at least 60 ml/min per 1.73 m2 consisting in tubular proteinuria for 50.7% of them. Factors associated with glomerular proteinuria were age [OR 1.34/10-year increment (95%CI: 1.08–1.66)], diabetes [OR 3.37 (95%CI: 1.53–7.44)], and arterial hypertension [OR 2.52 (95%CI: 1.36–4.66)]. Factors associated with tubular proteinuria were age [OR 1.43 (95%CI: 1.14–1.79)], current tenofovir use [OR 3.52 (95%CI: 1.86–6.65)], hepatitis C co-infection [OR 1.62 (95%CI: 1.00–2.65)], AIDS stage [OR 1.83 (95%CI: 1.18–2.82)], CD4 cell count less than 200 per μl [OR 2.48 (95%CI: 1.31–4.70)].
Conclusion: This study distinguished risk factors for tubular injury, mainly related to HIV disease and its treatment (tenofovir), and glomerular injury, linked to non HIV-related variables (age, diabetes, hypertension). Measuring uPCR, uACR and uAPR may help with the detection and specific management of early chronic kidney disease in HIV-infected patients having normal or sub-normal eGFR.
Chronic kidney disease (CKD) is an emerging healthcare problem in HIV-infected adults, with a risk concerning 4–8% of patients [1–3]. CKD is an important risk factor of cardiovascular diseases in HIV population [4,5] as well as in the general population. Risk factors for CKD in HIV patients include age, hypertension, diabetes, hepatitis C co-infection, black race , as well as factors related to HIV infection itself, namely low CD4 cell count and high HIV plasma viral load . In the era of antiretroviral therapy (ART), a significant reduction in the incidence of HIV-associated nephropathy (HIVAN) is observed whereas case reports of tubular injury emerged, especially with tenofovir [7,8]. Although severe tubular injuries are rare, tubular subclinical abnormalities with partial Fanconi syndrome seem very common for up to a quarter of ART experienced patients, related to tenofovir [9,10] or not [11,12]. In addition, a systematic review and meta-analysis revealed a mild decrease in glomerular filtration rate (GFR) with tenofovir use . Kidney damages have also been described with other antiretroviral drugs such as the protease inhibitors indinavir and atazanavir [14,15].
Screening subclinical renal injury is of particular interest to prevent adverse outcome of CKD. Indeed, early stages of CKD are defined by kidney damage, assessed through abnormal presence of urinary markers (protein, albumin), without alteration of the GFR. The early screening of glomerular or tubular proteinuria in HIV-infected patients using a simple method  can help identify factors associated with subclinical renal injury, hence to implement preventive or corrective measures. However, studies evaluating the prevalence and the determinants of proteinuria in HIV-infected patients are limited. The aim of this study was to assess the frequency of glomerular and tubular proteinuria as well as the associated risk factors in a HIV-infected adult population having normal or sub-normal eGFR (eGFR ≥ 60 ml/min per 1.73 m2).
Materials and Methods
This cross-sectional study included HIV-infected adults seen at the Montpellier University Hospital HIV outpatient clinic between 1st November 2010 and 1st May 2011.
All patients enrolled had at least one consultation in the Department of Infectious Diseases during the study period, with a standardized biological assessment (blood and urine) and were included in a computerized medical record (e-NADIS) , after receiving verbal information and giving written consent. The study was approved by the local ethic committee and was declared under the number DC-2012–1579 to be in accordance with French law. The clinical data collected were patient demographics (sex, age and ethnicity), comorbidities (arterial hypertension, diabetes), hepatitis C serology (antibodies anti-HCV), and HIV-related factors (clinical AIDS stage, HIV plasma viral load and CD4 cell count). AIDS stage was defined according to the European consensus .
Data on previous and current antiretroviral treatment including tenofovir, with duration of treatment were collected. Patients were considered with arterial hypertension if they had SBP at least 140 mmHg or DBP at least 90 mmHg or if they received antihypertensive agents. Patients were considered diabetic if they had fasting glycemia superior to 7 mmol/l or if they received antidiabetic agents .
The biological data collected were creatininemia (IDMS traceable enzymatic method from Diasys Diagnostic Systems, Germany) , glycemia (enzymatic method), phosphatemia and phosphaturia (colorimetric method), creatininuria (Jaffé method), proteinuria (colorimetric method) and albuminuria (immunoturbidimetric method). Tubular maximum reabsorption of phosphorus/glomerular filtration rate (TmPO4/GFR) was assessed using phosphate and creatinine levels in serum and urine. Estimated GFR was determined using the re-expressed modification of diet in renal disease (MDRD) for standardized serum creatinine . Spot urine protein to creatinine (uPCR), albumin to creatinine (uACR), and albumin to protein (uAPR) ratios were assessed. Proteinuria was defined as uPCR at least 200 mg/g or uACR at least 30 mg/g [22,23]. Two types of proteinuria were further defined: tubular if uPCR at least 200 mg/g with uAPR less than 0.4, and glomerular if uACR at least 30 mg/g or uPCR at least 200 mg/g with uAPR at least 0.4. The threshold of 0.4 for uAPR was applied according to the study of Smith et al., that reports a 88% sensitivity and a 99% specificity of this ratio for the diagnosis of primary tubuloinsterstitial disorders with reference to results of renal biopsies.
Quantitative variables were presented using medians and interquartile ranges (IQR) and categorical variables with frequencies and proportions. Chi-square tests were used to compare frequencies of tubular or glomerular proteinuria according to tenofovir and boosted protease inhibitors (r/PI) exposure. Multivariate logistic regressions were used to identify independent factors associated with tubular or glomerular proteinuria in patients with eGFR at least 60 ml/min per 1.73 m2. The variables included in the models were: age, sex, hypertension (yes vs. no), diabetes (yes vs. no), eGFR subnormal vs. normal (60–89 vs. at least 90 ml/min per 1.73 m2), hepatitis C serology (antibodies anti-HCV+ vs. anti-HCV−), AIDS stage (yes vs. no), CD4 cell count less than 200 cells/μl (yes vs. no), past or current exposure to tenofovir vs. never treated with tenofovir. An additional analysis was performed to test if the combination of tenofovir with a boosted protease inhibitors was associated with an increased risk of tubular proteinuria compared with tenofovir without r/PI.
The association between duration of tenofovir exposure (≥36 vs. <36 months) and tubular proteinuria was tested in 644 patients who were currently receiving tenofovir using a multivariate model.
All statistical tests were two-sided and considered statistically significant at a 5% threshold. Statistical analyses were performed using SAS statistical software (version 9.2; Cary, North Carolina, USA).
Among the 1295 patients seen in our clinic during the 6-month inclusion period, 1210 patients consented to participate to this study. Their clinical and biological characteristics are presented in Table 1. The majority of patients were ART-experienced white men. CKD stage 3 to 5 (GFR <60 ml/min per 1.73 m2) [22–23] was present in 52 of the 1210 patients (4.3%), essentially characterized (47 patients) by CKD stage 3 (GFR: 30–59 ml/min per 1.73 m2). Among the 1210 patients enrolled in the study, 1158 with eGFR at least 60 ml/min were further considered in the analysis (Fig. 1). Their median age was 48 years (IQR: 42–54), with most patients being between 40 and 59 years old (67.1%). Concerning the comorbid conditions, 18.4% of patients had hepatitis C co-infection (anti-HCV+), 6.8% arterial hypertension and 3.0% diabetes (Table 1). A total of 644 patients (55.6%) were currently treated with tenofovir, [median exposure: 36 months, IQR (17–56)], and 335 of them received concomitantly r/PI.
Frequency of proteinuria in patients with estimated glomerular filteration rate at least 60 ml/min per 1.73 m2
Urinary markers of kidney damage defined as proteinuria or albuminuria were present in 211 of the 1158 patients (18.2%). One hundred and fifteen patients were in CKD stage 1 (GFR≥90 ml/min per 1.73 m2) and 96 patients in CKD stage 2 (GFR: 60–89 ml/min per 1.73 m2) [22–23].
The main profile was a mild proteinuria with only 1.5% of patients having proteinuria over 1 g/l.
In patients with normal or subnormal eGFR, frequencies of tubular proteinuria and of glomerular proteinuria were 9.2 and 9%, respectively (Fig. 1). Although these values were similar, the frequencies of each type of proteinuria differed according to tenofovir exposure (Fig. 2). A trend towards lower frequency of glomerular proteinuria was noted for patients who were receiving tenofovir (7.3%) compared with those who never received tenofovir (10.8%). In contrast, the frequency of tubular injury was significantly higher (12.4%) in patients who were receiving tenofovir compared with patients who never received tenofovir (3.8%). In accordance with the presence of a tubular dysfunction in patients treated by tenofovir, lower TmPO4/GFR ratio was observed in the group currently receiving tenofovir (0.78 ± 0.17 mmol/l) compared with patients without tenofovir (0.82 ± 0.16 mmol/l) P < 0.05).
Moreover, the frequency of tubular proteinuria was significantly higher among patients who were receiving tenofovir in association with r/PI (16.1%) compared with those who were receiving a tenofovir-based regimen without r/PI (8.4%) (P = 0.001).
Presence of tubular proteinuria also tended to increase with duration of tenofovir exposure (Fig. 3).
Risk factors for tubular or glomerular proteinuria in patients with estimated glomerular filtration at least 60 ml/min per 1.73 m2
Multivariate analysis identified classical systemic risk factors for glomerular proteinuria; that is age, diabetes and hypertension (Table 2). By contrast, risk factors for tubular proteinuria were mainly HIV-related parameters, including the AIDS stage, CD4 cell count 200 cells per μl, anti-HCV+ and current treatment with tenofovir (Table 2). Older age was the only common risk factor for the two types of proteinuria.
Multivariate analysis confirmed that current use of tenofovir in combination with r/PI was associated with a two times higher odds of presenting with tubular proteinuria compared with use of tenofovir without r/PI [OR: 1.98 (95%CI: 1.19–3.31)]. Meanwhile, among the latter group, the odds of tubular proteinuria was still higher compared with patients who never received tenofovir [OR: 2.35 (95% CI: 1.15–4.82)].
Finally, the probability of having a tubular proteinuria tended to be associated with duration of exposure to tenofovir with an adjusted odds ratio of 1.67 (95% CI: 0.98–2.83; P = 0.06) for duration of exposure above the median (36 months) compared with duration below 36 months.
The aim of our study was to assess the prevalence of both tubular and glomerular proteinuria in HIV-infected patients and to identify factors associated with each injury. Among the 18.2% (n = 211) of patients with proteinuria, frequencies of tubular and glomerular injury were similar, according to the classification based on uAPR ratio presented in the method section.
Frequency of overall proteinuria (211 among 1158, 18.2%) was consistent with a recent study identifying 17.6% of patients with proteinuria (243 among 1378), in a comparable population of predominantly white male and ART-experienced patients . In our study, frequency of glomerular proteinuria (9%) was comparable with that determined for adults in the general population (10.1%) using a single spot urine . The similarity between frequency of tubular and glomerular proteinuria in HIV-patients seems to differ from the general population in which glomerular injury is predominant compared with chronic tubular disorders.
Previous studies identified many risk factors for CKD (black race, low CD4 cell count, high HIV viral load, diabetes, hypertension and HIV-HCV co-infection), without distinction between glomerular and tubular injury [2,6]. Considering the rising curve of CKD in HIV patients in industrialized countries [1–3], which was confirmed in the present study with more than 17% of patients in stage 1 and 2 and 4.3% in stage 3 to 5, a clinical management of specific risk factors for each nephropathy appears crucial to curb this increase in CKD in HIV patients. CKD-related healthcare problem is even higher in low-income and middle-income countries with a prevalence of CKD in HIV patients reaching 45% in some African countries [25,26]. The clinical concern associated with the CKD rise in HIV-patients includes cardiovascular complications. Indeed, decreased GFR and albuminuria were reported as independent risk factors of cardiovascular events and heart failure in HIV-patients  as well as in the general population . A complementary effect of both markers was observed highlighting the need to follow GFR and albuminuria in all HIV-patients .
In the present study, factors associated with each type of proteinuria were assessed. Age, diabetes and arterial hypertension were the only significant factors associated with glomerular abnormalities. Diabetes and hypertension are the two most frequent causes for glomerulopathy in the general population . Diabetes becomes an important feature in HIV patient outcomes, with a higher prevalence than in the general population, while its incidence in ART experienced HIV men is four times greater than that of HIV-seronegative . In our study, 3.4% of the whole cohort had diabetes, in agreement with data of French (2.6–6.1%) [29,30] or European (4.7%) cohorts . In addition, a recent study reported the additive effects of HIV and diabetes to predict albuminuria, an early stage of glomerulopathy . Hypertension, another recognized glomerulopathy risk factor also represents an important challenge in HIV clinical management, with a prevalence between 6.9  and 27.3% . In our study, hypertension was observed in 7.8% of the whole cohort and in 6.8% of patients having eGFR at least 60 ml/min per 1.73 m2. In order to prevent CKD, diabetes and hypertension need early recognition and optimal control, especially in HIV-infected population .
The significant factors associated with tubular proteinuria were age, current exposure to tenofovir, hepatitis C co-infection, AIDS stage and CD4 cell count less than 200/mm3. Tenofovir is largely recognized for its involvement in tubular dysfunction [8,33], which could be related to its renal excretion. Tenofovir is exclusively excreted by kidneys by a combination of glomerular filtration and active tubular secretion . Our data are consistent with the literature showing that patients treated with tenofovir had mainly proteinuria from tubular cause [8,30], which can occur without decreased GFR .
Another factor significantly associated with tubular proteinuria was the positive status for hepatitis C virus. A meta-analysis pooling data from four studies reported a higher prevalence and an increased relative risk of proteinuria in HIV-HCV co-infected patients vs. those without HCV infection . Although hepatitis C infection may be generating glomerulonephritis, the proportion of glomerular and tubular injury has not been defined .
In our study, the association of tenofovir with tubular proteinuria is twice higher in combination with r/PI, in agreement with previous studies [8,16]. In the study of Scherzer et al., ritonavir was associated with increased proteinuria risk and atazanavir with increased risk of rapid GFR decline. However, few data are available concerning the effect of tenofovir treatment duration with and without r/PI on tubular proteinuria.
In our study, a trend towards an increased risk for tubular proteinuria was observed after 36 months of treatment, similarly to another study in which the risk of proteinuria appears strengthened among patients with more than 3 years of exposure to tenofovir . In a recent study, a current tenofovir treatment for more than 5 years was significantly associated with tubular dysfunction, whereas a trend was observed for patients treated for less than 5 years . Others have reported the association between increasing cumulative exposure to tenofovir and a significant increased rate of CKD .
A strong association was found between current tenofovir treatment and tubular proteinuria while such an association was not found with past tenofovir treatment. In patients with past tenofovir treatment, the frequency of tubular proteinuria was intermediate between that of patients never and currently treated with tenofovir. There was no statistical difference between patients never and previously treated, suggesting a partial reversibility of the effect. Several case reports of tenofovir-related nephrotoxicity found a reversible decrease in eGFR [7,15]. However, a recent small study in HIV-infected men showed a reversibility of eGFR in only 42% of patients . Two studies assessed the reversibility of proteinuria after interruption of tenofovir [8,30]. In the first one, risk of kidney disease did not appear to decrease after tenofovir cessation . In the second, a longer tenofovir exposure duration (≥5 years) was associated with tubular proteinuria whether tenofovir was ongoing or had been interrupted before the inclusion .
By contrast, a trend towards lower odds ratio for glomerular proteinuria was evidenced in patients treated with tenofovir compared with patients never treated. A trend was also noted for a lower frequency of glomerular proteinuria in patients currently treated by tenofovir group compared with those never treated. It could be hypothesized that patients receiving tenofovir were less prone to subclinical glomerular injury in part due to a high efficiency of tenofovir to control HIV-infection. Nevertheless, this data should be confirmed in further studies.
An important finding of this study is that except age, specific and different factors were identified for each type of proteinuria. Although diabetes and hypertension were associated with glomerular dysfunction but not with tubular proteinuria, exposure to tenofovir, AIDS stage, CD4 cell count and HCV co-infection was associated with a risk of tubular damages but not with glomerulopathy. The knowledge of specific risk factors allows determining different preventive approach of CKD. Therefore, identification of patients with tubular or glomerular proteinuria on the basis of uPCR, uACR and uAPR ratios should lead to intensify their clinical monitoring. Patients with glomerular proteinuria should be addressed to nephrologists for an initial management of their glomerulopathy. Treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists could be discussed. Although, in the general population, these antihypertensive drugs significantly reduce protein excretion and further slow the progression rate of CKD , these agents have been little studied in HIV-infected patients. A recent preliminary study reported efficacy of angiotensin receptor antagonists in the control of hypertension and microalbuminuria in HIV-patients . Patients on tenofovir should be monitored for tubular proteinuria with regular urinalysis for protein and albumin. Moreover, although not performed in our study, plasmatic concentrations of tenofovir should be measured in patients with tubular proteinuria on the basis of previous study reporting that higher tenofovir plasma levels were associated with an increased risk of accumulation in renal tubules and thus an increased risk of renal toxicity .
The main strength of our study is the size of the cohort (1210 included patients), which can be considered as a representative cohort of European patients: mainly men (74%), aged around 45 years, with controlled disease. These data are similar to those reported in the Eurosida cohort . Additionally, this study focused on early stage of CKD as all patients had eGFR at least 60 ml/min per 1.73 m2, allowing to prevent adverse outcome of CKD progression. In addition, we applied a simple method (spot urine protein and albumin determination) to characterize the proteinuria, although other biomarkers have been described to distinguish origin of kidney damages . For example cystatin C and retinol binding-protein can be used to characterize tubular proteinuria [41,42]. However, albumin and protein are more widely used in biochemistry routine. Recently, a 0.4 uAPR threshold to detect tubular and glomerular proteinuria was confirmed in the general  and HIV population  in reference to biopsies results.
Our study has some limitations; first, this is a cross-sectional study without follow-up and with nonstandardized duration of treatment. Secondly, we have not distinguished the different protease inhibitors when analyzing the effect of tenofovir with boosted protease inhibitors.
In conclusion, this study demonstrated a high prevalence of proteinuria (18.2%) in HIV patients with normal or sub-normal eGFR. A similar frequency of tubular and glomerular proteinuria was observed with specific risk factors. Some of them are not alterable: age (for glomerular and tubular), AIDS stage, HCV status for tubular proteinuria. Nevertheless, it is possible to modify some other factors such as tenofovir exposure for tubular proteinuria and the control of glycemia and blood pressure with nephroprotective treatment for glomerular proteinuria.
The presence of urinary kidney damage markers in about one-fifth of HIV patient without eGFR less than 60 ml/min per 1.73 m2 highlighted the requirement of systematic patients screening. Determination of spot urine protein and albumin appeared as a simple method applicable in patient monitoring. Furthermore, specific risk factors of each proteinuria should be considered to prevent progression of CKD.
Contribution of authors: J.R. designed the study, included patients, was responsible for clinical support and reviewed/edited the article. A.C. was responsible for the statistical analysis. H.P. wrote the article. C.P. was involved in recruitment of patients and clinical support. M.C. performed biological analysis and data collection. E.G. was responsible for clinical data collection. J.P.C. designed the study and reviewed/edited the article. S.B. supervised the biological analyses and wrote the article. All the authors endorse the data and conclusions.
Conflicts of interest
Conflict of interest and source of fundings for this work: none for any authors.
Outside this work, J.R. has received funding from Abbott, Bristol-Myers Squibb, Gilead, Merck, Tibotec-Janssen, ViiV Healthcare for research, travel grants, speaking engagements or consultancy fees.
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albuminuria; glomerulopathy; HIV; proteinuria; tenofovir; tubular proteinuria
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