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Antiviral therapy  2011;16(4):591-596.
We previously reported an increased risk of all-cause and AIDS mortality among HIV-infected women with albuminuria (proteinuria or microalbuminuria) enrolled in the Women’s Interagency HIV Study (WIHS) prior to the introduction of highly active antiretroviral therapy (HAART).
The current analysis includes 1,073 WIHS participants who subsequently initiated HAART. Urinalysis for proteinuria and semi-quantitative testing for microalbuminuria from two consecutive study visits prior to HAART initiation were categorized as follows: confirmed proteinuria (both specimens positive for protein), confirmed microalbuminuria (both specimens positive with at least one microalbuminuria), unconfirmed albuminuria (one specimen positive for proteinuria or microalbuminuria), or negative (both specimens negative). Time from HAART initiation to death was modeled using proportional hazards analysis.
Compared to the reference group of women with two negative specimens, the hazard ratio (HR) for all-cause mortality was significantly elevated for women with confirmed microalbuminuria (HR 1.9; 95% CI 1.2–2.9). Confirmed microalbuminuria was also independently associated with AIDS death (HR 2.3; 95% CI 1.3–4.3), while women with confirmed proteinuria were at increased risk for non-AIDS death (HR 2.4; 95% CI 1.2–4.6).
In women initiating HAART, pre-existing microalbuminuria independently predicted increased AIDS mortality, while pre-existing proteinuria predicted increased risk of non-AIDS death. Urine testing may identify HIV-infected individuals at increased risk for mortality even after the initiation of HAART. Future studies should consider whether these widely available tests can identify individuals who would benefit from more aggressive management of HIV infection and comorbid conditions associated with mortality in this population.
PMCID: PMC3119869  PMID: 21685547
HIV; microalbuminuria; proteinuria; mortality; non-AIDS death
2.  Microalbuminuria in HIV infection 
AIDS (London, England)  2007;21(8):1003-1009.
Microalbuminuria is associated with increased risk of cardiovascular disease and mortality. The objective of the study was to evaluate if HIV infection was an independent risk factor for microalbuminuria.
Cross sectional.
The relationship between HIV infection and microalbuminuria was assessed using subjects enrolled in the study of Fat Redistribution and Metabolic Change in HIV Infection, which consists of HIV-positive and control men and women. Participants with proteinuria (dipstick ≥1+) were excluded.
Microalbuminuria (urinary albumin/creatinine ratio, ACR>30 mg/g) was present in 11% of HIV infected, and 2% of control participants (P<0.001); a fivefold odds after multivariate adjustment (odds ratio, 5.11; 95% confidence interval, 1.97–13.31; P=0.0008). Several cardiovascular risk factors were associated with higher ACR in HIV participants: insulin resistance (HOMA>4; 32%, P<0.0001), systolic blood pressure (21%, P=0.01 for 120–140 versus <120 mmHg, and 43%, P <0.06 for >140 versus <120 mmHg), and family history of hypertension (17%, P=0.03). Higher CD4 cell count was associated with lower albumin/creatinine ratio (−24%, P=0.009 for 200–400 versus <200 cells/ml and −26%, P=0.005 for >400 versus <200 cells/ml).
HIV infection had a strong and independent association with microalbuminuria, the severity of which was predicted by markers of insulin resistance, hypertension, and advanced HIV infection. These associations warrant further investigation, as the increased prevalence of microalbuminuria in HIV infection may be a harbinger of future risk of cardiovascular and kidney diseases.
PMCID: PMC3189480  PMID: 17457094
Microalbuminuria; kidney; urine protein; insulin resistance; lipodystrophy
3.  Microalbuminuria in HIV Disease 
American journal of nephrology  2013;37(5):10.1159/000350384.
Microalbuminuria is a marker for early kidney disease and cardiovascular risk. The purposes of this study were to determine the prevalence of microalbuminuria in an HIV-infected clinic population, to test the predictive value of a single urine albumin-creatinine ratio (ACR) to identify persistent microalbuminuria and to examine covariates of microalbuminuria.
We conducted a prospective cohort study of HIV-infected subjects (n=182) without proteinuria (P/C ratio ≥0.5 g/g), elevated serum creatinine, diabetes, or chronic inflammatory conditions. Subjects completed three research visits within nine months. Microalbuminuria was defined as the geometric mean ACR of 25–355 mg/g for women and 17–250 mg/g for men.
The prevalence of microalbuminuria was 14%. The negative predictive value of a single urine ACR determination was 98%, whereas the positive predictive value was only 74%. Microalbuminuria was similar among Black (15%) and non-Black (14%) subjects (p=0.8). Subjects with microalbuminuria were more likely to have hypertension (p=0.02) and metabolic syndrome (p=0.03). While duration of HIV infection and the level of HIV viremia were similar between groups, those with microalbuminuria were more likely to have a CD4 count <200 cells/μL (p=0.0003). In a multivariate logistic regression analysis, the only significant independent predictors of microalbuminuria were low CD4 count (p=0.018) and current ritonavir exposure (p=0.04).
The prevalence of microalbuminuria in an HIV-infected clinic population was similar to earlier reports, and was associated with hypertension and impaired immune function. A single normal ACR determination effectively excludes microalbuminuria, whereas an elevated ACR requires confirmation.
PMCID: PMC3809894  PMID: 23615312
HIV infection; microalbuminuria; urinary albumin-creatinine ratio
4.  Usefulness of Microalbuminuria vs. the Metabolic Syndrome as a Predictor of Cardiovascular Disease in Women and Men > 40 Years of Age (From the Rancho Bernardo Study) 
The American journal of cardiology  2008;101(9):1275-1280.
To examine the sex-specific contributions of the metabolic syndrome and microalbuminuria to cardiovascular disease (CVD) and coronary heart disease (CHD) mortality in community-dwelling older adults, between 1992–1995, 869 women and 575 men aged 40–96 years (mean 71) completed questionnaires, physical examinations, and fasting laboratory tests. Participants were followed over an average of 8 years. CVD and CHD mortality were analyzed using Cox proportional hazards models. At baseline, 267 participants had the Adult Treatment Panel III metabolic syndrome, 151 had microalbuminuria, and 34 had both. During follow up, there were 180 CVD deaths, including 83 CHD deaths. In women, microalbuminuria was associated with a 2-fold increased risk of CVD and CHD mortality (p ≤ 0.01). Women with both microalbuminuria and the metabolic syndrome (n = 18) had a 3-fold increased risk of CVD mortality and a 5-fold increased risk of CHD mortality compared with women without either (n = 657). A significant interaction existed between microalbuminuria and the metabolic syndrome in the prediction of both CVD and CHD (p = 0.021). In men, neither the combination of the metabolic syndrome and microalbuminuria (n = 16), nor either alone, significantly increased the risk of CVD or CHD mortality. In conclusion, in this cohort, microalbuminuria and the metabolic syndrome together were a more powerful predictor of CVD mortality than either alone in women but not in men. Screening for microalbuminuria in older women may identify women at high risk for CVD mortality, beyond that conferred by risk factors included in the metabolic syndrome.
PMCID: PMC2600883  PMID: 18435957
Cardiovascular disease; Elderly; Metabolic syndrome; Microalbuminuria
5.  Microalbuminuria associated with indicators of inflammatory activity in an HIV-positive population 
Nephrology Dialysis Transplantation  2008;23(10):3130-3137.
Background. The survival of human immunodeficiency virus (HIV)-infected patients has increased significantly since the introduction of combination antiretroviral therapy, leading to the development of important long-term complications including cardiovascular disease (CVD) and renal disease. Microalbuminuria, an indicator of glomerular injury, is associated with an increased risk of progressive renal deterioration, CVD and mortality. However, the prevalence of microalbuminuria has barely been investigated in HIV-infected individuals.
Methods. Based on three prospective urine samples in an unselected nonhypertensive, nondiabetic HIV-positive cohort (n = 495), we analysed the prevalence of microalbuminuria and compared the Caucasian share with that of a nonhypertensive, nondiabetic population-based control group (n = 2091). Significant predictors for microalbuminuria were analysed within the HIV-positive cohort.
Results. The prevalence of microalbuminuria was 8.7% in the HIV-infected cohort, which is three to five times higher than that in the general population. HIV-infected patients with microalbuminuria were older, and had higher blood pressure, longer duration of HIV infection, higher serum beta 2-microglobulin, higher serum creatinine and a reduced glomerular filtration rate of ≤90 mL/min, compared with those with normal albumin excretion. In multivariate analysis, systolic blood pressure, serum beta 2-microglobulin and duration of HIV infection were found to be independent predictors of microalbuminuria.
Conclusions. Our findings indicate that in addition to haemodynamic effects, inflammatory activity may be implicated as a cause of the development of microalbuminuria. With respect to the increasing risk of developing CVD or renal diseases and mortality, the high prevalence of microalbuminuria in HIV-infected individuals warrants special attention.
PMCID: PMC2542409  PMID: 18469311
beta 2-microglobulin; blood pressure; combination antiretroviral treatment; HIV; microalbuminuria
6.  Association of Subcutaneous and Visceral Adiposity with Albuminuria: The Framingham Heart Study 
Obesity (Silver Spring, Md.)  2010;19(6):1284-1289.
Microalbuminuria is a common condition associated with increased incidence of cardiovascular events and mortality. Abdominal obesity is associated with microalbuminuria, but studies linking visceral adipose tissue (VAT) and microalbuminuria are limited. Our objective was to determine the associations of albuminuria with VAT and subcutaneous adipose tissue (SAT). We performed a cross-sectional study in the Framingham Multi-detector Computed Tomography cohort (n = 3099, 48.2% women, mean age 53 years). VAT and SAT volumes were measured using computed tomography. Urinary albumin-to-creatinine ratio (UACR) was calculated from spot urine samples. Microalbuminuria was defined as a UACR >25 mg/g in women or >17 mg/g in men. Overall, 7.9% (n = 244) of the sample had microalbuminuria. Among men, VAT (Odds ratio [OR] 1.48 per standard deviation [SD], p<0.0001) and SAT (OR 1.37 per SD, p=0.0002) were associated with microalbuminuria in minimally-adjusted models, which remained significant after multivariable adjustment (VAT OR 1.34 per SD, p=0.001; SAT OR 1.28 per SD, p=0.005). Additionally, when considered jointly, VAT (p=0.002) but not SAT (p=0.2) was associated with microalbuminuria. In women, VAT was associated with microalbuminuria after minimal adjustment (OR 1.28, p=0.01), but not after multivariable adjustment (OR 1.03, p=0.8). In multivariable models in women, SAT was associated with a decreased odds of having microalbuminuria (OR 0.75 per SD, p=0.03). In conclusion, VAT is associated with microalbuminuria in men but not women. Albuminuria may be a manifestation of visceral adiposity.
PMCID: PMC3096746  PMID: 21183930
Abdominal obesity; Microalbuminuria; Computed Tomography
7.  Microalbuminuria predicts overt proteinuria among patients with HIV-infection 
HIV medicine  2010;11(7):419-426.
This study examines the association between microalbuminuria and the development of proteinuria among HIV-infected persons.
948 subjects provided urine samples for albumin, protein, and creatinine measurements semiannually. Microalbuminuria was an albumin-to-creatinine ratio of >30 mg/gm. Proteinuria was a protein-to-creatinine ratio of ≥0.350 mg/mg. The progression from microalbuminuria to proteinuria was described.
At baseline, 69.4% had no detectable proteinuria, 20.2% had microalbuminuria, and 10.4% had proteinuria. Subjects with microalbuminuria and proteinuria were more likely to be black (p=0.03), have lower CD4+ counts (p=0.02,0.0001 compared to subjects without abnormal proteinuria, respectively), and have a higher HIV RNA level (p=0.08,0.04). Among 658 subjects with normal urine protein, 82.7% continued to have no abnormality, 14.3% developed microalbuminuria, and 3.0% developed proteinuria. Subjects without baseline proteinuria (i.e. either normal protein excretion or microalbuminuria) who developed proteinuria were more likely to have microalbuminuria (p=0.001), a lower CD4+ count (p=0.06), and a higher plasma HIV RNA (p=0.03) than those who did not progress to proteinuria. In multivariate analysis, only microalbuminuria remained associated with the development of proteinuria (OR=2.9; 95% CI 1.5, 5.5; p=0.001).
Microalbuminuria predicts the development of proteinuria among HIV-infected persons. Because proteinuria has been linked to poorer outcomes, strategies to affect microalbuminuria should be tested.
PMCID: PMC2892228  PMID: 20059571
HIV-1; microalbuminuria; proteinuria; HIVAN; urine
8.  Screening for Microalbuminuria in HIV-Positive Children in Enugu 
Background. Human immunodeficiency virus associated nephropathy (HIVAN) is a rapidly progressive chronic renal parenchymal disease that occurs in HIV-infected individuals and manifests commonly as proteinuria, which is preceded by microalbuminuria (MA). This clinical entity is defined as a spot urine albumin of 20–200 mg/L. Objectives. To determine the prevalence of microalbuminuria in HIV positive children in UNTH, Enugu and compare it with that of HIV-negative children. Methods. A total of 154 HIV positive children aged 18 months to 14 years and 154 HIV-negative children of corresponding attributes were screened for microalbuminuria, using Micral test II strip which has a sensitivity of 90–99%. Results. No child among the groups (HIV positive and negative) had microalbuminuria. Majority (96.0%) of HIV-positive children had nonadvanced HIV disease at the time of the study (P = 0.00). About 77.3% were using HAART (P < 0.0001), the mean CD4 cell count of the subjects was 709.2 ± 443.9 cells/mm3; while 78.0% had nonsevere immunosuppression (P = 0.00). Furthermore, HIV-positive children with severe immunosuppression were younger and had shorter duration of treatment. Conclusion. Microalbuminuria may not be very common in Nigerian children irrespective of their HIV status.
PMCID: PMC3399360  PMID: 22830018
9.  Proteinuria in paediatric patients with human immunodeficiency virus infection 
In human immunodeficiency virus (HIV)-infected people kidney disease is as an important cause of morbidity and mortality. Clinical features of kidney damage in HIV-infected patients range from asymptomatic microalbuminuria to nephrotic syndrome. The lack of specific clinical features despite the presence of heavy proteinuria may mask the renal involvement. Indeed, it is important in HIV patients to monitor renal function to early discover a possible kidney injury. After the introduction of antiretroviral therapy, mortality and morbidity associated to HIV-infection have shown a substantial reduction, although a variety of side effects for long-term use of highly active antiretroviral therapy, including renal toxicity, has emerged. Among more than 20 currently available antiretroviral agents, many of them can occasionally cause reversible or irreversible nephrotoxicity. At now, three antiretroviral agents, i.e., indinavir, atazanavir and tenofovir disoproxil fumarate have a well established association with direct nephrotoxicity. This review focuses on major causes of proteinuria and other pathological findings related to kidney disease in HIV-infected children and adolescents.
PMCID: PMC3845933  PMID: 24303454
Human immunodeficiency virus-infection; Nephropathy; Proteinuria; Antiretroviral therapy; Children
10.  Danish general practitioners' estimation of urinary albumin concentration in the detection of proteinuria and microalbuminuria. 
BACKGROUND. Microalbuminuria may predict proteinuria and increased mortality in non-insulin dependent diabetic patients. Early detection of microalbuminuria may therefore be essential. AIM. The primary objective of this study was to describe the association between the presence of albuminuria in diabetic patients as detected by general practitioners using conventional reagent strip dipstick tests for albumin, and the urinary albumin concentration as measured in a hospital laboratory. METHOD. A total of 675 newly diagnosed diabetic patients aged 40 years or over were included in the Danish study, diabetes care in general practice. Data for urinary albumin concentration from a morning urine sample and the results of three consecutive dipstick tests for albumin were collected for 417 patients. RESULTS. When defining elevated urinary albumin concentration as 200 mg l-1 or more (proteinuria) the finding of at least one positive test out of the three dipstick tests for albumin had a diagnostic sensitivity of 73% and a specificity of 89%. When the microalbuminuric range (15.0 to 199.9 mg l-1) was added to the definition of renal involvement, the sensitivity of the dipstick test became as low as 28% with a specificity of 96%. CONCLUSION. It is essential for general practitioners to be able to identify proteinuric patients. To achieve this by means of the conventional dipstick test, general practice procedures need to be improved. As it is becoming increasingly well-documented that microalbuminuric non-insulin dependent diabetic patients may benefit from pharmacological treatment of even slight arterial hypertension and heart failure, it seems reasonable to suggest that the use of dipsticks for albumin in general practice be replaced by laboratory quantitative determination of urinary albumin concentration in a morning urine sample.
PMCID: PMC1239138  PMID: 7702885
11.  The association of microalbuminuria with mortality in patients with acute myocardial infarction. A ten-year follow-up study 
Heart International  2010;5(1):e2.
Our study evaluates the long-term effect of microalbuminuria on mortality among patients with acute myocardial infarction. We followed 151 patients from 1996 to 2007 to investigate if microalbuminuria is a risk factor in coronary heart disease. All patients admitted with acute myocardial infarction in 1996 were included. At baseline, we recorded urinary albumin/creatinine concentration ratio, body mass index, blood pressure, left ventricle ejection fraction by echocardiography, smoking status, medication, diabetes, age, and gender. Deaths were traced in 2007 by means of the Danish Personal Identification Register. Microalbuminuria, defined as a urinary albumin/creatinine concentration ratio above 0.65 mg/mmoL, occurred in 50% of the patients and was associated with increased all-cause mortality. Thus, 68% of the patients with microalbuminuria versus 48% of the patients without microalbuminuria had died during the 10 years of follow-up (P=0.04). The crude hazard ratio for death associated with microalbuminuria was 1.78 (CI: 1.18–2.68) (P=0.006), whereas the gender- and age-adjusted hazard ratio was 1.71 (CI: 1.03–2.83) (P=0.04). We concluded that microalbuminuria in hospitalized patients with acute myocardial infarction is prognostic for increased long-term mortality. We recommend measurement of microalbuminuria to be included as a baseline risk factor in patients with acute myocardial infarction and in future trials in patients with coronary heart disease.
PMCID: PMC3184708  PMID: 21977287
acute myocardial infarction; microalbuminuria; risk factors; atherosclerosis; cardiovascular disease.
12.  Prevalence of microalbuminuria, arterial hypertension, retinopathy, and neuropathy in patients with insulin dependent diabetes 
Diabetic nephropathy is the main cause of the increased morbidity and mortality in patients with insulin dependent diabetes. The prevalence of microalbuminuria was determined in adults with insulin dependent diabetes of five or more years' duration that had started before the age of 41. All eligible patients (n=982) attending a diabetes clinic were asked to collect a 24 hour urine sample for analysis of albumin excretion by radio-immunoassay; 957 patients complied. Normoalbuminuria was defined as urinary albumin excretion of ≤30 mg/24 h (n=562), microalbuminuria as 31-299 mg/24 h (n=215), and macroalbuminuria as ≥300 mg/24 h (n=180). The prevalence of microalbuminuria and macroalbuminuria was significantly higher in patients whose diabetes had developed before rather than after the age of 20. The prevalence of arterial hypertension increased with increased albuminuria, being 19%, 30%, and 65% in patients with normoalbuminuria, microalbuminuria, and macroalbuminuria respectively. The prevalence of proliferative retinopathy and blindness rose with increasing albuminuria, being 12% and 1·4%, respectively, in patients with normoalbuminuria, 28% and 5·6% in those with microalbuminuria and 58% and 10·6% in those with macroalbuminuria. An abnormal vibratory perception threshold was more common in patients with microalbuminuria (31%) and macroalbuminuria (50%) than in those with normoalbuminuria (21%).
This study found a high prevalence (22%) of microalbuminuria, which is predictive of the later development of diabetic nephropathy. Microalbuminuria is also characterised by an increased prevalence of arterial hypertension, proliferative retinopathy, blindness, and peripheral neuropathy. Thus, urinary excretion of albumin should be monitored routinely in patients with insulin dependent diabetes.
PMCID: PMC2544895  PMID: 3122980
13.  Does HIV infection promote early kidney injury in women? 
Antiviral therapy  2013;19(1):79-87.
In HIV-infected women, urine concentrations of novel tubulointerstitial injury markers, interleukin-18 (IL-18) and kidney injury marker-1 (KIM-1) are associated with kidney function decline and all-cause mortality. We hypothesized that HIV-infected individuals with preserved kidney filtration function would have more extensive kidney injury, as determined by urine injury markers, compared to the uninfected controls, and that risk factors for tubulointerstitial injury would differ from risk factors for albuminuria.
In this cross-sectional study, we compared urine concentrations of IL-18, KIM-1, and ACR in 908 HIV-infected and 289 HIV-uninfected women enrolled in the Women’s Interagency HIV Study, utilizing stored urine specimens from visits between 1999 and 2000.
After multivariate-adjusted linear regression analysis, mean urine concentrations were higher in HIV-infected individuals by 38% for IL-18 (p<0.0001), 12% for KIM-1 (p=0.081), and 47% for ACR (p<0.0001). Higher HIV RNA level (15% per 10-fold increase, p<0.0001), lower CD4 count (8% per doubling, p=0.0025), HCV infection (30%, p=0.00018), and lower HDL (5% per 10 mg/dL, p=0.0024) were each associated with higher IL-18 concentrations. In contrast, hypertension (81%, p<0.0001) and diabetes (47%, p=0.018) were among the strongest predictors of higher ACR, though HIV RNA level (15% per 10-fold increase, p=0.0004) was also associated with higher ACR.
HIV-infected women had more extensive tubulointerstitial and glomerular injury than uninfected women, but the associated factors differed among the urine biomarkers. Combinations of urinary biomarkers should be investigated to further characterize early kidney injury in HIV-infected women.
PMCID: PMC3933452  PMID: 23970313
14.  Renal Dysfunction among HIV-Infected Patients Starting Antiretroviral Therapy in Mwanza, Tanzania 
AIDS (London, England)  2011;25(11):1421-1425.
HIV-related renal dysfunction is associated with high mortality. Data on the prevalence of renal dysfunction among HIV-infected outpatients starting antiretroviral therapy (ART) in sub-Saharan Africa is limited. Recent recommendations to include the nephrotoxic drug tenofovir in first-line ART regimens make clarification of this issue urgent.
We screened for renal dysfunction by measuring serum creatinine, proteinuria, and microalbuminuria in HIV-positive outpatients initiating ART in Mwanza, Tanzania. We excluded patients with preexisting renal disease, hypertension, diabetes, or Hepatitis C virus co-infection. Estimated glomerular filtration rates (eGFRs) were calculated by Cockroft-Gault and Modification of Diet in Renal Disease (MDRD) equations.
Only 129 (36%) of 355 enrolled patients had normal eGFRs (Grade 0 or 1) above 90 ml/min/1.73m2. Grade 2 renal dysfunction (eGFR between 60 and 89 ml/min/1.73m2) was present in 137 patients (38.6%), and 87 patients (25%) had Grade 3 dysfunction (eGFR between 30 and 59 ml/min/1.73m2). Microalbuminuria and proteinuria were detected in 72% and 36% of patients, respectively. Factors predictive of renal dysfunction in multivariate analysis included female gender (OR 3.0, 95% confidence interval (CI) [1.8–5.1], p<0.0001), Body Mass Index (BMI) <18.5 (OR 2.3 [1.3–4.1], p=0.004), CD4+ T-cell count <200 cells/mm3 (OR 2.3 [1.1–4.8], p=0.04), and World Health Organization (WHO) clinical stage II or above (OR 1.6 [1.2–2.3], p=0.001).
Renal dysfunction was highly prevalent in this population of HIV-positive outpatients initiating first ART in Tanzania. This highlights the critical and underappreciated need to monitor renal function in HIV-positive patients in sub-Saharan Africa, particularly given the increasing use of tenofovir in first-line ART.
PMCID: PMC3631352  PMID: 21572304
renal dysfunction; HIV; antiretroviral therapy; sub-Saharan Africa
To compare association of microalbuminuria with outcomes in patients with different comorbidities.
The risk of adverse outcomes associated with proteinuria has been found to be linearly decreasing with even low-normal levels of microalbuminuria. It is unclear if comorbid conditions change these associations.
We examined the association of urine microalbumin-creatinine ratio (UACR) with mortality and the slopes of estimated glomerular filtration rate (eGFR) in a nationally representative cohort of 298,875 US veterans. Associations of UACR with all-cause mortality overall and in subgroups of patients with and without diabetes, hypertension, cardiovascular disease, congestive heart failure and advanced CKD were examined in Cox models, and with the slopes of eGFR in linear and logistic regression models.
Very low levels of UACR were linearly associated with decreased mortality and less progression of CKD overall: adjusted mortality hazard ratio and estimated glomerular filtration rate slope (95%CI) associated with UACR ≥200, compared to <5 mcg/mg were 1.53 (1.38–1.69, p<0.001) and −1.59 (−1.83, −1.35, p<0.001). Similar linearity was present in all examined subgroups, except in patients with CKD in whom a U-shaped association was present and in whom a UACR of 10–19 was associated with the best outcomes.
The association of UACR with mortality and with progressive CKD is modified in patients with CKD, who experience higher mortality and worse progression of CKD with the lowest levels of UACR. Proteinuria-lowering interventions in patients with advanced CKD should be implemented cautiously, considering the potential for adverse outcomes.
PMCID: PMC3625505  PMID: 23500283
microalbuminuria; chronic kidney disease; mortality
16.  Microalbuminuria, is it so important? 
Hippokratia  2007;11(3):105-107.
Microalbuminuria (defined as urinary albumin excretion of 30-300 mg/day, or 20-200 µg/min) is an earlier sign of vascular damage. It is a marker of general vascular dysfunction and nowadays is considered a predictor of worse outcomes for both kidney and heart patients. There is a significant correlation between blood pressure and microalbuminuria. Even high normal blood pressure is associated with significant higher frequency of microalbuminuria and this way may be a biomarker of increased cardiovascular risk. Microalbuminuria could be taken also, as an indicator of insulin resistance and of the increased renal and cardiovascular risk associated with metabolic syndrome. Renal involvement is a pivotal development in diabetes and microalbuminuria is generally the first clinical sign of renal dysfunction in diabetics. It is demonstrated that cardiovascular and renal risk is elevated even in the high normal range of microalbuminuria (below 30 mg/day). There is no doubt that therapies that prevent or delay the development of microalbuminuria and all measures that reduce it, may help to prevent or delay end organ damage.
PMCID: PMC2658722  PMID: 19582202
microalbuminuria; cardiovascular risk; high blood pressure; diabetic nephropathy
17.  The Impact of HAART on the Respiratory Complications of HIV Infection: Longitudinal Trends in the MACS and WIHS Cohorts 
PLoS ONE  2013;8(3):e58812.
To review the incidence of respiratory conditions and their effect on mortality in HIV-infected and uninfected individuals prior to and during the era of highly active antiretroviral therapy (HAART).
Two large observational cohorts of HIV-infected and HIV-uninfected men (Multicenter AIDS Cohort Study [MACS]) and women (Women’s Interagency HIV Study [WIHS]), followed since 1984 and 1994, respectively.
Adjusted odds or hazards ratios for incident respiratory infections or non-infectious respiratory diagnoses, respectively, in HIV-infected compared to HIV-uninfected individuals in both the pre-HAART (MACS only) and HAART eras; and adjusted Cox proportional hazard ratios for mortality in HIV-infected persons with lung disease during the HAART era.
Compared to HIV-uninfected participants, HIV-infected individuals had more incident respiratory infections both pre-HAART (MACS, odds ratio [adjusted-OR], 2.4; 95% confidence interval [CI], 2.2–2.7; p<0.001) and after HAART availability (MACS, adjusted-OR, 1.5; 95%CI 1.3–1.7; p<0.001; WIHS adjusted-OR, 2.2; 95%CI 1.8–2.7; p<0.001). Chronic obstructive pulmonary disease was more common in MACS HIV-infected vs. HIV-uninfected participants pre-HAART (hazard ratio [adjusted-HR] 2.9; 95%CI, 1.02–8.4; p = 0.046). After HAART availability, non-infectious lung diseases were not significantly more common in HIV-infected participants in either MACS or WIHS participants. HIV-infected participants in the HAART era with respiratory infections had an increased risk of death compared to those without infections (MACS adjusted-HR, 1.5; 95%CI, 1.3–1.7; p<0.001; WIHS adjusted-HR, 1.9; 95%CI, 1.5–2.4; p<0.001).
HIV infection remained a significant risk for infectious respiratory diseases after the introduction of HAART, and infectious respiratory diseases were associated with an increased risk of mortality.
PMCID: PMC3595204  PMID: 23554932
18.  The Impact of Kidney Function at HAART Initiation on Mortality in HIV-infected Women 
In the early highly active antiretroviral therapy (HAART) era, kidney dysfunction was strongly associated with death among HIV-infected individuals. We re-examined this association in the later HAART period to determine whether chronic kidney disease (CKD) remains a predictor of death after HAART-initiation.
To evaluate the effect of kidney function at the time of HAART initiation on time to all-cause mortality, we evaluated 1415 HIV-infected women initiating HAART in the Women’s Interagency HIV Study (WIHS). Multivariable proportional hazards models with survival times calculated from HAART initiation to death were constructed; participants were censored at the time of the last available visit or December 31, 2006.
CKD (eGFR <60 ml/min/1.73 m2) at HAART initiation was associated with higher mortality risk adjusting for age, race, hepatitis C serostatus, AIDS history and CD4+ cell count (hazard ratio [HR]=2.23, 95% confidence interval [CI]: 1.45–3.43). Adjustment for hypertension and diabetes history attenuated this association (HR=1.89, CI: 0.94–3.80). Lower kidney function at HAART initiation was weakly associated with increased mortality risk in women with prior AIDS (HR=1.09, CI: 1.00–1.19, per 20% decrease in eGFR).
Kidney function at HAART initiation remains an independent predictor of death in HIV-infected individuals, especially in those with a history of AIDS. Our study emphasizes the necessity of monitoring kidney function in this population. Additional studies are needed to determine mechanisms underlying the increased mortality risk associated with CKD in HIV-infected persons.
PMCID: PMC3243740  PMID: 20581688
kidney disease; mortality; HIV; WIHS; antiretroviral therapy
19.  Host APOL1 genotype is independently associated with proteinuria in HIV infection 
Kidney international  2013;84(4):834-840.
Proteinuria is associated with adverse clinical outcomes in HIV infection. Here we evaluated whether APOL1 risk alleles, previously associated with advanced kidney disease, is independently associated with proteinuria in HIV infection in a cross-sectional study of HIV-infected women in the Women’s Interagency HIV Study. We estimated the percent difference in urine protein excretion and odds of proteinuria (200 mg/g and higher) associated with two versus one or no APOL1 risk allele using linear and logistic regression, respectively. Of 1285 women successfully genotyped, 379 carried one and 80 carried two risk alleles. Proteinuria was present in 124 women; 78 of whom had proteinuria confirmed on a second sample. In women without prior AIDS, two risk alleles were independently associated with a 69% higher urine protein excretion (95% CI: 36%, 108%) and 5-fold higher odds of proteinuria (95% CI: 2.45, 10.37) versus one or no risk allele. No association was found in women with prior AIDS. Analyses in which women with impaired kidney function were excluded and proteinuria was confirmed by a second urine sample yielded similar estimates. Thus, APOL1 risk alleles are associated with significant proteinuria in HIV-infected persons without prior clinical AIDS, independent of clinical factors traditionally associated with proteinuria. Trials are needed to determine whether APOL1 genotyping identifies individuals who could benefit from earlier intervention to prevent overt renal disease.
PMCID: PMC3788838  PMID: 23715117
20.  Prevalence of and Factors Associated with Albuminuria in the Korean Adult Population: The 2011 Korea National Health and Nutrition Examination Survey 
PLoS ONE  2013;8(12):e83273.
Microalbuminuria is associated with increased risk of renal disease and cardiovascular diseases even in non-diabetic subjects. High incidence rates of microalbuminuria have been found in a number of population-based studies. However, the prevalence and risk factors associated with microalbuminuria in the general population in Korea are unclear.
The present study was performed to estimate the prevalence of microalbuminuria and investigate the associated risk factors in the general adult population using the Fifth Korea National Health and Nutrition Examination Survey (KNHANES V-2) data from 2011.
A total of 5,202 participants (mean age, 45.6 years; men, 2,337; women, 2,865) were included in the analysis. Microalbuminuria was evaluated in participants of KNHANES V-2 based on the urine albumin–creatinine ratio. Estimated glomerular filtration rate was calculated using the Modification of Diet in Renal Disease study equation.
The weighted prevalence of microalbuminuria was 5.2% (95% CI, 4.4–6.1) in the general population. The prevalence of albuminuria is increased with age. After adjustment for age and sex, the presence of albuminuria was associated with increased waist circumference, systolic and diastolic blood pressure, aspartate aminotransferase, triglyceride, fasting plasma glucose, and the presence of hypertension and diabetes. In logistic regression analyses, older age, female sex, diabetes, hypertension, and serum aspartate aminotransferase were independently associated with the presence of albuminuria.
The prevalence of microalbuminuria was found to be 5.2%, and conventional risk factors for cardiovascular diseases are closely related to the presence of microalbuminuria in Korea. Microalbuminuria may be a useful marker to identify individuals with increased risk of cardiovascular disease.
PMCID: PMC3873941  PMID: 24386169
21.  Diabetic nephropathy: Is it time yet for routine kidney biopsy? 
World Journal of Diabetes  2013;4(6):245-255.
Diabetic nephropathy (DN) is one of the most important long-term complications of diabetes. Patients with diabetes and chronic kidney disease have an increased risk of all-cause mortality, cardiovascular mortality, and kidney failure. The clinical diagnosis of DN depends on the detection of microalbuminuria. This usually occurs after the first five years from the onset of diabetes, and predictors of DN development and progression are being studied but are not yet implemented into clinical practice. Diagnostic tests are useful tools to recognize onset, progression and response to therapeutic interventions. Microalbuminuria is an indicator of DN, and it is considered the only noninvasive marker of early onset. However, up to now there is no diagnostic tool that can predict which patients will develop DN before any damage is present. Pathological renal injury is hard to predict only with clinical and laboratory findings. An accurate estimate of damage in DN can only be achieved by the histological analysis of tissue samples. At the present time, renal biopsy is indicated on patients with diabetes under the suspicion of the presence of nephropathies other than DN. Results from renal biopsies in patients with diabetes had made possible the classification of renal biopsies in three major groups associated with different prognostic features: diabetic nephropathy, non-diabetic renal disease (NDRD), and a superimposed non-diabetic condition on underlying diabetic nephropathy. In patients with type 2 diabetes with a higher degree of suspicion for NDRD, it is granted the need of a renal biopsy. It is important to identify and differentiate these pathologies at an early stage in order to prevent progression and potential complications. Therefore, a more extensive use of biopsy is advisable.
PMCID: PMC3874483  PMID: 24379914
Diabetic nephropathy; Kidney biopsy; Non-diabetic renal disease
22.  Assessing mortality in women with hepatitis C virus and HIV using indirect markers of fibrosis 
AIDS (London, England)  2012;26(5):599-607.
Co-infection with hepatitis C virus (HCV) is a major cause of morbidity and mortality in HIV-infected individuals. However, predictors of mortality are poorly defined and most studies have focused predominantly on co-infection in men. We evaluated whether two indirect markers of hepatic fibrosis, aspartate aminotransferase-to-platelet ratio index (APRI) and FIB-4 scores, were predictive of mortality in a well defined longitudinal cohort of HCV/HIV-co-infected women on HAART.
HCV/HIV-co-infected women on antiretroviral therapy enrolled in Women’s Interagency HIV Study (WIHS), a National Institutes of Health-funded prospective, multicenter, cohort study of women with and at risk for HIV infection were included. Using Cox regression analysis, associations between APRI and FIB-4 with all-cause mortality were assessed.
Four hundred and fifty HCV/HIV-co-infected women, of whom 191 women died, had a median follow-up of 6.6 years and 5739 WIHS visits. Compared with women with low APRI or FIB-4 levels, severe fibrosis was significantly associated with an increased risk of all-cause mortality {APRI: hazard ratio 2.78 [95% confidence interval (CI) 1.87, 4.12]; FIB-4: hazard ratio 2.58 (95% CI 1.68, 3.95)}. Crude death rates per 1000 patient-years increased with increasing liver fibrosis: 34.8 for mild, 51.3 for moderate and 167.9 for severe fibrosis as measured by FIB-4. Importantly, both APRI and FIB-4 increased during the 5 years prior to death for all women: the slope of increase was greater for women dying a liver-related death compared with nonliver-related death.
Both APRI and FIB-4 are independently associated with all-cause mortality in HCV/HIV-co-infected women and may have clinical prognostic utility among women with HIV and HCV.
PMCID: PMC3698040  PMID: 22156972
fibrosis markers; hepatitis C virus; HIV; longitudinal study; mortality
23.  Correlation between Microalbuminuria and Hypertension in Type 2 Diabetic Patients 
Background: Hypertension is commonly found in patients with Diabetic Kidney Disease (DKD). Microalbuminuria is the first clinical sign of involvement of kidneys in patients with type 2 diabetes. Uncontrolled hypertension induces a higher risk of cardiovascular events, including death, increasing proteinuria and progression to kidney disease.
Objectives: To determine the correlation between microalbuminuria and hypertension and their association with other risk factors in type 2 diabetic patients.
Methods: One hundred and thirteen type 2 diabetic patients attending the diabetic clinic of Shaikh Zayed Postgraduate Medical Institute, Lahore, Pakistan were screened for microalbuminuria and raised blood pressure. The study was conducted from November 2012 to June 2013.
Results: Patients were divided into two groups. Group 1, those with normoalbuminuria (n=63) and Group 2, those having microalbuminuria (n=50). Group 2 patients showed higher blood pressure values as compared to Group 1. The results were statistically significant and showed poor glycemic control as a contributing risk factor.
Conclusion: The study concluded that there is high frequency of hypertension among type 2 diabetics but still much higher among those having microalbuminuria. So, early recognition of renal dysfunction through detection of microalbuminuria and to start treatment without any delay will confer future protection from end stage renal disease as well as hypertension and its complications in type 2 diabetic patients.
PMCID: PMC4048496  PMID: 24948969
Diabetic kidney disease; Hypertension; Microalbuminuria; Type 2 Diabetes Mellitus
24.  Factors Associated with Preclinical Disability and Frailty among HIV-Infected and HIV-Uninfected Women in the Era of cART 
Journal of Women's Health  2009;18(12):1965-1974.
HIV-associated immune injury is hypothesized to increase the risk of preclinical disability and frailty via inflammatory pathways. We investigated the role of CD4+ T cell depletion and clinical AIDS on preclinical disability and frailty in HIV-positive women with a history of combination antiretroviral therapy (cART) and HIV-negative women.
This was a cross-sectional study nested within the Women's Interagency HIV Study (WIHS), a prospective cohort study initiated in 1994 across five U.S. cities. Questionnaires and tests were performed by 573 HIV-negative and 1206 HIV-positive women. Prevalence ratios were computed using regression models.
Severe CD4+ cell depletion was an independent predictor of slowness, weakness, and frailty in HIV-positive women compared with HIV-negative women. Women with CD4+ counts <100 cells/mm3 were 0.13 seconds slower to complete 4 meters (95% CI 0.06-0.21), 1.25 kg weaker (95% CI −2.31-−0.19), and had 2.7 times higher prevalence of frailty (95% CI 1.46-5.01).
This study is one of the largest studies to administer performance-based tests to investigate disability and frailty in HIV-positive women. HIV-positive women with intact immune systems and without a history of clinical AIDS were no different from HIV-negative women on tests of slowness, weakness, and frailty phenotype.
PMCID: PMC2828186  PMID: 20044858
25.  Associations among systemic blood pressure, microalbuminuria and albuminuria in dogs affected with pituitary- and adrenal-dependent hyperadrenocorticism 
Hypertension and proteinuria are medical complications associated with the multisystemic effects of long-term hypercortisolism in dogs with hyperadrenocorticism (HAC).
This study investigated the relationships among adrenocorticotropic hormone (ACTH)-stimulation test results, systemic blood pressure, and microalbuminuria in clinically-healthy dogs (n = 100), in dogs affected with naturally occurring pituitary-dependent (PDH; n = 40), or adrenal-dependent hyperadrenocorticism (ADH; n = 30).
Mean systemic blood pressure was similar between clinically healthy dogs and dogs with HAC (p = 0.803). However the incidence of hypertension was highest in dogs with ADH (p = 0.017), followed by dogs with PDH, with the lowest levels in clinically healthy dogs (p = 0.019). Presence of microalbuminuria and albuminuria in clinically healthy dogs and dogs affected with HAC was significantly different (p < 0.001); incidences of albuminuria followed the same pattern of hypertension; highest incidence in dogs with ADH, and lowest level in clinically healthy dogs; but microalbuminuria showed a different pattern: clinically healthy dogs had highest incidences and dogs with ADH had lowest incidence. The presence of albuminuria was not associated with blood pressure values, regardless of whether dogs were clinically healthy or affected with ADH or PDH (p = 0.306).
Higher incidence of hypertension and albuminuria, not microalbuminuria was seen in dogs affected with HAC compared to clinically healthy dogs; incidence of hypertension and albuminuria was significantly higher in dogs affected with ADH compared to PDH. However, presence of albuminuria was not correlated with systemic blood pressure.
PMCID: PMC2994942  PMID: 21070672

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