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1.  Reduced Glomerular Filtration Rate and Its Association with Clinical Outcome in Older Patients at Risk of Vascular Events: Secondary Analysis 
PLoS Medicine  2009;6(1):e1000016.
Background
Reduced glomerular filtration rate (GFR) is associated with increased cardiovascular risk in young and middle aged individuals. Associations with cardiovascular disease and mortality in older people are less clearly established. We aimed to determine the predictive value of the GFR for mortality and morbidity using data from the 5,804 participants randomized in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER).
Methods and Findings
Glomerular filtration rate was estimated (eGFR) using the Modification of Diet in Renal Disease equation and was categorized in the ranges ([20–40], [40–50], [50–60]) ≥ 60 ml/min/1.73 m2. Baseline risk factors were analysed by category of eGFR, with and without adjustment for other risk factors. The associations between baseline eGFR and morbidity and mortality outcomes, accrued after an average of 3.2 y, were investigated using Cox proportional hazard models adjusting for traditional risk factors. We tested for evidence of an interaction between the benefit of statin treatment and baseline eGFR status. Age, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, C-reactive protein (CRP), body mass index, fasting glucose, female sex, histories of hypertension and vascular disease were associated with eGFR (p = 0.001 or less) after adjustment for other risk factors. Low eGFR was independently associated with risk of all cause mortality, vascular mortality, and other noncancer mortality and with fatal and nonfatal coronary and heart failure events (hazard ratios adjusted for CRP and other risk factors (95% confidence intervals [CIs]) for eGFR < 40 ml/min/1.73m2 relative to eGFR ≥ 60 ml/min/1.73m2 respectively 2.04 (1.48–2.80), 2.37 (1.53–3.67), 3.52 (1.78–6.96), 1.64 (1.18–2.27), 3.31 (2.03–5.41). There were no nominally statistically significant interactions (p < 0.05) between randomized treatment allocation and eGFR for clinical outcomes, with the exception of the outcome of coronary heart disease death or nonfatal myocardial infarction (p = 0.021), with the interaction suggesting increased benefit of statin treatment in subjects with impaired GFRs.
Conclusions
We have established that, in an elderly population over the age of 70 y, impaired GFR is associated with female sex, with presence of vascular disease, and with levels of other risk factors that would be associated with increased risk of vascular disease. Further, impaired GFR is independently associated with significant levels of increased risk of all cause mortality and fatal vascular events and with composite fatal and nonfatal coronary and heart failure outcomes. Our analyses of the benefits of statin treatment in relation to baseline GFR suggest that there is no reason to exclude elderly patients with impaired renal function from treatment with a statin.
Using data from the PROSPER trial, Ian Ford and colleagues investigate whether reduced glomerular filtration rate is associated with cardiovascular and mortality risk among elderly people.
Editors' Summary
Background.
Cardiovascular disease (CVD)—disease that affects the heart and/or the blood vessels—is a common cause of death in developed countries. In the USA, for example, the single leading cause of death is coronary heart disease, a CVD in which narrowing of the heart's blood vessels slows or stops the blood supply to the heart and eventually causes a heart attack. Other types of CVD include stroke (in which narrowing of the blood vessels interrupts the brain's blood supply) and heart failure (a condition in which the heart can no longer pump enough blood to the rest of the body). Many factors increase the risk of developing CVD, including high blood pressure (hypertension), high blood cholesterol, having diabetes, smoking, and being overweight. Tools such as the “Framingham risk calculator” assess an individual's overall CVD risk by taking these and other risk factors into account. CVD risk can be minimized by taking drugs to reduce blood pressure or cholesterol levels (for example, pravastatin) and by making lifestyle changes.
Why Was This Study Done?
Another potential risk factor for CVD is impaired kidney (renal) function. In healthy people, the kidneys filter waste products and excess fluid out of the blood. A reduced “estimated glomerular filtration rate” (eGFR), which indicates impaired renal function, is associated with increased CVD in young and middle-aged people and increased all-cause and cardiovascular death in people who have vascular disease. But is reduced eGFR also associated with CVD and death in older people? If it is, it would be worth encouraging elderly people with reduced eGFR to avoid other CVD risk factors. In this study, the researchers determine the predictive value of eGFR for all-cause and vascular mortality (deaths caused by CVD) and for incident vascular events (a first heart attack, stroke, or heart failure) using data from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). This clinical trial examined pravastatin's effects on CVD development among 70–82 year olds with pre-existing vascular disease or an increased risk of CVD because of smoking, hypertension, or diabetes.
What Did the Researchers Do and Find?
The trial participants were divided into four groups based on their eGFR at the start of the study. The researchers then investigated the association between baseline CVD risk factors and baseline eGFR and between baseline eGFR and vascular events and deaths that occurred during the 3-year study. Several established CVD risk factors were associated with a reduced eGFR after allowing for other risk factors. In addition, people with a low eGFR (between 20 and 40 units) were twice as likely to die from any cause as people with an eGFR above 60 units (the normal eGFR for a young person is 100 units; eGFR decreases with age) and more than three times as likely to have nonfatal coronary heart disease or heart failure. A low eGFR also increased the risk of vascular mortality, other noncancer deaths, and fatal coronary heart disease and heart failure. Finally, pravastatin treatment reduced coronary heart disease deaths and nonfatal heart attacks most effectively among participants with the greatest degree of eGFR impairment.
What Do These Findings Mean?
These findings suggest that, in elderly people, impaired renal function is associated with levels of established CVD risk factors that increase the risk of vascular disease. They also suggest that impaired kidney function increases the risk of all-cause mortality, fatal vascular events, and fatal and nonfatal coronary heat disease and heart failure. Because the study participants were carefully chosen for inclusion in PROSPER, these findings may not be generalizable to all elderly people with vascular disease or vascular disease risk factors. Nevertheless, increased efforts should probably be made to encourage elderly people with reduced eGFR and other vascular risk factors to make lifestyle changes to reduce their overall CVD risk. Finally, although the effect of statins in elderly patients with renal dysfunction needs to be examined further, these findings suggest that this group of patients should benefit at least as much from statins as elderly patients with healthy kidneys.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000016.
The MedlinePlus Encyclopedia has pages on coronary heart disease, stroke, and heart failure (in English and Spanish)
MedlinePlus provides links to many other sources of information on heart disease, vascular disease, and stroke (in English and Spanish)
The US National Institute of Diabetes and Digestive and Kidney Diseases provides information on how the kidneys work and what can go wrong with them, including a list of links to further information about kidney disease
The American Heart Association provides information on all aspects of cardiovascular disease for patients, caregivers, and professionals (in several languages)
More information about PROSPER is available on the Web site of the Vascular Biochemistry Department of the University of Glasgow
doi:10.1371/journal.pmed.1000016
PMCID: PMC2628400  PMID: 19166266
2.  Antiretroviral-Treated HIV-Infected Women Have Similar Long-Term Kidney Function Trajectories as HIV-Uninfected Women 
Abstract
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.
doi:10.1089/aid.2012.0248
PMCID: PMC3636577  PMID: 23273313
3.  HIV-infected persons continue to lose kidney function despite successful antiretroviral therapy 
AIDS (London, England)  2009;23(16):2143-2149.
Objective
To identify risk factors associated with kidney function decline in a contemporary cohort of treated and untreated HIV-infected patients.
Methods
We followed individuals enrolled in the Study of the Consequences Of the Protease inhibitor Era cohort for longitudinal changes in kidney function, defined as glomerular filtration rate estimated from serum creatinine (eGFR). eGFR slope was calculated using linear mixed effects models adjusted for age, sex, race, and time-updated CD4 cell count, viral load, antiretroviral therapy (ART), and comorbid conditions.
Results
We followed 615 patients for a mean of 3.4 (± 2.5) years. In multivariable adjusted analyses, predictors of eGFR decline included female sex, diabetes, and hyperlipidemia; CD4 cell count and viral load were not associated with eGFR loss. Among patients who initiated treatment, antiretroviral exposure was associated with a +2.8 (95% confidence interval 0.8–4.7) ml/min per 1.73 m2 per year effect on eGFR slope. Although these patients appeared to benefit from ART based on the slowing of their eGFR decline, they continued to lose kidney function at a rate of −1.9 (95% confidence interval −3.7 to −0.1) ml/min per 1.73 m2 per year. In the subgroup of individuals receiving suppressive ART with viral loads maintained below 500 copies/ml, intermittent viremic episodes (blips) were strongly associated with more rapid rates of eGFR loss [−6.7 (95% confidence interval −11.1 to −2.4) ml/min per 1.73 m2 per - year].
Conclusion
Although ART appears to help curb kidney function decline, patients who achieved durable viral suppression continue to manifest substantial loss of eGFR. Loss of kidney function may be attributable to treatment-related factors, intermittent viremia, and traditional risk factors for kidney disease.
doi:10.1097/QAD.0b013e3283313c91
PMCID: PMC2839451  PMID: 19684507
antiretroviral therapy; glomerular filtration rate; HIV; kidney diseases; viral load
4.  The impact of tenofovir disoproxil fumarate on kidney function: four-year data from the HIV-infected outpatient cohort 
Journal of the International AIDS Society  2014;17(4Suppl 3):19565.
Introduction
With improvements in survival and disease progression in the era of combined antiretroviral therapy, complications such as kidney disease are becoming increasingly prevalent in HIV-infected patients. Tenofovir disoproxil fumarate (TDF) has been associated with nephrotoxicity, including decline in glomerular filtration rate, proximal tubular damage and acute kidney injury.
Objective
Characterize kidney safety of TDF-containing antiretroviral treatment (ART) regimens in HIV-infected patients.
Methods
Non-controlled, observational, retrospective study was based on the clinical files registry of HIV patients who started TDF between January and December 2008. We assessed outpatients followed at a single Portuguese center. Demographic, clinical, virological and immunological data at baseline were collected. Serum creatinine, estimated glomerular filtration rate (eGFR) and creatinine clearance (CrCL) were assessed at baseline, after six months and every year up to four years. CrCL and eGFR were calculated by Cockroft–Gault and Modification of Diet in Renal Disease equations, respectively.
Results
A total of 176 patients (71.6% males) with a mean age of 43 years were enrolled. Ninety-six (52%) were ART-naive patients at TDF initiation. At baseline 12.5% had hypertension, 4% diabetes, 25% chronic hepatitis C and 9% chronic hepatitis B infections; 58% had normal renal function (eGFR ≥90 ml/min/1.73 m2), 36% had mild (eGFR 60-89 ml/min/1.73 m2) renal dysfunction and 2.3% had moderate (eGFR 30-59 ml/min/1.73 m2) renal dysfunction at initiation of TDF. Eighty-three (47%) patients were on protease inhibitors and the remaining on NNRTIs containing regimens. During 48 months follow-up, 5% experienced moderate renal dysfunction and 1.7% severe renal dysfunction. Twenty-one (12%) patients met the definition criteria of rapid decline of renal function (annual decline of eGFR ≥3 ml/min/1.73 m2 in two consecutive years). The development of kidney events was associated with age above 50 years, presence of comorbidities and advanced stage HIV infection (p>0.05 in univariate analysis).
Conclusions
These data reveal a favourable renal safety profile of TDF, during a four-year follow-up. Screening for kidney disease markers, regular follow-up and control and prevention of risk factors for renal failure are crucial for adequate management of HIV-infected patients.
doi:10.7448/IAS.17.4.19565
PMCID: PMC4224877  PMID: 25394072
5.  The prevalence and predictive value of dipstick urine protein in HIV-positive persons in Europe 
Journal of the International AIDS Society  2014;17(4Suppl 3):19561.
Introduction
Proteinuria (PTU) is an important marker for the development and progression of renal disease, cardiovascular disease and death, but there is limited information about the prevalence and factors associated with confirmed PTU in predominantly white European HIV+ persons, especially in those with an estimated glomerular filtration rate (eGFR) of 60 mL/min/1.73 m2.
Patients and methods
Baseline was defined as the first of two consecutive dipstick urine protein (DPU) measurements during prospective follow-up >1/6/2011 (when systematic data collection began). PTU was defined as two consecutive DUP >1+ (>30 mg/dL) >3 months apart; persons with eGFR <60 at either DPU measurement were excluded. Logistic regression investigated factors associated with PTU.
Results
A total of 1,640 persons were included, participants were mainly white (n=1,517, 92.5%), male (n=1296, 79.0%) and men having sex with men (n=809; 49.3%). Median age at baseline was 45 (IQR 37–52 years), and CD4 was 570 (IQR 406–760/mm3). The median baseline date was 2/12 (IQR 11/11–6/12), and median eGFR was 99 (IQR 88–109 mL/min/1.73 m2). Sixty-nine persons had PTU (4.2%, 95% CI 3.2–4.7%). Persons with diabetes had increased odds of PTU, as were those with a prior non-AIDS [1] or AIDS event and those with prior exposure to indinavir. Among females, those with a normal eGFR (>90) and those with prior abacavir use had lower odds of PTU (Figure 1).
There was no significant association between past or current use of tenofovir, lopinavir, atazanvir (boosted or unboosted) or any other boosted PI and PTU (p>0.2). During 688.2 person-years of follow up (PYFU), three persons developed chronic kidney disease (CKD; confirmed [>3 months apart] eGFR<60); 2/685 (0.3%) without PTU and 1/38 (2.8%) with PTU (p=0.032). The crude incidence of CKD in those with baseline PTU and eGFR>60 was almost 10 times higher than in those without baseline PTU and eGFR>60 (rate ratio 9.61; 95% CI 0.87–105.9, p=0.065).
Conclusions
One in 25 persons with eGFR>60 had confirmed proteinuria at baseline. Factors associated with PTU were similar to those associated with CKD. The lack of association with antiretrovirals, particularly tenofovir, may be due to the cross-sectional design of this study, and additional follow-up is required to address progression to PTU in those without PTU at baseline. It may also suggest other markers are needed to capture the deteriorating renal function associated with antiretrovirals may be needed at higher eGFRs. Our findings suggest PTU is an early marker for impaired renal function.
doi:10.7448/IAS.17.4.19561
PMCID: PMC4224881  PMID: 25394068
6.  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
7.  Factors Affecting Glomerular Filtration Rate, as Measured by Iohexol Disappearance, in Men with or at Risk for HIV Infection 
PLoS ONE  2014;9(2):e86311.
Objective
Formulae used to estimate glomerular filtration rate (GFR) underestimate higher GFRs and have not been well-studied in HIV-infected (HIV(+)) people; we evaluated the relationships of HIV infection and known or potential risk factors for kidney disease with directly measured GFR and the presence of chronic kidney disease (CKD).
Design
Cross-sectional measurement of iohexol-based GFR (iGFR) in HIV(+) men (n = 455) receiving antiretroviral therapy, and HIV-uninfected (HIV(−)) men (n = 258) in the Multicenter AIDS Cohort Study.
Methods
iGFR was calculated from disappearance of infused iohexol from plasma. Determinants of GFR and the presence of CKD were compared using iGFR and GFR estimated by the CKD-Epi equation (eGFR).
Results
Median iGFR was higher among HIV(+) than HIV(−) men (109 vs. 106 ml/min/1.73 m2, respectively, p = .046), and was 7 ml/min higher than median eGFR. Mean iGFR was lower in men who were older, had chronic hepatitis C virus (HCV) infection, or had a history of AIDS. Low iGFR (≤90 ml/min/1.73 m2) was associated with these factors and with black race. Other than age, factors associated with low iGFR were not observed with low eGFR. CKD was more common in HIV(+) than HIV(−) men; predictors of CKD were similar using iGFR and eGFR.
Conclusions
iGFR was higher than eGFR in this population of HIV-infected and -uninfected men who have sex with men. Presence of CKD was predicted equally well by iGFR and eGFR, but associations of chronic HCV infection and history of clinically-defined AIDS with mildly decreased GFR were seen only with iGFR.
doi:10.1371/journal.pone.0086311
PMCID: PMC3917840  PMID: 24516530
8.  Comparisons between validated estimated glomerular filtration rate (GFR) equations and isotopic GFR in HIV patients 
AIDS (London, England)  2012;26(14):1781-1788.
Objective
Understanding how best to measure renal function in HIV-infected patients is critical because estimated glomerular filtration rate (eGFR) in HIV-infected patients can be affected by ethnicity and body composition. We validated the available eGFR equations and compared them to the plasma 99mTc-diethylenetriaminepentaacetic acid (99mTc-DTPA) clearance in HIV-infected patients.
Design
Test of diagnostic accuracy.
Methods
196 HIV-infected patients underwent measuring 99mTc-DTPA plasma clearance, 5 creatinine-based eGFR equations, cystatin-C GFR and 24-hour urine creatinine clearance (CrCl).
Results
Mean (SD) 99mTc-DTPA GFR was 117.7±29.2 mL/min per 1.73 m2. The re-expressed MDRD, CKD-EPI, re-expressed MDRD formula with Thai racial correction factor, Thai eGFR equation, Cockcroft & Gault, cystatin-C GFR, and 24 hr urine CrCl, underestimated the reference GFR. The bias estimated by the mean of differences the limits of agreement for the re-expressed MDRD equation, CKD-EPI, re-expressed MDRD formula with Thai racial correction factor, Thai eGFR, Cockcroft & Gault, cystatin C, and 24 hr urine CrCl can be expressed as 18.9±27.3, 11.1±25.5, 6.2±28.8, 13.5±27.0, 30.4±28.0, 3.2±36.1, and 5.0±12.1 mL/min per 1.73 m2 respectively.
Conclusion
The available eGFR equations underestimated GFR in HIV-infected adults. However, the eGFR by cystacin C GFR was the most precise and accurate. Among Cr-based eGFR equations, re-expressed MDRD formula with Thai racial correction factor was the most precise and accurate. The racial factor for each ethnicity is important and the existing eGFR equation should be validated before using it in the HIV population.
doi:10.1097/QAD.0b013e328356480d
PMCID: PMC3782632  PMID: 22713478
99mTc-DTPA GFR; eGFR equation; glomerular filtration rate; HIV-infected patients; race
9.  Impact of Antiretroviral Therapy on Renal Function among HIV-Infected Tanzanian Adults: A Retrospective Cohort Study 
PLoS ONE  2014;9(2):e89573.
Background
Data regarding the outcomes of HIV-infected adults with baseline renal dysfunction who start antiretroviral therapy are conflicting.
Methods
We followed up a previously-published cohort of HIV-infected adult outpatients in northwest Tanzania who had high prevalence of renal dysfunction at the time of starting antiretroviral therapy (between November 2009 and February 2010). Patients had serum creatinine, proteinuria, microalbuminuria, and CD4+ T-cell count measured at the time of antiretroviral therapy initiation and at follow-up. We used the adjusted Cockroft-Gault equation to calculate estimated glomerular filtration rates (eGFRs).
Results
In this cohort of 171 adults who had taken antiretroviral therapy for a median of two years, the prevalence of renal dysfunction (eGFR <90 mL/min/1.73 m2) decreased from 131/171 (76.6%) at the time of ART initiation to 50/171 (29.2%) at the time of follow-up (p<0.001). Moderate dysfunction (eGFR<60 mL/min/1.73 m2) decreased from 21.1% at antiretroviral therapy initiation to 1.1% at follow-up (p<0.001), as did the prevalence of microalbuminuria (72% to 44%, p<0.001). Use of tenofovir was not associated with renal dysfunction at follow-up.
Conclusion
Mild and moderate renal dysfunction were common in this cohort of HIV-infected adults initiating antiretroviral therapy, and both significantly improved after a median follow-up time of 2 years. Our work supports the renal safety of antiretroviral therapy in African adults with mild-moderate renal dysfunction, suggesting that these regimens do not lead to renal damage in the majority of patients and that they may even improve renal function in patients with mild to moderate renal dysfunction.
doi:10.1371/journal.pone.0089573
PMCID: PMC3935873  PMID: 24586882
10.  Renal Dysfunction among HIV-Infected Patients Starting Antiretroviral Therapy in Mwanza, Tanzania 
AIDS (London, England)  2011;25(11):1421-1425.
Objective
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1097/QAD.0b013e328348a4b1
PMCID: PMC3631352  PMID: 21572304
renal dysfunction; HIV; antiretroviral therapy; sub-Saharan Africa
11.  Factors associated with renal dysfunction within an urban HIV-infected cohort in the era of highly active antiretroviral therapy 
HIV medicine  2009;10(6):343-350.
Background
Kidney disease remains a prevalent problem in HIV care. The contribution of highly active antiretroviral therapy (HAART), HIV disease factors and traditional factors needs further evaluation.
Methods
A cross-sectional study of all patients seen at an HIV outpatient clinic during 2005 was performed. All data were collected from medical record review. Multivariate regression modelling was used to identify independent predictors of lower glomerular filtration rate (eGFR) and chronic renal failure (CRF) from factors significant in univariate analysis. eGFR was calculated using the simplified modification of diet in renal disease equation. Results were compared with those for persons from the National Health and Nutrition Examination Survey (NHANES) matched for age, race and gender.
Results
Of 845 HIV-infected persons, 64% were men and 34% were Caucasian, and the mean age was 39.8 years. Thirty per cent of the patients had proteinuria and 43% had eGFR<90 mL/min/1.73 m2. Persons on HAART (63%) had a lower mean eGFR than those not on HAART (92.0 vs. 101.6). In multivariate analyses, significant predictors of eGFR decline were diagnoses of hypertension, hyperlipidaemia, proteinuria, use of tenofovir or stavudine, and lower viral load. Compared with those in NHANES, HIV-infected persons had a lower mean eGFR (94.9 vs. 104.2) and a higher prevalence of CRF (8% vs. 2%).
Conclusion
In this cohort, the prevalence of CRF is low, but remains higher than that of the general population. Clinicians should routinely screen for early asymptomatic kidney disease to address risk factors that can be treated.
doi:10.1111/j.1468-1293.2009.00693.x
PMCID: PMC3918930  PMID: 19490182
AIDS; chronic kidney disease; highly active antiretroviral therapy; HIV
12.  Association Between Antiretroviral Exposure and Renal Impairment Among HIV-Positive Persons With Normal Baseline Renal Function: the D:A:D Studya 
The Journal of Infectious Diseases  2013;207(9):1359-1369.
Background. Several antiretroviral agents (ARVs) are associated with chronic renal impairment, but the extent of such adverse events among human immunodeficiency virus (HIV)–positive persons with initially normal renal function is unknown.
Methods. D:A:D study participants with an estimated glomerular filtration rate (eGFR) of ≥90 mL/min after 1 January 2004 were followed until they had a confirmed eGFR of ≤70 mL/min (the threshold below which we hypothesized that renal interventions may begin to occur) or ≤60 mL/min (a value indicative of moderately severe chronic kidney disease [CKD]) or until the last eGFR measurement during follow-up. An eGFR was considered confirmed if it was detected at 2 consecutive measurements ≥3 months apart. Predictors and eGFR-related ARV discontinuations were identified using Poisson regression.
Results. Of 22 603 persons, 468 (2.1%) experienced a confirmed eGFR of ≤70 mL/min (incidence rate, 4.78 cases/1000 person-years of follow-up [95% confidence interval {CI}, 4.35–5.22]) and 131 (0.6%) experienced CKD (incidence rate, 1.33 cases/1000 person-years of follow-up [95% CI, 1.10–1.56]) during a median follow-up duration of 4.5 years (interquartile range [IQR], 2.7–6.1 years). A current eGFR of 60–70 mL/min caused significantly higher rates of discontinuation of tenofovir (adjusted incidence rate ratio [aIRR], 1.72 [95% CI, 1.38–2.14]) but not other ARVs compared with a current eGFR of ≥90 mL/min. Cumulative tenofovir use (aIRR, 1.18/year [95% CI, 1.12–1.25]) and ritonavir-boosted atazanavir use (aIRR, 1.19/year [95% CI, 1.09–1.32]) were independent predictors of a confirmed eGFR of ≤70 but were not significant predictors of CKD whereas ritonavir-boosted lopinavir use was a significant predictor for both end points (aIRR, 1.11/year [95% CI, 1.05–1.17] and 1.22/year [95% CI, 1.16–1.28], respectively). Associations were unaffected by censoring for concomitant ARV use but diminished after discontinuation of these ARVs.
Conclusions. Tenofovir, ritonavir-boosted atazanavir, and ritonavir-boosted lopinavir use were independent predictors of chronic renal impairment in HIV-positive persons without preexisting renal impairment. Increased tenofovir discontinuation rates with decreasing eGFR may have prevented further deteriorations. After discontinuation, the ARV-associated incidence rates decreased.
doi:10.1093/infdis/jit043
PMCID: PMC3610424  PMID: 23382571
HIV; eGFR; ART; tenofovir; atazanavir; lopinavir; chronic kidney disease; nephrotoxicity
13.  The Impact of Kidney Function at HAART Initiation on Mortality in HIV-infected Women 
Background
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1097/QAI.0b013e3181e674f4
PMCID: PMC3243740  PMID: 20581688
kidney disease; mortality; HIV; WIHS; antiretroviral therapy
14.  Prevalence and Factors Associated with Renal Dysfunction Among HIV-Infected Patients 
AIDS Patient Care and STDs  2010;24(6):353-360.
Abstract
Renal dysfunction is an increasingly recognized non-AIDS–defining comorbidity among HIV-infected persons. The role of HIV-related factors in renal dysfunction remains unclear. We performed a cross-sectional study at two military clinics with open access to care to determine the impact of HIV factors, including antiretroviral therapy, on renal function. Renal dysfunction was defined as a glomerular filtration rate (GFR) < 60 mL/min/1.73 m2. We evaluated 717 HIV patients with a median age of 41 years; 92% were male, 49% Caucasian, and 38% African American; median CD4 count was 515 cells/mm3 and 73% were receiving highly active antiretroviral therapy (HAART). Twenty-two patients (3%) had renal dysfunction. Factors associated with renal dysfunction in the multivariate logistic analyses included older age (odds ratio [OR] 2.0 per 10 year increase, p = 0.006), lower CD4 nadir (OR 0.6 per 100 cell change, p = 0.02), and duration of tenofovir use (OR 1.5 per year use, p = 0.01). Among persons initiating tenofovir (n = 241), 50% experienced a reduction in GFR (median −10.5 mL/min/1.73 m2, 95% CI, −8.9 to −13.3) within 2 years. Among tenofovir users, factors associated with a reduction in GFR included female gender (p < 0.001), African American ethnicity (p = 0.003), and lower CD4 nadir (p = 0.002). In summary, renal dysfunction was relatively uncommon among our HIV-infected patients, perhaps due to their young age, lack of comorbidities, or as a result of our definition that did not include proteinuria. Renal dysfunction was associated with duration of tenofovir use. Factors associated with renal loss among tenofovir users included female gender, African American ethnicity, and CD4 nadir <200 cells/mm3. Consideration for more frequent monitoring of kidney function among these select HIV patients may be warranted.
doi:10.1089/apc.2009.0326
PMCID: PMC2933561  PMID: 20515419
15.  Use of glomerular filtration rate estimating equations for drug dosing in HIV-positive patients 
Antiviral therapy  2013;18(6):793-802.
Background
Current HIV treatment guidelines recommend using the Cockcroft-Gault equation for drug dosing adjustments. The use of newer glomerular filtration rate (GFR) estimating equations for drug dosing and the appropriateness of physician antiretroviral dosing based on estimated kidney function have not been studied in an HIV-positive population.
Methods
We evaluated concordance between measured and estimated GFR for the assignment of kidney function categories designated by the Food and Drug Administration (FDA) Guidance for Industry for pharmacokinetic studies, and appropriateness of physician antiretroviral drug dosing for level of kidney function in 200 HIV-positive patients on stable antiretroviral therapy. Estimated kidney function was determined using the Chronic Kidney Disease-Epidemiology collaboration (CKD-EPI), Modification of Diet in Renal Disease (MDRD) Study and Cockcroft-Gault equations.
Results
For assignment of FDA-designated kidney function categories, concordance rates between measured and estimated GFR using the CKD-EPI, MDRD Study and Cockcroft-Gault equations were 79%, 71% and 77%, respectively. This pattern was consistent across most subgroups. When actual prescribed dosages were compared to recommended dosages based on the level of estimated kidney function, 3% to 19% of study participants were prescribed higher than recommended dosages. The largest discordance between prescribed and recommended dosages was observed for the Cockcroft-Gault equation.
Conclusions
The CKD-EPI equation has the highest concordance with measured GFR for the assignment of FDA-designated kidney function categories. Its use may lead to lower dosing related errors in HIV-infected US adults on stable antiretroviral therapy. More education is required with respect to dose adjustment for level of kidney function.
doi:10.3851/IMP2676
PMCID: PMC4018994  PMID: 23963249
16.  Emergence of Drug Resistance Is Associated with an Increased Risk of Death among Patients First Starting HAART 
PLoS Medicine  2006;3(9):e356.
Background
The impact of the emergence of drug-resistance mutations on mortality is not well characterized in antiretroviral-naïve patients first starting highly active antiretroviral therapy (HAART). Patients may be able to sustain immunologic function with resistant virus, and there is limited evidence that reduced sensitivity to antiretrovirals leads to rapid disease progression or death. We undertook the present analysis to characterize the determinants of mortality in a prospective cohort study with a median of nearly 5 y of follow-up. The objective of this study was to determine the impact of the emergence of drug-resistance mutations on survival among persons initiating HAART.
Methods and Findings
Participants were antiretroviral therapy naïve at entry and initiated triple combination antiretroviral therapy between August 1, 1996, and September 30, 1999. Marginal structural modeling was used to address potential confounding between time-dependent variables in the Cox proportional hazard regression models. In this analysis resistance to any class of drug was considered as a binary time-dependent exposure to the risk of death, controlling for the effect of other time-dependent confounders. We also considered each separate class of mutation as a binary time-dependent exposure, while controlling for the presence/absence of other mutations. A total of 207 deaths were identified among 1,138 participants over the follow-up period, with an all cause mortality rate of 18.2%. Among the 679 patients with HIV-drug-resistance genotyping done before initiating HAART, HIV-drug resistance to any class was observed in 53 (7.8%) of the patients. During follow-up, HIV-drug resistance to any class was observed in 302 (26.5%) participants. Emergence of any resistance was associated with mortality (hazard ratio: 1.75 [95% confidence interval: 1.27, 2.43]). When we considered each class of resistance separately, persons who exhibited resistance to non-nucleoside reverse transcriptase inhibitors had the highest risk: mortality rates were 3.02 times higher (95% confidence interval: 1.99, 4.57) for these patients than for those who did not exhibit this type of resistance.
Conclusions
We demonstrated that emergence of resistance to non-nucleoside reverse transcriptase inhibitors was associated with a greater risk of subsequent death than was emergence of protease inhibitor resistance. Future research is needed to identify the particular subpopulations of men and women at greatest risk and to elucidate the impact of resistance over a longer follow-up period.
Emergence of resistance to both non-nucleoside reverse transcriptase inhibitors and protease inhibitors was associated with a higher risk of subsequent death, but the risk was greater in patients with NNRTI-resistant HIV.
Editors' Summary
Background.
In the 1980s, infection with the human immunodeficiency virus (HIV) was effectively a death sentence. HIV causes AIDS (acquired immunodeficiency syndrome) by replicating inside immune system cells and destroying them, which leaves infected individuals unable to fight off other viruses and bacteria. The first antiretroviral drugs were developed quickly, but it soon became clear that single antiretrovirals only transiently suppress HIV infection. HIV mutates (accumulates random changes to its genetic material) very rapidly and, although most of these changes (or mutations) are bad for the virus, by chance some make it drug resistant. Highly active antiretroviral therapy (HAART), which was introduced in the mid-1990s, combines three or four antiretroviral drugs that act at different stages of the viral life cycle. For example, they inhibit the reverse transcriptase that the virus uses to replicate its genetic material, or the protease that is necessary to assemble new viruses. With HAART, the replication of any virus that develops resistance to one drug is inhibited by the other drugs in the mix. As a consequence, for many individuals with access to HAART, AIDS has become a chronic rather than a fatal disease. However, being on HAART requires patients to take several pills a day at specific times. In addition, the drugs in the HAART regimens often have side effects.
Why Was This Study Done?
Drug resistance still develops even with HAART, often because patients don't stick to the complicated regimens. The detection of resistance to one drug is usually the prompt to change a patient's drug regimen to head off possible treatment failure. Although most patients treated with HAART live for many years, some still die from AIDS. We don't know much about how the emergence of drug-resistance mutations affects mortality in patients who are starting antiretroviral therapy for the first time. In this study, the researchers looked at how the emergence of drug resistance affected survival in a group of HIV/AIDS patients in British Columbia, Canada. Here, everyone with HIV/AIDS has access to free medical attention, HAART, and laboratory monitoring, and full details of all HAART recipients are entered into a central reporting system.
What Did the Researchers Do and Find?
The researchers enrolled people who started antiretroviral therapy for the first time between August 1996 and September 1999 into the HAART Observational Medical Evaluation and Research (HOMER) cohort. They then excluded anyone who was infected with already drug-resistant HIV strains (based on the presence of drug-resistance mutations in viruses isolated from the patients) at the start of therapy. The remaining 1,138 patients were followed for an average of five years. All the patients received either two nucleoside reverse transcriptase inhibitors and a protease inhibitor, or two nucleoside and one non-nucleoside reverse transcriptase inhibitor (NNRTI). Nearly a fifth of the study participants died during the follow-up period. Most of these patients actually had drug-sensitive viruses, possibly because they had neglected taking their drugs to such an extent that there had been insufficient drug exposure to select for drug-resistant viruses. In a quarter of the patients, however, HIV strains resistant to one or more antiretroviral drugs emerged during the study (again judged by looking for mutations). Detailed statistical analyses indicated that the emergence of any drug resistance nearly doubled the risk of patients dying, and that people carrying viruses resistant to NNRTIs were three times as likely to die as those without resistance to this class of antiretroviral drug.
What Do These Findings Mean?
These results provide new information about the emergence of drug-resistant HIV during HAART and possible effects on the long-term survival of patients. In particular, they suggest that clinicians should watch carefully for the emergence of resistance to NNRTIs in their patients. Because this type of resistance is often due to poor adherence to drug regimens, these results also suggest that increased efforts should be made to ensure that patients comply with the prescribed HAART regimens, especially those whose antiretroviral therapy includes NNRTIs. As with all studies in which a group of individuals who share a common characteristic are studied over time, it is possible that some other, unmeasured difference between the patients who died and those who didn't—rather than emerging drug resistance—is responsible for the observed differences in survival. Additional studies are needed to confirm the findings here, and to investigate whether specific subpopulations of patients are at particular risk of developing drug resistance and/or dying during HAART.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030356.
US National Institute of Allergy and Infectious Diseases fact sheet on HIV infection and AIDS
US Department of Health and Human Services information on AIDS, including details of approved drugs for the treatment of HIV infection
US Centers for Disease Control and Prevention information on HIV/AIDS
Aidsmap, information on HIV and AIDS provided by the charity NAM, which includes details on antiretroviral drugs
doi:10.1371/journal.pmed.0030356
PMCID: PMC1569883  PMID: 16984218
17.  Kidney function of HIV-infected children in Lagos, Nigeria: using Filler's serum cystatin C-based formula 
Background
Limited data is available on kidney function in HIV-infected children in sub-Saharan Africa. In addition, malnutrition in these children further reduces the utility of diagnostic methods such as creatinine-based estimates of glomerular filtration rate. We determined the serum cystatin C level and estimated glomerular filtration rate of 60 antiretroviral-naïve, HIV-infected children and 60 apparently healthy age and sex matched children.
Methods
Serum cystatin C level was measured using enzyme-linked immunosorbent assay technique, while glomerular filtration rate was estimated using Filler's serum cystatin C formula. Student t test, Mann Whitney U test, Pearson chi square and Fisher's exact test were used, where appropriate, to test difference between groups.
Results
Compared to the controls, the HIV-infected group had significantly higher median (interquartile range) serum cystatin C levels {0.77 (0.29) mg/l versus 0.66 (0.20) mg/l; p = 0.025} and a higher proportion of children with serum cystatin C level >1 mg/l {10 (16.7%) versus one (1.7%); p = 0.004}. The HIV-infected children had a mean (± SD) eGFR of 96.8 (± 36.1) ml/min/1.73 m2 compared with 110.5 (± 27.8) ml/min/1.73 m2 in the controls (p = 0.021). After controlling for age, sex and body mass index, only the study group (HIV infected versus control) remained a significant predictor of serum cystatin C level (β = -0.216, p = 0.021). The proportion of HIV-infected children with eGFR <60 ml/min/1.73 m2 was eight (13.3%) versus none (0%) in the control group (p = 0.006). However, the serum cystatin C level, eGFR and proportions of children with serum cystatin C level >1 mg/l and eGFR <60 ml/min/1.73 m2 were not significantly different between the HIV-infected children with advanced disease and those with milder disease.
Conclusions
HIV-infected children in Nigeria have higher serum cystatin C level and lower eGFR compared to age and sex matched controls.
doi:10.1186/1758-2652-13-17
PMCID: PMC2888781  PMID: 20482807
18.  Hepatitis C Seropositivity and Kidney Function Decline Among Women With HIV: Data From the Women's Interagency HIV Study 
Background
How co-infection with hepatitis C virus (HCV) impacts on the trajectory of kidney function among HIV-infected patients is unclear. This study examined the effect of HCV on kidney function over time among women infected with HIV.
Study Design
Retrospective observational cohort
Setting and Participants
Study sample included participants from the Women's Interagency HIV Study who were HIV-infected and had received HCV antibody testing and serum creatinine measurement at baseline.
Predictor
HCV seropositivity
Outcomes and Measurement
Estimated glomerular filtration rate (eGFR) calculated from semi-annual serum creatinine measurements using the 4-variable Modification of Diet in Renal Diseases (MDRD) Study equation. Linear mixed models were used to evaluate the independent effect of being HCV seropositive on eGFR over time, adjusting for demographic factors, co-morbid conditions, illicit drug use, measures of HIV disease status, use of medications, and interactions with baseline low eGFR (<60 mL/min/1.73m2).
Results
Of the 2,684 HIV-infected women, 952 (35%) were found to be HCV seropositive. For 180 women with CKD at baseline (eGFR <60 mL/min/1.73m2), being HCV seropositive was independently associated with a fully-adjusted net decline in eGFR of about 5% per year (95% CI: 3.2 to 7.2%), relative to women who were seronegative. In contrast, HCV was not independently associated with decline in eGFR among women without low eGFR at baseline (p<0.001 for interaction).
Limitations
The MDRD Study equation has not been validated as a measure of GFR among persons with HIV or HCV. Proteinuria was not included in the study analysis. Because the study is observational, the effects of residual confounding cannot be excluded.
Conclusions
Among HIV-infected women with CKD, co-infection with HCV is associated with a modest, but statistically significant decline in eGFR over time. More careful monitoring of kidney function may be warranted for HIV-infected patients with CKD who are also co-infected with HCV.
doi:10.1053/j.ajkd.2009.02.009
PMCID: PMC2997705  PMID: 19394735
hepatitis C virus; HIV; kidney diseases; women
19.  Hyperuricemia and deterioration of renal function in autosomal dominant polycystic kidney disease 
BMC Nephrology  2014;15:63.
Background
The role of hyperuricemia in disease progression of autosomal dominant polycystic kidney disease (ADPKD) has not been defined well. We investigated the association of serum uric acid (sUA) with renal function and the effect of hypouricemic treatment on the rate of renal function decline.
Methods
This is a single-center, retrospective, observational cohort study. A total of 365 patients with ADPKD who had estimated glomerular filtration rate (eGFR) ≥ 15 mL/min/1.73 m2 and who were followed up for > 1 year were included in our analysis. Hyperuricemia was defined by a sUA level of ≥ 7.0 mg/dL in male and ≥ 6.0 mg/dL in female or when hypouricemic medications were prescribed.
Results
Hyperuricemia was associated with reduced initial eGFR, independent of age, sex, hypertension, albuminuria, and total kidney volume. During a median follow-up period of over 6 years, patients with hyperuricemia showed a faster annual decline in eGFR (−6.3% per year vs. −0.9% per year, p = 0.008). However, after adjusting for age, sex, hypertension and initial eGFR, sUA was no longer associated with either annual eGFR decline or the development of ESRD. Among 53 patients who received hypouricemic treatment, the annual eGFR decline appeared to be attenuated after hypouricemic treatment (pretreatment vs. posttreatment: −5.3 ± 8. 2 vs. 0.2 ± 6.2 mL/min/1.73 m2 per year, p = 0.001 by Wilcoxon signed-rank test).
Conclusions
Although hyperuricemia was associated with reduced eGFR, it was not an independent factor for renal progression in ADPKD. However, the correction of hyperuricemia may attenuate renal function decline in some patients with mild renal insufficiency.
doi:10.1186/1471-2369-15-63
PMCID: PMC4021172  PMID: 24739095
Glomerular filtration rate; Hyperuricemia; Polycystic kidney; Autosomal dominant; Uric acid
20.  The Effect of Highly Active Antiretroviral Therapy on the Survival of HIV-Infected Children in a Resource-Deprived Setting: A Cohort Study 
PLoS Medicine  2011;8(6):e1001044.
This observational cohort study by Andrew Edmonds and colleagues reports that treatment with highly active antiretroviral therapy (HAART) markedly improves the survival of HIV-infected children in Kinshasa, DRC, a resource-deprived setting.
Background
The effect of highly active antiretroviral therapy (HAART) on the survival of HIV-infected children has not been well quantified. Because most pediatric HIV occurs in low- and middle-income countries, our objective was to provide a first estimate of this effect among children living in a resource-deprived setting.
Methods and Findings
Observational data from HAART-naïve children enrolled into an HIV care and treatment program in Kinshasa, Democratic Republic of the Congo, between December 2004 and May 2010 were analyzed. We used marginal structural models to estimate the effect of HAART on survival while accounting for time-dependent confounders affected by exposure. At the start of follow-up, the median age of the 790 children was 5.9 y, 528 (66.8%) had advanced or severe immunodeficiency, and 405 (51.3%) were in HIV clinical stage 3 or 4. The children were observed for a median of 31.2 mo and contributed a total of 2,089.8 person-years. Eighty children (10.1%) died, 619 (78.4%) initiated HAART, six (0.8%) transferred to a different care provider, and 76 (9.6%) were lost to follow-up. The mortality rate was 3.2 deaths per 100 person-years (95% confidence interval [CI] 2.4–4.2) during receipt of HAART and 6.0 deaths per 100 person-years (95% CI 4.1–8.6) during receipt of primary HIV care only. The mortality hazard ratio comparing HAART with no HAART from a marginal structural model was 0.25 (95% CI 0.06–0.95).
Conclusions
HAART reduced the hazard of mortality in HIV-infected children in Kinshasa by 75%, an estimate that is similar in magnitude but with lower precision than the reported effect of HAART on survival among children in the United States.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
In 2009, an estimated 2.5 million children were living with HIV, the majority of whom (2.3 million) were in sub-Saharan Africa. Most (90%) of these children acquired HIV from their HIV-infected mothers during pregnancy, birth, or breastfeeding, highlighting the importance of giving effective drugs for the prevention of mother to child transmission. As such interventions are still not widely accessible or available in most resource-limited countries, where the burden of HIV is highest, every day an estimated 1,000 children were newly infected with HIV in 2009, but only 360,000 children were receiving highly active antiretroviral therapy (HAART).
Although HAART improves the survival of adults living with HIV, less is known about the degree to which HAART affects the survival of HIV-infected children—although response to antiretroviral treatment is known to differ across age groups. Furthermore, as the course of HIV disease in children is different from that in adults (partly because of the impact of the virus on the immature thymus, which can lead to high HIV RNA viremia and rapid death), it is inappropriate to extrapolate results from studies of adults to pediatric populations. Therefore, it is imperative that the effect of HAART on survival be quantified specifically in children.
Why Was This Study Done?
Most observational studies of the effects of treatment on child survival have been undertaken in high-income countries, such as Italy and the United States. As most children with HIV live in low-resource areas, where multiple factors, such as delayed presentation to care and a higher incidence of co-occurring conditions, might adversely affect treatment outcomes, there is a specific need for information on the effects of HAART in children with HIV living in low-income countries. Although some investigations have taken place in pediatric cohorts from such countries (for example, Côte d'Ivoire, Haiti, Lesotho, Thailand, and Zambia), the effect of HAART on mortality has not been accurately quantified among children in a resource-deprived setting. Therefore, in this observational clinical cohort study, the researchers investigated the effect of HAART on mortality in HIV-infected children in Kinshasa, in the Democratic Republic of the Congo (DRC).
What Did the Researchers Do and Find?
The researchers analyzed data from 790 children enrolled into an HIV program in Kinshasa, DRC, between December 2004 and May 2010 and used a statistical model (marginal structural models) to adjust for time-dependent confounding factors, such as the fact that HAART is typically initiated in sicker patients, for example, those with lower CD4 cell percentages. Assuming that all children starting HAART received it uninterruptedly throughout follow-up, using this statistical model, the researchers were able to compare the hazard ratio of death had all children initiated HAART to that had no children initiated HAART during follow-up.
In the study, 619 out of the 790 children (78.4%) initiated HAART during follow-up and were followed for a median of 31.2 months, with a median of 30 HIV care visits. Of those who started treatment, 110 (17.8%) switched to an alternative regimen because of an adverse event or treatment failure. During the 2,089.8 accrued person-years of follow-up, 80 children (10.1%) died, giving an overall mortality rate of 3.8 deaths per 100 person-years. The unadjusted mortality rate ratio comparing HAART to no HAART was 0.54. Using a marginal structural model, the researchers estimated that compared to no HAART, HAART reduced the hazard (rate) of mortality during follow-up by 75%.
What Do These Findings Mean?
These findings show that treatment with HAART markedly improved the survival of children infected with HIV in Kinshasa, DRC, and suggest that HAART is as effective in improving the survival of HIV-infected children in a severely resource-deprived country (still recovering from civil war) as in more resource-privileged settings—an important finding given that the vast majority of children receiving HAART live in resource-poor areas. This study provides additional evidence that accelerating rollout of antiretroviral therapy to children with HIV in resource-poor countries is lifesaving and effective. Future research needs to address how effective HAART is in understudied populations in resource-poor countries, such as undernourished children or those with co-infections such as tuberculosis.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001044.
The World Health Organization's Web site has more information about the treatment of children living with HIV
Médecins Sans Frontières's Campaign for Access to Essential Medicines Web site has more information on pediatric HAART
doi:10.1371/journal.pmed.1001044
PMCID: PMC3114869  PMID: 21695087
21.  Renal Function in Ghanaian HIV-Infected Patients on Highly Active Antiretroviral Therapy: A Case-Control Study 
PLoS ONE  2014;9(6):e99469.
Background
HAART is anticipated to result in an increase in long-term survival, but may present with the development of associated complications. The aim of this study was to assess the renal function of HIV-infected patients on antiretroviral therapy.
Methods
A case-control study (January to May 2013) conducted at the Suntreso Government Hospital, Kumasi, Ghana. A total of 163 HIV-infected patients (mean age 39.9±10.22) were studied, of which 111 were on HAART (HIV-HAART) and 52 were not (HIV-Controls). Serum urea, creatinine, potassium, sodium, chloride and CD4 counts were measured with the determination of eGFR (CKD-EPI and MDRD). Data was analysed using GraphPad Prism. The Chi-square, t-test, one-way ANOVA and Spearman's correlation were used. P values <0.05 were considered significant.
Results
Mean CD4 count of HIV-Controls was higher than that of HIV-HAART but was not significant (p = 0.304). But for sodium levels which were higher in HIV-Controls (p = 0.0284), urea (p = 0.1209), creatinine (p = 0.7155), potassium (p = 0.454) and chloride (p = 0.6282) levels did not differ significantly between both groups. All serum biochemical parameters did not differ significantly, irrespective of duration on therapy and CD4 counts. Based on regimen, sodium, chloride, urea and creatinine did not differ significantly between TDF, EVF and NVP-based therapies. Prevalence of CKD (eGFR <60 ml/min/1.73 m2) in the total population was 9.9% and 3.7% with the MDRD and EPI-CKD equations respectively.
Conclusions
Renal insufficiency remains prevalent in HIV patients. Changes in renal function occur in HIV infection and over the course of HAART but the difference at either stage is not significant. This suggests the role of HIV infection, HAART and the presence of traditional risk factors but not HAART in itself, in renal dysfunction. We however recommend a close monitoring of patients before and during HAART, to aid in evaluating drug combinations and implement dose modifications when necessary.
doi:10.1371/journal.pone.0099469
PMCID: PMC4055675  PMID: 24921259
22.  Clinical Assessment of Follow-Up Cystatin C-Based eGFR in Live Kidney Donors 
Korean Journal of Urology  2012;53(10):721-725.
Purpose
We aimed to compare the cystatin C-based estimated glomerular filtration rate (eGFR) and the serum creatinine-based eGFR and to investigate the clinical roles of the cystatin C-based eGFR in assessing the follow-up renal function of kidney donors.
Materials and Methods
We enrolled 121 healthy kidney donors who underwent live donor nephrectomy between October 2009 and December 2010 in a prospective manner. Serum creatinine and cystatin C were measured preoperatively and were followed after the surgery (1st, 4th, and 7th postoperative day and 1st, 3rd, 6th, and 12th postoperative month). We also compared the sensitivity and specificity of each eGFR method for predicting the development of chronic kidney disease (CKD) after donor nephrectomy.
Results
For those who had a Modification of Diet in Renal Disease postoperative day 4 eGFR of less than 60 ml/min/1.73 m2, the probability of developing CKD was 89.0% (Chronic Kidney Disease Epidemiology Collaboration eGFR, 66.0%; Cockcroft-Gault eGFR, 74.0%; cystatin C eGFR, 57.1%). A cystatin C eGFR of below 60 ml/min/1.73 m2 at postoperative day 4 predicted CKD at 6 months with a specificity of 90.3%, which was the highest among the estimation methods used. Cystatin C eGFRs were generally higher than the creatinine-based eGFRs.
Conclusions
We conclude that cystatin C-based estimations of the GFR are helpful for predicting the recovery of renal function in kidney donors and could be added to the follow-up protocol of kidney donors who may develop CKD, especially patients whose immediate postoperative renal function is marginal.
doi:10.4111/kju.2012.53.10.721
PMCID: PMC3490094  PMID: 23136634
Kidney function tests; Kidney transplantation; Living donors; Nephrectomy
23.  Impact of comorbidities and drug therapy on development of renal impairment in a predominantly African American and Hispanic HIV clinic population 
Purpose
Renal impairment in human immunodeficiency virus (HIV)-infected patients could potentially be caused by many factors. HIV-related renal impairment risks have been little studied in African Americans and Hispanics. We investigated the impact of HIV itself, highly active antiretroviral therapy (HAART), comorbidities, and non-HIV-related drug treatment on glomerular filtration rate in a predominantly African American/Hispanic HIV-infected population who had received HAART for at least one year. This study was a retrospective electronic medical record database evaluation of renal impairment risks in a largely African American/Hispanic HIV population obtaining medical care at an HIV clinic in Dallas, Texas.
Methods
Proportional hazards models were used to investigate an association between an estimated glomerular filtration rate decrease >25% from baseline (ie, renal impairment) and demographics, antiretroviral/nonantiretroviral medications, comorbidities (hypertension, diabetes mellitus, hepatitis C virus [HCV] infection, hepatitis B virus [HBV] infection), CD4+ counts, viral load, and duration patients were monitored at the clinic (time on study).
Results
In total, 323 patients were evaluated: 82% males; 61% African American/12% Hispanic/19% Caucasian; mean age 37.9 years (standard deviation [SD] 8.5); 6% HBV-positive; 34% HCV-positive; 29% hypertensive; 3% diabetic; 52% tenofovir-treated; mean weight 75.4 kg (SD, 15.4); mean estimated glomerular filtration 114.5 mL/min/1.73 m2 (SD, 36.7) using the Modification of Diet in Renal Disease (MDRD) calculation method; mean creatinine clearance (from which estimated glomerular filtration was extrapolated) by the Cockcroft-Gault calculation method 120.6 mL/min/1.73 m2 (SD, 41.2); mean time on study 2.7 years (SD, 1.0 year). An estimated glomerular filtration rate decrease of >25% from baseline was significantly associated with time on study (P = 0.0017; hazards ratio [HR] = 0.999) and hypertension (HR = 1.706; P = 0.0158) by the MDRD method, and with age (HR = 1.039; P = 0.0077), weight (HR = 0.987; P = 0.0023), and time on study (HR = 0.999; P = 0.0043) by extrapolation of Cockcroft-Gault creatinine clearance calculation. No specific HAART agent was associated with significant renal impairment risk by the definition used in this study.
Conclusion
This retrospective database study showed time on study, hypertension, weight, and age to be the only significant predictors of an estimated glomerular filtration rate decrease >25% from baseline.
doi:10.2147/HIV.S13902
PMCID: PMC3218712  PMID: 22096402
nephropathy; antiretroviral therapy; comorbidities; tenofovir; African American; Hispanic
24.  Prevalence of low glomerular filtration rate, proteinuria and associated risk factors in North India using Cockcroft-Gault and Modification of Diet in Renal Disease equation: an observational, cross-sectional study 
BMC Nephrology  2009;10:4.
Background
Chronic kidney disease (CKD) is increasingly being recognized as an emerging public health problem in India. However, community based estimates of low glomerular filtration rate (GFR) and proteinuria are few. Validity of traditional serum creatinine based GFR estimating equations in South Asian subjects is also debatable. We intended to estimate and compare the prevalence of low GFR, proteinuria and associated risk factors in North India using Cockcroft-Gault (CG) and Modification of Diet In Renal Disease (MDRD) equation.
Methods
A community based, cross-sectional study involving multistage random cluster sampling was done in Delhi and its surrounding regions. Adults ≥ 20 years were surveyed. CG and MDRD equations were used to estimate GFR (eGFR). Low GFR was defined as eGFR < 60 ml/min/1.73 m2. Proteinuria (≥ 1+) was assessed using visually read dipsticks. Odds ratios, crude and adjusted, were calculated to ascertain associations between renal impairment, proteinuria and risk factors.
Results
The study population had 3,155 males and 2,097 females. The mean age for low eGFR subjects was 54 years. The unstandardized prevalence of low eGFR was 13.3% by CG equation and 4.2% by MDRD equation. The prevalence estimates of MDRD equation were lower across gender and age groups when compared with CG equation estimates. There was a strong correlation but poor agreement between GFR estimates of two equations. The survey population had a 2.25% prevalence of proteinuria. In a multivariate logistic regression analysis; age above 60 years, female gender, low educational status, increased waist circumference, hypertension and diabetes were associated with low eGFR. Similar factors were also associated with proteinuria. Only 3.3% of subjects with renal impairment were aware of their disease.
Conclusion
The prevalence of low eGFR in North India is probably higher than previous estimates. There is a significant difference between GFR estimates derived from CG and MDRD equations. These equations may not be useful in epidemiological research. GFR estimating equations validated for South Asian populations are needed before reliable estimates of CKD prevalence can be obtained. Till then, primary prevention and management targeted at CKD risk factors must play a critical role in controlling rising CKD magnitude. Cost-benefit analysis of targeted screening programs is needed.
doi:10.1186/1471-2369-10-4
PMCID: PMC2663556  PMID: 19220921
25.  Reduced renal function is associated with progression to AIDS but not with overall mortality in HIV-infected kenyan adults not initially requiring combination antiretroviral therapy 
Background
The World Health Organization (WHO) has recently recommended that antiretrovirals be initiated in all individuals with CD4 counts of less than 350 cells/mm3. For countries with resources too limited to expand care to all such patients, it would be of value to able to identify and target populations at highest risk of HIV progression. Renal disease has been identified as a risk factor for disease progression or death in some populations.
Methods
Times to meeting combination antiretroviral therapy (cART) initiation criteria (developing either a CD4 count < 200 cells/mm3 or WHO stage 3 or 4 disease) and overall mortality were evaluated in cART-naïve, HIV-infected Kenyan adults with CD4 cell counts ≥200/mm3 and with WHO stage 1 or 2 disease. Cox proportional hazard regression models were used to evaluate the associations between renal function and these endpoints.
Results
We analyzed data of 7383 subjects with a median follow-up time of 59 (interquartile range, 27-97) weeks. In Cox regression analyses adjusted for age, sex, WHO disease stage, CD4 cell count and haemoglobin, estimated creatinine clearance (CrCl) < 60 mL/min was significantly associated with shorter times to meeting cART initiation criteria (HR 1.34; 95% CI, 1.23-1.52) and overall mortality (HR 1.73; 95% CI, 1.19-2.51) compared with CrCl ≥60 mL/min. Estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 was associated with shorter times to meeting cART initiation criteria (HR 1.39; 95% CI, 1.22-1.58), but not with overall mortality. CrCl and eGFR remained associated with shorter times to cART initiation criteria, but neither was associated with mortality, in weight-adjusted analyses.
Conclusions
In this large natural history study, reduced renal function was strongly associated with faster HIV disease progression in adult Kenyans not initially meeting cART initiation criteria. As such, renal function measurement in resource-limited settings may be an inexpensive method to identify those most in need of cART to prevent progression to AIDS. The initial association between reduced CrCl, but not reduced eGFR, and greater mortality was explained by the low weights in this population.
doi:10.1186/1758-2652-14-31
PMCID: PMC3125307  PMID: 21663693

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