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1.  Podocyte effacement closely links to suPAR levels at time of post-transplant focal segmental glomerulosclerosis occurrence and improves with therapy 
Transplantation  2013;96(7):649-656.
Focal segmental glomerulosclerosis (FSGS) recurs after kidney transplantation in more than 30 % of cases and can lead to allograft loss. Serum soluble urokinase -type plasminogen activator receptor (suPAR) is implicated in the pathogenesis of native and recurrent FSGS.
We conducted a retrospective study of 25 adults with post-transplant FSGS. We investigated the relationship between suPAR levels and podocyte changes and the impact of therapy on podocyte structure. We assessed response to therapy by improvement in proteinuria, allograft function and resolution of histologic changes.
A median of 15 (interquartile range: 10–23) plasmapheresis sessions was administered; 13 of the subjects also received rituximab. Median pre-treatment suPAR levels were higher among those with severe (≥75%) versus those with mild (≤25%) podocyte foot process effacement (13,030 vs. 4,806 pg/mL; P=0.02). Overall, mean ± standard deviation of proteinuria improved from 5.1 ± 3.8 to 2.1 ± 2.8 mg/dL (P=0.003), mean podocyte effacement decreased from 57 ± 33% to 22 ± 22 % (P=0.0001), estimated glomerular filtration rates increased from median (interquartile range) of 32.9 (20.6 – 44.2) to 39.3 (28.8 – 63.4) (P<0.0001) and suPAR levels decreased from a median of 6,781 pg/ml to 4,129 pg/ml (P=0.02) with therapy.
Podocyte effacement is the first pathological manifestation of FSGS post-transplant. The degree of podocyte effacement correlates with suPAR levels at time of diagnosis. Response to therapy results in significant reduction of suPAR levels and complete or significant improvement of podocyte effacement.
PMCID: PMC4026282  PMID: 23842190
kidney transplant; podocyte effacement; FSGS; suPAR; rituximab
2.  HIV therapy, metabolic and cardiovascular health are associated with glomerular hyperfiltration in the Multicenter AIDS Cohort Study 
AIDS (London, England)  2014;28(3):377-386.
Diabetes and hypertension, common conditions in antiretroviral (ART) treated HIV-infected individuals, are associated with glomerular hyperfiltration, which precedes the onset of proteinuria and accelerated kidney function decline. In the Multicenter AIDS Cohort Study, we examined the extent to which hyperfiltration is present and associated with metabolic, cardiovascular, HIV and treatment risk factors among HIV-infected men.
Cross-sectional cohort using direct measurement of glomerular filtration rate (GFR) by iohexol plasma clearance for 367 HIV-infected men and 241 HIV-uninfected men who were free of CKD.
Hyperfiltration was defined as GFR >140 ml/min/1.73m2 - 1 ml/min/1.73m2 per each year over age 40. Multivariate logistic regression was used to estimate the odds ratios (OR) of prevalent hyperfiltration for metabolic, cardiovascular, HIV and cumulative ART exposure factors.
Among subjects without CKD, the prevalence of hyperfiltration was higher for HIV-infected participants (25%) compared to uninfected participants (17%; p=0.01). HIV infection was associated with hyperfiltration (OR: 1.70, 95%CI: 1.11, 2.61) and modified the association between diabetes and hyperfiltration, such that the association among HIV-uninfected men (OR: 2.56 95%CI: 1.33, 5.54) was not observed among HIV-infected men (OR: 1.19, 95%CI: 0.69, 2.05). These associations were independent of known risk factors for hyperfiltration. Indicators of hyperglycemia and hypertension were also associated with hyperfiltration as was cumulative zidovudine exposure.
Hyperfiltration, a potential modifiable predictor of kidney disease progression, is common among ART-treated HIV-infected men. HIV infection is associated with significant odds of hyperfiltration in addition to known risk factors for kidney damage.
PMCID: PMC3972628  PMID: 24670523
Glomerular hyperfiltration; glomerular filtration rate; HIV; antiretroviral therapy; iohexol
3.  Antiretroviral-Treated HIV-Infected Women Have Similar Long-Term Kidney Function Trajectories as HIV-Uninfected Women 
Natural history studies suggest increased risk for kidney function decline with HIV infection, but few studies have made comparisons with HIV-uninfected women. We examined whether HIV infection treated with highly active antiretroviral therapy (HAART) remains associated with faster kidney function decline in the Women's Interagency HIV Study. HIV-infected women initiating HAART with (n=105) or without (n=373) tenofovir (TDF) were matched to HIV-uninfected women on calendar and length of follow-up, age, systolic blood pressure, hepatitis C antibody serostatus, and diabetes history. Linear mixed models were used to evaluate differences in annual estimated glomerular filtration rate (eGFR). Person-visits were 4,741 and 11,512 for the TDF-treated and non-TDF-treated analyses, respectively. Mean baseline eGFRs were higher among women initiated on TDF-containing HAART and lower among those on TDF-sparing HAART compared to their respective HIV-uninfected matches (p<0.05 for both). HIV-infected women had annual rates of eGFR changes similar to HIV-uninfected matches (p-interaction >0.05 for both). Adjusting for baseline eGFR, mean eGFRs at 1 and 3 years of follow-up among women initiated on TDF-containing HAART were lower than their uninfected matches (−4.98 and −4.26 ml/min/1.73 m2, respectively; p<0.05 for both). Mean eGFR of women initiated on TDF-sparing HAART was lower versus uninfected matches at 5 years (–2.19 ml/min/1.73 m2, p=0.03). HAART-treated HIV-infected women had lower mean eGFRs at follow-up but experienced rates of annual eGFR decline similar to HIV-uninfected women. Tenofovir use in HIV-infected women with normal kidney function did not accelerate long-term kidney function decline relative to HIV-uninfected women.
PMCID: PMC3636577  PMID: 23273313
4.  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
5.  Hepatitis C Viremia and the Risk of Chronic Kidney Disease in HIV-Infected Individuals 
Lucas, Gregory M. | Jing, Yuezhou | Sulkowski, Mark | Abraham, Alison G. | Estrella, Michelle M. | Atta, Mohamed G. | Fine, Derek M. | Klein, Marina B. | Silverberg, Michael J. | Gill, M. John | Moore, Richard D. | Gebo, Kelly A. | Sterling, Timothy R. | Butt, Adeel A. | Kirk, Gregory D. | Benson, Constance A. | Bosch, Ronald J. | Collier, Ann C. | Boswell, Stephen | Grasso, Chris | Mayer, Ken | Hogg, Robert S. | Harrigan, Richard | Montaner, Julio | Cescon, Angela | Brooks, John T. | Buchacz, Kate | Gebo, Kelly A. | Moore, Richard D. | Carey, John T. | Rodriguez, Benigno | Horberg, Michael A. | Silverberg, Michael J. | Horberg, Michael A. | Thorne, Jennifer E. | Goedert, James J. | Jacobson, Lisa P. | Klein, Marina B. | Rourke, Sean B. | Burchell, Ann | Rachlis, Anita R. | Rico, Puerto | Hunter-Mellado, Robert F. | Mayor, Angel M. | Gill, M. John | Deeks, Steven G. | Martin, Jeffrey N. | Patel, Pragna | Brooks, John T. | Saag, Michael S. | Mugavero, Michael J. | Willig, James | Eron, Joseph J. | Napravnik, Sonia | Kitahata, Mari M. | Crane, Heidi M. | Justice, Amy C. | Dubrow, Robert | Fiellin, David | Sterling, Timothy R. | Haas, David | Bebawy, Sally | Turner, Megan | Gange, Stephen J. | Anastos, Kathryn | Moore, Richard D. | Saag, Michael S. | Gange, Stephen J. | Kitahata, Mari M. | McKaig, Rosemary G. | Justice, Amy C. | Freeman, Aimee M. | Moore, Richard D. | Freeman, Aimee M. | Lent, Carol | Kitahata, Mari M. | Van Rompaey, Stephen E. | Crane, Heidi M. | Webster, Eric | Morton, Liz | Simon, Brenda | Gange, Stephen J. | Althoff, Keri N. | Abraham, Alison G. | Lau, Bryan | Zhang, Jinbing | Jing, Jerry | Golub, Elizabeth | Modur, Shari | Hanna, David B. | Rebeiro, Peter | Wong, Cherise | Mendes, Adell
The Journal of Infectious Diseases  2013;208(8):1240-1249.
Background. The role of active hepatitis C virus (HCV) replication in chronic kidney disease (CKD) risk has not been clarified.
Methods. We compared CKD incidence in a large cohort of HIV-infected subjects who were HCV seronegative, HCV viremic (detectable HCV RNA), or HCV aviremic (HCV seropositive, undetectable HCV RNA). Stages 3 and 5 CKD were defined according to standard criteria. Progressive CKD was defined as a sustained 25% glomerular filtration rate (GFR) decrease from baseline to a GFR < 60 mL/min/1.73 m2. We used Cox models to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs).
Results. A total of 52 602 HCV seronegative, 9508 HCV viremic, and 913 HCV aviremic subjects were included. Compared with HCV seronegative subjects, HCV viremic subjects were at increased risk for stage 3 CKD (adjusted HR 1.36 [95% CI, 1.26, 1.46]), stage 5 CKD (1.95 [1.64, 2.31]), and progressive CKD (1.31 [1.19, 1.44]), while HCV aviremic subjects were also at increased risk for stage 3 CKD (1.19 [0.98, 1.45]), stage 5 CKD (1.69 [1.07, 2.65]), and progressive CKD (1.31 [1.02, 1.68]).
Conclusions. Compared with HIV-infected subjects who were HCV seronegative, both HCV viremic and HCV aviremic individuals were at increased risk for moderate and advanced CKD.
PMCID: PMC3778973  PMID: 23904290
HIV; hepatitis C virus; chronic kidney disease; hepatitis C RNA; cohort study; glomerular filtration rate; injection drug use
6.  A chronic kidney disease risk score to determine tenofovir safety in a prospective cohort of HIV-positive male veterans 
AIDS (London, England)  2014;28(9):1289-1295.
Tenofovir disoproxil fumarate is a widely used antiretroviral for HIV infection that has been associated with an increased risk of chronic kidney disease (CKD). Our objective was to derive a scoring system to predict 5-year risk of developing CKD in HIV-infected individuals and to estimate difference in risk associated with tenofovir use.
We evaluated time to first occurrence of CKD (estimated glomerular filtration rate <60 ml/min per 1.73 m2) in 21 590 HIV-infected men from the Veterans Health Administration initiating antiretroviral therapy from 1997 to 2010.
We developed a point-based score using multivariable Cox regression models. Median follow-up was 6.3 years, during which 2059 CKD events occurred.
Dominant contributors to the CKD risk score were traditional kidney risk factors (age, glucose, SBP, hypertension, triglycerides, proteinuria); CD4+ cell count was also a component, but not HIV RNA. The overall 5-year event rate was 7.7% in tenofovir users and 3.8% in nonusers [overall adjusted hazard ratio 2.0, 95% confidence interval (CI) 1.8–2.2]. There was a progressive increase in 5-year CKD risk, ranging from less than 1% (zero points) to 16% (≥9 points) in nonusers of tenofovir, and from 1.4 to 21.4% among tenofovir users. The estimated number-needed-to-harm (NNH) for tenofovir use ranged from 108 for those with zero points to 20 for persons with at least nine points. Among tenofovir users with at least 1 year exposure, NNH ranged from 68 (zero points) to five (≥9 points).
The CKD risk score can be used to predict an HIV-infected individual’s absolute risk of developing CKD over 5 years and may facilitate clinical decision-making around tenofovir use.
PMCID: PMC4188545  PMID: 24922479
chronic kidney disease; HIV; risk score; tenofovir
7.  Antiretroviral Therapy-Induced Changes in Plasma Lipids and the Risk of Kidney Dysfunction in HIV-Infected Men 
AIDS Research and Human Retroviruses  2013;29(10):1346-1352.
In the context of HIV, the initiation of effective antiretroviral therapy (ART) has been found to increase the risk of dyslipidemia in HIV-infected individuals, and dyslipidemia has been found to be a risk factor for kidney disease in the general population. Therefore, we examined changes in lipid profiles in HIV-infected men following ART initiation and the association with future kidney dysfunction. HIV-infected men from the Multicenter AIDS Cohort Study initiating ART between December 31, 1995 and September 30, 2011 with measured lipid and serum creatinine values pre-ART and post-ART were selected. The associations between changes in total cholesterol or high-density lipoprotein following ART initiation and the estimated change in glomerular filtration rate (eGFR) over time were assessed using piecewise linear mixed effects models. There were 365 HIV-infected men who contributed to the analysis. In the adjusted models, at 3 years post-ART, those with changes in total cholesterol >50 mg/dl had an average decrease in eGFR of 2.6 ml/min/1.73 m2 per year (p<0.001) and at 5 years post-ART, the average decrease was 2.4 ml/min/1.73 m2 per year (p=0.008). This decline contrasted with the estimates for those with changes in total cholesterol ≤50 mg/dl: 1.4 ml/min/1.73 m2 decrease per year (p<0.001) and 0.1 ml/min/1.73 m2 decrease per year (p=0.594) for the same time periods, respectively. Large decreases in high-density lipoprotein (a decline of greater than 5 mg/dl) were not associated with declines in eGFR. These results indicate that large ART-related increases in total cholesterol may be a risk factor for kidney function decline in HIV-infected men. Should these results be generalizable to the broader HIV population, monitoring cholesterol changes following the initiation of ART may be important in identifying HIV-infected persons at risk for kidney disease.
PMCID: PMC3785801  PMID: 23758574
8.  The Clinical Characteristics and Pathological Patterns of Postinfectious Glomerulonephritis in HIV-Infected Patients 
PLoS ONE  2014;9(10):e108398.
Postinfectious glomerulonephritis (PIGN), a form of immune complex GN, is not well-defined in HIV-infected patients. This study characterizes PIGN in this patients’ population and determine the impact of histopathological patterns on renal outcome and mortality.
HIV-infected patients with PIGN from September 1998 to July 2013 were identified. Archived slides were reviewed by a blinded renal pathologist, classified into acute, persistent and healed PIGN. Groups were compared using Wilcoxon rank-sum and Fisher’s exact test. Survival analyses were performed to determine association of histopathological pattern with renal outcome and mortality.
Seventy-two HIV-infected predominantly African American males were identified with PIGN. Median (interquartile range) age and creatinine at the time of renal biopsy was 48 years (41, 53) and 2.5 mg/dl (1.5, 4.9) respectively. Only 2 (3%) had acute PIGN, 42 (58%) had persistent PIGN and 28 (39%) had healed PIGN. Three patients (4%) had IgA-dominant PIGN. Only 46% of the patients had confirmed positive cultures with Staphylococcus the most common infectious agent. During a median follow up of 17 months, the pathological pattern had no impact on renal outcome (P = 0.95). Overall mortality was high occurring in 14 patients (19%); patients with healed PIGN had significantly increased mortality (P = 0.05).
In HIV-infected patients, Staphylococcus is the most common cause of PIGN. Renal outcome was not influenced by the histopathological pattern but those with healed PIGN had greater mortality which was potentially due to a confounder not accounted for in the study.
PMCID: PMC4182733  PMID: 25272150
9.  Vitamin D Deficiency and Persistent Proteinuria among HIV-infected and –uninfected Injection Drug Users 
AIDS (London, England)  2012;26(3):295-302.
Proteinuria occurs commonly among HIV-infected and -uninfected injection drug users (IDUs) and is associated with increased mortality risk. Vitamin D deficiency, highly prevalent among IDUs and potentially modifiable, may contribute to proteinuria. To determine whether vitamin D is associated with proteinuria in this population, we conducted a cross-sectional study in the AIDS Linked to the IntraVenous Experience (ALIVE) Study.
25(OH)-vitamin D levels were measured in 268 HIV-infected and 614 HIV-uninfected participants. The association between vitamin D deficiency (<10 ng/mL) and urinary protein excretion was evaluated by linear regression. The odds of persistent proteinuria (urine protein-to-creatinine ratio >200 mg/g on two occasions) associated with vitamin D deficiency was examined using logistic regression.
One-third of participants were vitamin D-deficient. Vitamin D deficiency was independently associated with higher urinary protein excretion (P<0.05) among HIV-infected and diabetic IDUs (P-interaction<0.05 for all). Persistent proteinuria occurred in 18% of participants. Vitamin D deficiency was associated with >6-fold odds of persistent proteinuria among diabetic IDUs (odds ratio [OR]=6.29, 95% confidence interval [CI]: 1.54, 25.69) independent of sociodemographic characteristics, co-morbid conditions, body mass index, and impaired kidney function (estimated GFR <60 mL/min|1.73 m2); no association, however, was observed among non-diabetic IDUs (OR=1.06, 95% CI: 0.64, 1.76) (P-interaction<0.05).
Vitamin D deficiency was associated with higher urinary protein excretion among those with HIV infection and diabetes. Vitamin D deficiency was independently associated with persistent proteinuria among diabetic IDUs, although not in non-diabetic persons. Whether vitamin D repletion ameliorates proteinuria in these patients requires further study.
PMCID: PMC3766727  PMID: 22156964
Vitamin D deficiency; proteinuria; HIV; injection drug use; diabetes
10.  Risk Factors for Vitamin D Deficiency among HIV-Infected and Uninfected Injection Drug Users 
PLoS ONE  2014;9(4):e95802.
Vitamin D deficiency is highly prevalent and is associated with bone disease, cardiovascular disease, metabolic syndrome and malignancy. Injection drug users (IDUs), with or without HIV infection, are at risk for these conditions; however, limited data on vitamin D deficiency exist in this population. We determined the prevalence and correlates of vitamin D deficiency among urban IDUs in the AIDS Linked to the IntraVenous Experience (ALIVE) Study cohort.
For this cross-sectional sub-study, vitamin D deficiency was defined as a serum 25(OH)-vitamin D level <20 ng/mL. Multivariable logistic regression was used to identify factors independently associated with vitamin D deficiency.
Of 950 individuals analyzed, 29% were HIV-infected. The median age was 49 years; 65% were male, and 91% were black. The median vitamin D level was 13.5 ng/mL (IQR, 9.0–20.3); 74% were deficient (68% in HIV-infected vs. 76% in HIV-uninfected, p = 0.01). Non-black race, fall/winter season, multivitamin intake, higher serum albumin, HCV seropositivity and HIV-infection were associated with significantly lower odds of vitamin D deficiency.
Vitamin D deficiency is prevalent among IDUs. Notably, HIV-infected IDUs were less likely to be vitamin D deficient. Higher vitamin D levels were associated with multivitamin intake and with higher albumin levels, suggesting that nutritional status contributes substantially to deficiency. The association between HCV serostatus and vitamin D level remains unclear. Further investigation is needed to define the clinical implications of the heavy burden of vitamin D deficiency in this high-risk, aging population with significant co-morbidities.
PMCID: PMC3995810  PMID: 24756000
11.  Chronic kidney disease and estimates of kidney function in HIV infection: a cross-sectional study in the Multicenter AIDS Cohort Study 
Cystatin C has been proposed as an alternative marker of kidney function among HIV-infected persons in whom serum creatinine is affected by extra-renal factors.
In this cross-sectional study, we compared estimated glomerular filtration rates (eGFR) using serum creatinine versus cystatin C between 150 HIV-uninfected and 783 HIV-infected men. We evaluated the prevalence of chronic kidney disease (CKD; eGFR<60 mL/min/1.73 m2) and examined the influence of extra-renal factors on GFR-estimates among HIV-infected men.
Estimated GFRSCR was similar by HIV serostatus, but eGFRCYSC was lower in HIV-infected men. A higher proportion of HIV-infected men were classified as having CKD when using eGFRCYSC versus eGFRSCR (7% vs. 5%, P<0.01). In HIV-infected individuals without CKD, eGFRSCR was higher than eGFRCYSC while it was lower than eGFRCYSC in persons with CKD. In HIV-infected men, older age, proteinuria, and prior clinical AIDS were inversely associated with both GFR-estimates. Higher serum albumin levels and ACE-inhibitor/ARB use were associated with lower eGFRSCR. HIV viral load, hepatitis C co-infection, and serum alkaline phosphatase were inversely associated with eGFRCYSC.
Among HIV-uninfected and HIV-infected men of similar social risk behaviors, GFR estimates differed by biomarker and kidney function level. Estimated GFRCYSC classified a larger proportion of HIV-infected men with CKD compared to eGFRSCR. Differences between these GFR-estimating methods may be due to the effects of extra-renal factors on serum creatinine and cystatin C. Until GFR-estimating equations are validated among HIV-infected individuals, current GFR estimates based on these biomarkers should be interpreted with care in this patient population.
PMCID: PMC3159728  PMID: 21646913
HIV; kidney disease; serum creatinine; cystatin C; glomerular filtration rate; Multicenter AIDS Cohort Study
12.  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
13.  Comparisons of creatinine and cystatin C for detection of kidney disease and prediction of all-cause mortality in HIV-infected women 
AIDS (London, England)  2013;27(14):2291-2299.
Cystatin C could improve chronic kidney disease (CKD) classification in HIV-infected women relative to serum creatinine.
Retrospective cohort analysis.
Cystatin C and creatinine were measured from specimens taken and stored during the 1999–2000 exam among 908 HIV-infected participants in the Women’s Interagency HIV study (WIHS). Mean follow-up was 10.2 years. The associations of baseline categories (<60, 60–90, and >90 mL/min/1.73m2) of creatinine eGFR (eGFRcr), cystatin C eGFR (eGFRcys), and combined creatinine-cystatin C eGFR (eGFRcr-cys) with all-cause mortality were evaluated using multivariable Cox regression. The net reclassification index (NRI) was calculated to evaluate the effect of cystatin C on reclassification of CKD staging.
The prevalence of CKD (eGFR<60) at baseline was higher with eGFRcys (10.1%) compared to eGFRcr (6.7%, p=0.0006) and eGFRcr-cys (7.5%, p=0.011). Relative to eGFR >90, the eGFR <60 category by eGFRcys (Adjusted HR: 2.56; 95% CI: 1.63, 4.02), eGFRcr-cys (3.11; 1.94–5.00), and eGFRcr (2.34; 1.44–3.79) was associated with increased mortality risk. However, the eGFR 60–90 category was associated with increased mortality risk for eGFRcys (1.80; 1.28–2.53) and eGFRcr-cys (1.91; 1.38–2.66) but not eGFRcr (1.20; 0.85–1.67). The overall NRI for mortality was 26% when reclassifying from eGFRcr to eGFRcys (p<0.001) and was 20% when reclassifying from eGFRcr to eGFRcr-cys (p<0.001).
Cystatin C detected a higher prevalence of CKD relative to creatinine and improves CKD staging relative to creatinine by reclassifying individuals at the highest mortality risk to lower eGFR categories.
PMCID: PMC3919542  PMID: 23669156
Creatinine; Cystatin C; Glomerular Filtration Rate; HIV; Mortality; Kidney; Women
14.  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
15.  HIV Viremia and T-Cell Activation Differentially Affect the Performance of Glomerular Filtration Rate Equations Based on Creatinine and Cystatin C 
PLoS ONE  2013;8(12):e82028.
Serum creatinine and cystatin C are used as markers of glomerular filtration rate (GFR). The performance of these GFR markers relative to exogenously measured GFR (mGFR) in HIV-positive individuals is not well established.
We assessed the performance of the chronic kidney disease epidemiology collaboration equations based on serum concentrations of creatinine (eGFRcr), cystatin C (eGFRcys) and both biomarkers combined (eGFRcr-cys) in 187 HIV-positive and 98 HIV-negative participants. Measured GFR was calculated by plasma iohexol clearance. Bias and accuracy were defined as the difference between eGFR and mGFR and the percentage of eGFR observations within 30% of mGFR, respectively. Activated CD4 and CD8 T-cells (CD38+ HLA-DR+) were measured by flow cytometry.
The median mGFR was >100 ml/min/1.73 m2 in both groups. All equations tended to be less accurate in HIV-positive than in HIV-negative subjects, with eGFRcr-cys being the most accurate overall. In the HIV-positive group, eGFRcys was significantly less accurate and more biased than eGFRcr and eGFRcr_cys. Additionally eGFRcys bias and accuracy were strongly associated with use of antiretroviral therapy, HIV RNA suppression, and percentages of activated CD4 or CD8 T-cells. Hepatitis C seropositivity was associated with larger eGFRcys bias in both HIV-positive and HIV-negative groups. In contrast, eGFRcr accuracy and bias were not associated with HIV-related factors, T-cell activation, or hepatitis C.
The performance of eGFRcys relative to mGFR was strongly correlated with HIV treatment factors and markers of T-cell activation, which may limit its usefulness as a GFR marker in this population.
PMCID: PMC3871673  PMID: 24376511
16.  Prevalence of kidney disease in anaemia differs by GFR-estimating method: The Third National Health and Nutrition Examination Survey (1988–94) 
Nephrology Dialysis Transplantation  2010;25(8):2542-2548.
Background. Anaemia worsens as kidney function declines. Both conditions are associated with increased mortality. Serum cystatin C is purportedly a more sensitive marker of kidney disease and a better predictor of mortality than serum creatinine. However, studies suggest that extrarenal factors also influence cystatin C levels.
Methods. We determined whether estimates of glomerular filtration rate [estimated glomerular filtration rate (eGFR)] based on serum cystatin C alone or in combination with serum creatinine were superior to those based on serum creatinine in recognizing impaired kidney function in the setting of anaemia in a sub-sample of the Third National Health and Nutrition Examination Survey of the USA consisting of 6734 participants, 20 years or older.
Results. The prevalence of moderate to severe kidney disease (eGFR 15–59 mL/min/1.73 m2) among anaemic persons was 15–16% when based on serum creatinine alone (eGFRSCR) or combined with cystatin C (eGFRSCR + CYSC); this estimate increased to nearly 25% when kidney function was estimated by cystatin C (eGFRCYSC). The adjusted odds ratios of kidney disease in anaemic versus non-anaemic persons were slightly higher with eGFRCYSC than eGFRSCR and eGFRSCR + CYSC in younger adults [odds ratio (OR) = 5.22, 95% confidence interval (CI): 2.23, 12.17], women (OR = 5.34, 95% CI: 2.36, 12.06) and those with elevated C-reactive protein (CRP) (OR = 7.36, 95% CI: 1.98–27.36).
Conclusions. Impaired kidney function was common in individuals with anaemia. Among anaemic individuals, the prevalence estimate for kidney disease was notably higher when kidney function was estimated by cystatin C alone compared with the estimations by serum creatinine alone or in combination with serum cystatin C. eGFRCYSC may be particularly helpful in identifying kidney disease in the setting of anaemia among younger persons, women and those with elevated CRP. Regardless of which renal biomarker is used, our study suggests that an evaluation for underlying kidney disease should be considered in the standard workup of anaemia.
PMCID: PMC2910334  PMID: 20176612
anaemia; chronic kidney failure; creatinine; cystatin C; glomerular filtration rate
17.  The Impact of Impaired Kidney Function and HIV Infection on the Risk of Anemia 
AIDS Research and Human Retroviruses  2012;28(12):1666-1671.
Chronic kidney disease and HIV infection both independently increase the risk of anemia. It is not known if individuals with both HIV infection and kidney dysfunction are at greater than expected risk of anemia resulting from the combined effect of these factors. Men from the Multicenter AIDS Cohort Study with AIDS-free time after 1996 were included in the analysis if they had an initial hemoglobin value greater than 13 g/dl and available serum creatinine measurements for the estimation of glomerular filtration rate. Hemoglobin data were fit parametrically using a linear mixed effects model and effects of medication use on hemoglobin levels were removed using censoring methods. The effect of both HIV infection and glomerular filtration rate less than 60 ml/min/1.73 m2 on the mean hemoglobin value was assessed. The risk of having anemia (hemoglobin level falling below 13 g/dl) was estimated. There were 862 HIV-infected and 1,214 HIV-uninfected men who contributed to the analysis. Hemoglobin values across all 17,341 person-visits, adjusting for age, were generally lower in HIV-infected AIDS-free men with impaired kidney function by −0.22 g/dl (95% CI: −0.42, −0.03) compared to men with either HIV infection or impaired kidney function, but not both. HIV-infected AIDS-free men with impaired kidney function have a higher risk of anemia by 1.2% compared to HIV-uninfected men with normal kidney function. Comorbid conditions and medication use did not explain this increase in risk. HIV infection and impaired kidney function have a combined impact on lowering hemoglobin levels, resulting in a higher risk of anemia.
PMCID: PMC3505063  PMID: 22632256
18.  Perceptions and use of the national kidney foundation KDOQI guidelines: a survey of U.S. renal healthcare providers 
BMC Nephrology  2013;14:230.
The National Kidney Foundation (NKF) Kidney Disease Outcomes Quality Initiative (KDOQI) developed guidelines to care for patients with chronic kidney disease (CKD). While these are disseminated through the NKF’s website and publications, the guidelines’ usage remains suboptimal. The KDOQI Educational Committee was formed to identify barriers to guideline implementation, determine provider and patient educational needs and develop tools to improve care of patients with CKD.
An online survey was conducted from May to September 2010 to evaluate renal providers’ familiarity, current use of and attitudes toward the guidelines and tools to implement the guidelines.
Most responders reported using the guidelines often and felt that they could be easily implemented into clinical practice; however, approximately one-half identified at least one barrier. Physicians and physician extenders most commonly cited the lack of evidence supporting KDOQI guidelines while allied health professionals most commonly listed patient non-adherence, unrealistic guideline goals and provider time-constraints. Providers thought that the guidelines included too much detail and identified the lack of a quick resource as a barrier to clinical implementation. Most were unaware of the Clinical Action Plans.
Perceived barriers differed between renal clinicians and allied health professionals; educational and implementation tools tailored for different providers are needed.
PMCID: PMC4016578  PMID: 24152744
KDOQI; Chronic kidney disease; Guidelines; Survey
19.  Screening for Chronic Kidney Disease in HIV-Infected Patients 
With improved survival afforded by highly-active antiretroviral therapy (HAART), CKD has emerged as one of the primary comorbid conditions affecting human immunodeficiency virus (HIV)-infected individuals. Although CKD in HIV-infected individuals is classically thought of as a consequence of advanced HIV infection such as in the case of HIV-associated nephropathy (HIVAN), several factors likely contribute to the development CKD in HIV infection. These factors include genetic predisposition, age-related decline in kidney function, HAART-related metabolic changes, exposure to multiple nephrotoxic medications, and concurrent conditions such as hepatitis C or illicit drug use. Similar to the general population, proteinuria and impaired kidney function are associated with faster progression to acquired immune deficiency syndrome (AIDS) and death. Given the prevalence and impact of kidney disease on the course of HIV infection and its management, current guidelines recommend screening all HIV-infected individuals for kidney disease. This review focuses on the current guidelines for kidney disease screening and discusses traditional as well as promising strategies for detecting CKD in this vulnerable population.
PMCID: PMC2818858  PMID: 20005486
HIV infection; proteinuria; estimated GFR; MDRD equation; cystatin C
20.  HIV-associated nephropathy patients with and without apolipoprotein L1 gene variants have similar clinical and pathologic characteristics 
Kidney international  2012;82(3):338-343.
Recently, an association was found between non-diabetic kidney disease in African Americans and two independent sequence variants in the APOL1 gene, encoding apolipoprotein L1. In this study we determined the frequency of APOL1 risk variants in patients with biopsy-proven HIV-associated nephropathy (HIVAN) and distinctive pathological characteristics potentially driven by those risk variants. Among 76 patients with HIVAN, 60 were successfully genotyped for APOL1 G1 and G2 polymorphisms. In this cohort, 37 had two risk alleles, 18 were heterozygous and 5 had neither risk variant. There were no differences in the pathological findings of HIVAN and the number of APOL1 risk alleles. Further, the progression to end stage kidney disease or death did not differ by the number of risk alleles. Median renal survival was 9.3 months in patients with none or one risk allele compared to 11.7 months in patients with two APOL1 risk alleles. Thus, our study suggests that although the majority of African American patients with HIVAN have two APOL1 risk alleles, other as yet unknown factors in the host including genetic risk variants and environmental or viral factors may influence the development of this disorder in those with none or one APOL1 risk allele.
PMCID: PMC3463138  PMID: 22495294
21.  Efficacy of an internet-based tool for improving physician knowledge of chronic kidney disease: an observational study 
BMC Nephrology  2012;13:126.
Early recognition and management of chronic kidney disease (CKD) are associated with better outcomes. Internal medicine residency should prepare physicians to diagnose and manage CKD.
To examine whether residency training and program characteristics were associated with CKD knowledge and investigate the effectiveness of an internet-based training module in improving CKD knowledge, we analyzed data from CKD training modules administered annually to U.S. internal medicine residents from July 1, 2005 to June 30, 2009. Baseline CKD knowledge was assessed using pre-tests. The modules’ effectiveness was evaluated by post-tests. Comparisons were performed using X2 tests and paired t-tests.
Of 4,702 residents, 38%, 33%, and 29% were program year (PGY)-1, PGY-2, and PGY-3, respectively. Baseline CKD knowledge was poor, with mean pre-test scores of 45.1-57.0% across the four years. The lowest pre-test performance was on CKD recognition. Pre-test scores were better with higher training levels (P-trend < 0.001 except 2005–2006 [P-trend = 0.35]). Affiliation with a renal fellowship program or program location within a region of high end-stage kidney disease prevalence was not associated with better baseline CKD knowledge. Completion of the CKD module led to significant improvements from pre- to post-test scores (mean improvement 27.8% [SD: 21.3%] which were consistent from 2005 to 2009.
Knowledge of diagnosis and management of CKD improves during residency training but remains poor among graduating residents. Web-based training can be effective in educating physicians on CKD-related issues. Studies are needed to determine whether knowledge gained from such an intervention translates to improved care of CKD patients.
PMCID: PMC3536684  PMID: 23016990
Kidney disease; Education; Internet; Primary care
22.  Kidney function and mortality post-liver transplant in the Model for End-Stage Liver Disease era 
The Model for End-Stage Liver Disease (MELD) score incorporates serum creatinine and was introduced to facilitate allocation of orthotopic liver transplantation (LT). The objective is to determine the impact of MELD and kidney function on all-cause mortality. Among LTs performed in a tertiary referral hospital between 1995 and 2009, 419 cases were studied. Cox proportional hazards models were constructed to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for death. Over mean follow-ups of 8.4 and 3.1 years during the pre-MELD and MELD era, 57 and 63 deaths were observed, respectively. Those transplanted during the MELD era had a higher likelihood of hepatorenal syndrome (8% vs 2%, P < 0.01), lower kidney function (median estimated glomerular filtration rate [eGFR] 77.8 vs 92.6 mL/ min/1.73 m2, P < 0.01), and more pretransplantation renal replacement therapy (RRT) (5% vs 1%; P < 0.01). All-cause mortality risk was similar in the MELD vs the pre-MELD era (HR: 0.98, 95% CI: 0.58–1.65). The risk of death, however, was nearly 3-fold greater (95% CI: 1.14–6.60) among those requiring pre- transplant RRT. Similarly, eGFR < 60 mL/min/1.73 m2 post-transplant was associated with a 2.5-fold higher mortality (95% CI: 1.48–4.11). The study suggests that MELD implementation had no impact on all-cause mortality post-LT. However, the need for pre-transplant RRT and post-transplant kidney dysfunction was associated with a more than 2-fold greater risk of subsequent death.
PMCID: PMC3234151  PMID: 22163170
eGFR; mortality; MELD; liver transplant
23.  Recent developments in HIV-related kidney disease 
HIV therapy  2010;4(5):589-603.
Although kidney disease has been a recognized complication of HIV infection since the beginning of the HIV epidemic, its epidemiology, underlying causes and treatment have evolved in developed countries where HAART has been widely available. HIV-associated nephropathy and HIV immune complex-mediated kidney disease were the prominent renal diagnoses in the earlier period of the HIV epidemic. While HIV immune complex-mediated kidney disease remains a common finding among HIV-infected individuals with kidney disease, the incidence of HIV-associated nephropathy has been diminishing in developed countries. The role of the metabolic effects of long-term HAART exposure and nephrotoxicity of certain antiretroviral medications on the development and progression of chronic kidney disease is now of increasing concern. The long-term clinical implications of acute kidney injury among HIV-infected persons are increasingly recognized. Kidney disease in HIV-infected persons continues to be a major risk factor for morbidity and mortality in this patient population; therefore, early recognition and treatment of kidney disease are imperative in lessening the impact of kidney disease on the health of HIV-infected individuals. This review focuses on recent developments and ongoing challenges in the understanding, diagnosis and management of HIV-related kidney disease.
PMCID: PMC3038636  PMID: 21331321
glomerular filtration rate; HIV; HIVAN; kidney disease; serum creatinine; tenofovir

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