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1.  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.
doi:10.1038/ki.2013.203
PMCID: PMC3788838  PMID: 23715117
2.  Acute Kidney Injury in HIV- Infected Patients 
Seminars in nephrology  2008;28(6):556-562.
Acute kidney injury is common in HIV-infected patients, and has been associated with increased morbidity and mortality. Prior to the introduction of effective antiretroviral therapy, acute kidney injury in HIV-positive patients was most commonly the result of volume depletion, septicemia, or nephrotoxic medications. Acute kidney injury remains a significant problem in the antiretroviral era, and is still commonly attributed to infection or nephrotoxic medications. Less common causes such as direct infectious insults, immune restoration inflammatory syndrome, rhabdomyolysis, and obstruction should be considered when the underlying process is not obvious. In addition to advanced HIV disease, several other patient characteristics have emerged as potential risk factors for acute kidney injury in the antiretroviral era, including older age, diabetes, pre-existing chronic kidney disease, and hepatitis co-infection or liver disease.
doi:10.1016/j.semnephrol.2008.08.008
PMCID: PMC2676161  PMID: 19013326
Acute kidney injury; acute tubular necrosis; HIV
3.  HIV-Associated Nephropathy: Clinical Presentation, Pathology, and Epidemiology in the Era of Antiretroviral Therapy 
Seminars in nephrology  2008;28(6):513-522.
The classic kidney disease of Human Immunodeficiency Virus (HIV) infection, HIV-associated nephropathy, is characterized by progressive acute renal failure, often accompanied by proteinuria and ultrasound findings of enlarged, echogenic kidneys. Definitive diagnosis requires kidney biopsy, which demonstrates collapsing focal segmental glomerulosclerosis with associated microcystic tubular dilatation and interstitial inflammation. Podocyte proliferation is a hallmark of HIV-associated nephropathy, although this classic pathology is observed less frequently in antiretroviral-treated patients. The pathogenesis of HIV-associated nephropathy involves direct HIV infection of renal epithelial cells, and the widespread introduction of combination antiretroviral therapy has had a significant impact on the natural history and epidemiology of this unique disease. These observations have established antiretroviral therapy as the cornerstone of treatment for HIV-associated nephropathy, in the absence of prospective clinical trials. Adjunctive therapy for HIV-associated nephropathy includes ACE inhibitors or angiotensin receptor blockers, as well as corticosteroids in selected patients with significant interstitial inflammation or rapid progression.
doi:10.1016/j.semnephrol.2008.08.005
PMCID: PMC2656916  PMID: 19013322
HIV-associated nephropathy; focal segmental glomerulosclerosis; HIV; kidney
4.  PRE-EXISTING ALBUMINURIA PREDICTS AIDS AND NON-AIDS MORTALITY IN WOMEN INITIATING ANTIRETROVIRAL THERAPY 
Antiviral therapy  2011;16(4):591-596.
Background
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).
Methods
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.
Results
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).
Conclusions
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.
doi:10.3851/IMP1766
PMCID: PMC3119869  PMID: 21685547
HIV; microalbuminuria; proteinuria; mortality; non-AIDS death
5.  MICROALBUMINURIA IS ASSOCIATED WITH ALL-CAUSE AND AIDS MORTALITY IN WOMEN WITH HIV INFECTION 
Prevalence of microalbuminuria is increased in patients with HIV. Microalbuminuria is associated with increased mortality in other populations, including diabetics, for whom microalbuminuria testing is standard of care. We investigated whether microalbuminuria is associated with mortality in HIV-infected women not receiving antiretroviral therapy.
Methods
Urinalysis for proteinuria and semi-quantitative testing for microalbuminuria were performed in specimens from two consecutive visits in 1,547 HIV-infected women enrolled in the Women’s Interagency HIV Study in 1994–1995. Time to death was modeled using proportional hazards analysis.
Results
Compared to women without albuminuria, the hazard ratio (HR) for all-cause mortality was increased in women with one (HR 3.4; 95% CI 2.2–5.2) or two specimens positive for either proteinuria or microalbuminuria (HR 3.9; 95% CI 2.1–7.0). The highest risk was observed in women with both specimens positive for proteinuria (HR 5.8; 95% CI 3.4–9.8). The association between albuminuria and all-cause mortality risk remained significant after adjustment for demographics, HIV disease severity, and related comorbidities. Similar results were obtained for AIDS death.
Conclusions
We identified a graded relationship between albuminuria and the risk of all-cause and AIDS mortality.
doi:10.1097/QAI.0b013e3181cc1070
PMCID: PMC2888617  PMID: 20098331
HIV; microalbuminuria; proteinuria; mortality
6.  Short Communication: Inadequate Vitamin D Exacerbates Parathyroid Hormone Elevations in Tenofovir Users 
Abstract
Parathyroid hormone (PTH) elevations are associated with reduced bone mineral density and adverse health outcomes and have been reported in patients with HIV infection. We aimed to examine the impact of vitamin D status and tenofovir (TDF) use on PTH levels among HIV-infected patients receiving combination antiretroviral therapy (cART). Demographics, medication and supplement use, and clinical data, including 25-hydroxyvitamin D [25(OH)D] and PTH, were collected on 45 HIV-infected men on ART. Suboptimal vitamin D status was defined as 25(OH)D < 30 ng/ml. The relationship between antiretroviral agents, suboptimal 25(OH)D, and PTH levels was examined. Among subjects with suboptimal vitamin D status, PTH values greater than or equal to the ULN (87 pg/ml) were more common among TDF users than nonusers: 41% versus 0% (p = 0.018); and median PTH was higher in TDF users: 80 pg/ml versus 55 pg/ml (p = 0.02). Among TDF users, PTH was higher in the group with suboptimal 25(OH)D (p = 0.045). Multivariable linear regression showed that PTH was independently and directly related to TDF use (p = 0.017) and inversely related to 25(OH)D (p = 0.017). PTH was not related to the estimated glomerular filtration rate (p = 0.9). In this cross-sectional study of HIV-infected men on ART, the use of TDF and the level of 25(OH)D were independently associated with PTH levels. Because TDF is a potent and widely used antiretroviral drug, information about cofactors that may exacerbate its side effects is of significant clinical value.
doi:10.1089/aid.2009.0308
PMCID: PMC2957627  PMID: 20672993
7.  Prevalence of Kidney Disease in HIV-Infected and Uninfected Rwandan Women 
PLoS ONE  2011;6(3):e18352.
Background
In the United States, HIV-related kidney disease disproportionately affects individuals of African descent; however, there are few estimates of kidney disease prevalence in Africa. We evaluated the prevalence of kidney disease among HIV-infected and uninfected Rwandan women.
Methods
The Rwandan Women's Interassociation Study and Assessment prospectively enrolled 936 women. Associations with estimated glomerular filtration rate (eGFR)<60 mL/min/1.73 m2 and proteinuria were assessed in separate logistic regression models.
Results
Among 891 non-pregnant women with available data, 2.4% had an eGFR<60 mL/min/1.73 m2 (calculated by the Modification of Diet in Renal Disease equation, MDRD eGFR) and 8.7% had proteinuria ≥1+. The prevalence of decreased eGFR varied markedly depending on the estimating method used, with the highest prevalence by Cockcroft-Gault. Regardless of the method used to estimate GFR, the proportion with decreased eGFR or proteinuria did not differ significantly between HIV-infected and -uninfected women in unadjusted analysis. After adjusting for age and blood pressure, HIV infection was associated with significantly higher odds of decreased MDRD eGFR but not proteinuria.
Conclusion
In a well-characterized cohort of Rwandan women, HIV infection was associated with decreased MDRD eGFR. The prevalence of decreased eGFR among HIV-infected women in our study was lower than that previously reported in African-Americans and in other Central and East African HIV populations, although there was substantial variability depending on the equation used to estimate GFR. Future studies are needed to optimize GFR estimates and to determine the impact of antiretroviral therapy on kidney disease in this population.
doi:10.1371/journal.pone.0018352
PMCID: PMC3065469  PMID: 21464937
8.  Hepatitis C and the Risk of Kidney Disease and Mortality in Veterans With HIV 
Objectives
To examine the effect of hepatitis C virus (HCV) on the prevalence of chronic kidney disease (CKD) among veterans with HIV and to evaluate independent associations of HCV and CKD with mortality.
Methods
We studied a national cohort of HIV-infected patients receiving care through the Veterans Healthcare Administration from 1998 to 2004. CKD was defined as an estimated glomerular filtration rate [eGFR (mL/min/1.73 m2)] < 60. Poisson regression was used to assess relationships between CKD, HCV, and mortality.
Results
Among 23,155 HIV-infected veterans, 12% had CKD. Forty percent of the cohort was coinfected with HCV, and a higher proportion of coinfected subjects had CKD compared with monoinfected subjects (14% vs 11%, P < 0.001). During the median follow-up of 7.6 years, 37% of subjects died and a graduated increase in adjusted mortality rates occurred with lower levels of eGFR (P < 0.001). Adjusted mortality rates were consistently higher in HCV-coinfected subjects across all levels of eGFR (P < 0.001). HCV was independently associated with increased mortality (incidence rate ratio 1.23, 95% confidence interval 1.17–1.29).
Conclusions
CKD is prevalent in HIV-infected veterans and associated with substantially higher mortality. Compared with their monoinfected counterparts, veterans coinfected with HCV have significantly higher rates of CKD and mortality.
doi:10.1097/QAI.0b013e3181b980d4
PMCID: PMC3032564  PMID: 20104121
death; HIV; hepatitis C; kidney failure; veterans
9.  Kidney Disease in HIV Infection: Introduction 
Seminars in nephrology  2008;28(6):511-512.
doi:10.1016/j.semnephrol.2008.08.004
PMCID: PMC2640835  PMID: 19013321
10.  The Impact of Hepatitis C Virus Co-infection on HIV-Related Kidney Disease: A Systematic Review and Meta-analysis 
AIDS (London, England)  2008;22(14):1799-1807.
In the era of antiretroviral therapy, non-AIDS complications such as kidney disease are important contributors to morbidity and mortality.
Objective
To estimate the impact of hepatitis C co-infection on the risk of kidney disease in HIV patients.
Design/ Methods
Two investigators identified English-language citations in MEDLINE and Web of Science from 1989 through July 1, 2007. References of selected articles were reviewed. Observational studies and clinical trials of HIV-related kidney disease and antiretroviral nephrotoxicity were eligible if they included at least 50 participants and reported hepatitis C status. Data on study characteristics, population, and kidney disease outcomes were abstracted by two independent reviewers.
Results
After screening 2,516 articles, twenty-seven studies were eligible and 24 authors confirmed or provided data. Separate meta-analyses were performed for chronic kidney disease outcomes (n=10), proteinuria (n=4), acute renal failure (n=2), and indinavir toxicity (n=5). The pooled incidence of chronic kidney disease was higher in patients with hepatitis C co-infection (6.2% versus 4.0%; RR 1.49, 95% CI 1.08–2.06). In meta-regression, prevalence of black race and the proportion of patients with documented hepatitis C status were independently associated with the risk of chronic kidney disease. The relative risk associated with hepatitis C co-infection was significantly increased for proteinuria (1.15; 95% CI 1.02–1.30) and acute renal failure (1.64; 95% CI 1.21–2.23), with no significant statistical heterogeneity. The relative risk of indinavir toxicity was 1.59 (95% CI 0.99–2.54) with Hepatitis C co-infection.
Conclusions
Hepatitis C co-infection is associated with a significant increase in the risk of HIV-related kidney disease.
doi:10.1097/QAD.0b013e32830e0152
PMCID: PMC2733170  PMID: 18753863
11.  The spectrum of kidney disease in patients with AIDS in the era of antiretroviral therapy 
Kidney international  2008;75(4):428-434.
With prolonged survival and aging of the HIV-infected population in the era of antiretroviral therapy, biopsy series have found a broad spectrum of HIV-related and co-morbid kidney disease in these patients. Our study describes the variety of renal pathology found in a prospective cohort of antiretroviral-experienced patients (the Manhattan HIV Brain Bank) who had consented to postmortem organ donation. Nearly one-third of 89 kidney tissue donors had chronic kidney disease, and evidence of some renal pathology was found in 75. The most common diagnoses were arterionephrosclerosis, HIV-associated nephropathy and glomerulonephritis. Other diagnoses included pyelonephritis, interstitial nephritis, diabetic nephropathy, fungal infection and amyloidosis. Excluding 2 instances of acute tubular necrosis, slightly over one-third of the cases would have been predicted using current diagnostic criteria for chronic kidney disease. Based on semi-quantitative analysis of stored specimens, pre-mortem microalbuminuria testing could have identified an additional 12 cases. Future studies are needed to evaluate the cost-effectiveness of more sensitive methods for defining chronic kidney disease, in order to identify HIV-infected patients with early kidney disease who may benefit from antiretroviral therapy and other interventions known to delay disease progression and prevent complications.
doi:10.1038/ki.2008.604
PMCID: PMC2704860  PMID: 19052538
AIDS; histopathology; HIV-associated nephropathy; kidney disease
12.  Fanconi Syndrome Accompanied by Renal Function Decline with Tenofovir Disoproxil Fumarate: A Prospective, Case-Control Study of Predictors and Resolution in HIV-Infected Patients 
PLoS ONE  2014;9(3):e92717.
Objective
The predictors of Fanconi syndrome (FS) accompanied by renal function decline with use of the antiretroviral tenofovir disoproxil fumarate (TDF) have not been assessed. In addition, the natural history of renal recovery from FS after TDF discontinuation is not well-described.
Design
We prospectively enrolled HIV-infected patients receiving TDF with newly identified FS (defined as at least two markers of proximal tubulopathy and either a >25% decline in creatinine clearance (CrCl) from pre-TDF values or a CrCl <60 mL/min in those without a known pre-TDF CrCl) in a multicenter observational study. These case participants were matched 1∶2 to controls; characteristics between the two groups were compared. Case participants with known pre-TDF CrCl values were then followed over 48 weeks to assess renal recovery.
Results
Nineteen cases and 37 controls were enrolled. In multivariable analysis, previous or concurrent use of lopinavir/ritonavir [OR 16.37, 95% CI (2.28, 117.68); P = 0.006] and reduced creatinine clearance prior to initiation of TDF [OR 1.44 for every 5 mL/min reduction, 95% CI (1.09, 1.92); P = 0.012; OR 19.77 for pre-TDF CrCl lower than 83 mL/min, 95% CI (2.24, 174.67); P = 0.007] were significantly associated with FS. Of the 14 cases followed for resolution, 7 (50%) achieved at least partial resolution (defined as recovering CrCl >70% of pre-TDF values) although most participants had full normalization of proximal tubulopathy markers within two months of TDF discontinuation.
Conclusions
FS, defined by specific CrCl decreases and markers of tubulopathy, is more likely in those who have received or are currently receiving concomitant lopinavir/ritonavir or who had lower CrCl prior to TDF initiation. Half of those with protocol-defined FS had CrCl recover to near pre-TDF values during the first year after TDF discontinuation.
doi:10.1371/journal.pone.0092717
PMCID: PMC3961428  PMID: 24651857
13.  Estimating Kidney Function in HIV-Infected Adults in Kenya: Comparison to a Direct Measure of Glomerular Filtration Rate by Iohexol Clearance 
PLoS ONE  2013;8(8):e69601.
Background
More than two-thirds of the world's HIV-positive individuals live in sub-Saharan Africa, where genetic susceptibility to kidney disease is high and resources for kidney disease screening and antiretroviral therapy (ART) toxicity monitoring are limited. Equations to estimate glomerular filtration rate (GFR) from serum creatinine were derived in Western populations and may be less accurate in this population.
Methods
We compared results from published GFR estimating equations with a direct measure of GFR by iohexol clearance in 99 HIV-infected, ART-naïve Kenyan adults. Iohexol concentration was measured from dried blood spots on filter paper. The bias ratio (mean of the ratio of estimated to measured GFR) and accuracy (percentage of estimates within 30% of the measured GFR) were calculated.
Results
The median age was 35 years, and 60% were women. The majority had asymptomatic HIV, with median CD4+ cell count of 355 cells/mm3. Median measured GFR was 115 mL/min/1.73 m2. Overall accuracy was highest for the Chronic Kidney Disease Epidemiology Consortium (CKD-EPI) equation. Consistent with a prior report, bias and accuracy were improved by eliminating the coefficient for black race (85% of estimates within 30% of measured GFR). Accuracy of all equations was poor in participants with GFR 60–90 mL/min/1.73 m2 (<65% of estimates within 30% of measured GFR), although this subgroup was too small to reach definitive conclusions.
Conclusions
Overall accuracy was highest for the CKD-EPI equation. Eliminating the coefficient for race further improved performance. Future studies are needed to determine the most accurate GFR estimate for use in individuals with GFR <90 mL/min/1.73 m2, in whom accurate estimation of kidney function is important to guide drug dosing. Direct measurement of GFR by iohexol clearance using a filter paper based assay is feasible for research purposes in resource-limited settings, and could be used to develop more accurate GFR estimates in African populations.
doi:10.1371/journal.pone.0069601
PMCID: PMC3738577  PMID: 23950899
14.  Comorbid diabetes and the risk of progressive chronic kidney disease in HIV-infected adults: Data from the Veterans Aging Cohort Study 
Introduction
Approximately 15% of HIV-infected individuals have comorbid diabetes. Studies suggest that HIV and diabetes have an additive effect on chronic kidney (CKD) progression; however, this observation may be confounded by differences in traditional CKD risk factors.
Methods
We studied a national cohort of HIV-infected and matched HIV-uninfected individuals who received care through the Veterans Healthcare Administration. Subjects were divided into four groups based on baseline HIV and diabetes status, and the rate of progression to an estimated glomerular filtration rate (eGFR) < 45ml/min/1.73m2 was compared using Cox-proportional hazards modeling to adjust for CKD risk factors.
Results
31,072 veterans with baseline eGFR ≥ 45ml/min/1.73m2 (10,626 with HIV only, 5,088 with diabetes only, and 1,796 with both) were followed for a median of 5 years. Mean baseline eGFR was 94ml/min/1.73m2, and 7% progressed to an eGFR < 45ml/min/1.73m2. Compared to those without HIV or diabetes, the relative rate of progression was increased in individuals with diabetes only [adjusted hazard ratio (HR) 2.48; 95% confidence interval (CI) 2.19–2.80], HIV only [HR 2.80, 95% CI 2.50–3.15], and both HIV and diabetes [HR 4.47, 95% CI 3.87–5.17].
Discussion
Compared to patients with only HIV or diabetes, patients with both diagnoses are at significantly increased risk of progressive CKD even after adjusting for traditional CKD risk factors. Future studies should evaluate the relative contribution of complex comorbidities and accompanying polypharmacy to the risk of CKD in HIV-infected individuals, and prospectively investigate the use of cART, glycemic control, and adjunctive therapy to delay CKD progression.
doi:10.1097/QAI.0b013e31825b70d9
PMCID: PMC3392432  PMID: 22592587
non-AIDS complications; HIV; chronic kidney disease; diabetes; risk factors
15.  Hepatitis B and C Co-Infection Are Independent Predictors of Progressive Kidney Disease in HIV-Positive, Antiretroviral-Treated Adults 
PLoS ONE  2012;7(7):e40245.
Chronic kidney disease (CKD) is an important cause of morbidity and mortality in HIV-positive individuals. Hepatitis C (HCV) co-infection has been associated with increased risk of CKD, but prior studies lack information on potential mechanisms. We evaluated the association between HCV or hepatitis B (HBV) co-infection and progressive CKD among 3,441 antiretroviral-treated clinical trial participants. Progressive CKD was defined as the composite of end-stage renal disease, renal death, or significant glomerular filtration rate (eGFR) decline (25% decline to eGFR <60 mL/min/1.73 m2 or 25% decline with a baseline <60). Generalized Estimating Equations were used to model the odds of progressive CKD. At baseline, 13.8% and 3.3% of participants were co-infected with HCV and HBV, respectively. Median eGFR was 111, and 3.7% developed progressive CKD. After adjustment, the odds of progressive CKD were increased in participants with HCV (OR 1.72, 95% CI 1.07–2.76) or HBV (OR 2.26, 95% CI 1.15–4.44). Participants with undetectable or low HCV-RNA had similar odds of progressive CKD as HCV seronegative participants, while participants with HCV-RNA >800,000 IU/ml had increased odds (OR 3.07; 95% CI 1.60–5.90). Interleukin-6, hyaluronic acid, and the FIB-4 hepatic fibrosis index were higher among participants who developed progressive CKD, but were no longer associated with progressive CKD after adjustment. Future studies should validate the relationship between HCV viremia and CKD.
Trial Registration
ClinicalTrials.gov NCT00027352; NCT00004978
doi:10.1371/journal.pone.0040245
PMCID: PMC3401192  PMID: 22911697

Results 1-15 (15)