Lucy J. Campbell

Spectrum of chronic kidney disease in HIV-infected patients.

The aim of the study was to investigate the prevalence and aetiology of chronic kidney disease (CKD) and trends in estimated glomerular filtration rate (eGFR) in HIV‐infected patients.

HIV Care and the Incidence of Acute Renal Failure

BACKGROUND The clinical epidemiology of acute renal failure (ARF) in human immunodeficiency virus (HIV)-infected patients remains poorly defined. METHODS We conducted a retrospective analysis of patients who developed ARF while attending Kings College Hospital (London, United Kingdom) during January 1998-December 2005. Serum creatinine level and estimated glomerular filtration rate were used to identify ARF. ARF episodes were classified as early onset if they occurred <3 months after initiation of HIV care and as late onset if they occurred > or =3 months after initiation of HIV care. RESULTS During the study period, 130 (5.7%) of 2274 patients developed 144 episodes of ARF. The incidences of early-onset and late-onset ARF were 19.3 episodes per 100 person-years (95% confidence interval [CI], 15.4-24.1 episodes per 100 person-years) and 1.1 episodes per 100 person-years (95% CI, 0.83-1.49 episodes per 100 person-years), respectively (rate ratio, 17.4; P<0.001). In multivariate analysis, nadir CD4 T cell count <100 x 10(9) cells/L (odds ratio [OR], 6.7; 95% CI, 2.5-18.3) and acquired immunodeficiency syndrome (OR, 6.7; 95% CI, 3.4-13.3) were associated with early-onset ARF, whereas injection drug use (OR, 4.8; 95% CI, 1.3-17.7), hepatitis C virus coinfection (OR, 3.4; 95% CI, 1.3-8.6), and nadir CD4 T cell count <100 x 10(9) cells/L (OR, 5.8; 95% CI, 2.5-13.4) were associated with late-onset ARF. CONCLUSIONS ARF was common and was associated with advanced immunodeficiency. The incidence of ARF decreased >10-fold in patients who had received HIV care for > or =3 months.

Predictors of Renal Outcome in HIV-Associated Nephropathy

BACKGROUND Human immunodeficiency virus (HIV)-associated nephropathy (HIVAN) is an important cause of end-stage renal disease among African American patients. This study was performed to study the epidemiology of HIVAN in a predominantly black African population and the impact of highly active antiretroviral therapy and other factors on the development of end-stage renal disease. METHODS We retrospectively identified all patients with HIVAN, defined by biopsy or strict clinical criteria, in 8 clinics in the United Kingdom. Baseline renal function, HIV parameters, renal pathological index of chronic damage, and responses to highly active antiretroviral therapy were analyzed, and factors associated with adverse renal outcome were identified. RESULTS From 1998 through 2004, we studied 16,834 patients, 61 of whom had HIVAN. HIVAN prevalence in black patients was 0.93%, and HIVAN incidence in those without renal disease at baseline was 0.61 per 1000 person-years. After a median of 4.2 years, 34 patients (56%) had developed end-stage renal disease. There were no significant differences in renal function and HIV parameters at baseline, time to initiation of highly active antiretroviral therapy, and rates of HIV RNA suppression between the 20 patients who developed end-stage renal disease >3 months after receiving the HIVAN diagnosis and the 23 patients who maintained stable renal function. However, the index of chronic damage score was significantly higher in those who developed end-stage renal disease (P < .001), and an index of chronic damage score >75 was associated with shorter renal survival (P < .001). CONCLUSIONS Whereas overall patient survival suggested an important benefit of highly active antiretroviral therapy, no additional renal benefit of early initiation of highly active antiretroviral therapy or viral suppression could be demonstrated in this large cohort of patients with established HIVAN. Severity of chronic kidney damage, as quantified by biopsy, was the strongest predictor of renal outcome.

Incomplete Reversibility of Estimated Glomerular Filtration Rate Decline Following Tenofovir Disoproxil Fumarate Exposure

Background. Tenofovir disoproxil fumarate (TDF) has been linked to renal impairment, but the extent to which this impairment is reversible is unclear. We aimed to investigate the reversibility of renal decline during TDF therapy. Methods. Cox proportional hazards models assessed factors associated with discontinuing TDF in those with an exposure duration of >6 months. In those who discontinued TDF therapy, linear piecewise regression models estimated glomerular filtration rate (eGFR) slopes before initiation of, during, and after discontinuation of TDF therapy. Factors associated with not achieving eGFR recovery 6 months after discontinuing TDF were assessed using multivariable logistic regression. Results. We observed declines in the eGFR during TDF exposure (mean slopes, −15.7 mL/minute/1.73 m2/year [95% confidence interval {CI}, −20.5 to −10.9] during the first 3 months and −3.1 mL/minute/1.73 m2/year [95% CI, −4.6 to −1.7] thereafter) and evidence of eGFR increases following discontinuation of TDF therapy (mean slopes, 12.5 mL/minute/1.73 m2/year [95% CI, 8.9–16.1] during the first 3 months and 0.8 mL/minute/1.73 m2/year [95% CI, .1–1.5] thereafter). Following TDF discontinuation, 38.6% of patients with a decline in the eGFR did not experience recovery. A higher eGFR at baseline, a lower eGFR after discontinuation of TDF therapy, and more-prolonged exposure to TDF were associated with an increased risk of incomplete recovery 6 months after discontinuation of TDF therapy. Conclusions. This study shows that a decline in the eGFR during TDF therapy was not fully reversible in one third of patients and suggests that prolonged TDF exposure at a low eGFR should be avoided.

Immunodeficiency and renal impairment are risk factors for HIV-associated acute renal failure

Objective:To identify risk factors for acute renal failure (ARF) in HIV-infected patients. Design:Observational cohort study of HIV-infected patients attending a South London HIV centre between January 1999 and December 2008. Methods:ARF was defined as a transient, more than 40% reduction in renal function as assessed by estimated glomerular filtration rate. Multivariate Poisson regression analysis was used to identify baseline and time-updated factors associated with ARF. Results:The incidence of ARF was 2.8 (95% confidence interval 2.41–3.24) episodes per 100 person-years. We observed a stepwise increase in ARF incidence with time accrued at lower CD4 cell count and at lower estimated glomerular filtration rate, with adjusted incidence rate ratios of 1 (reference), 1.56 (0.97–2.48), 2.08 (1.11–3.91), 6.38 (3.18–12.78) and 10.29 (5.11–20.98) for CD4 cell counts of more than 350, 201–350, 101–200, 51–100 and of 50/μl or less, and 1 (reference), 1.46 (0.86–2.51), 4.19 (2.37–7.42) and 27.00 (16.13–44.95) for estimated glomerular filtration rate more than 90, 75–89, 60–74 and less than 60 ml/min, respectively. Ethnicity, hepatitis B or C coinfection, exposure to combination antiretroviral therapy with or without indinavir, tenofovir or atazanavir and HIV viraemia were not associated with ARF. Conclusion:Current levels of immunodeficiency and renal function were independent predictors of HIV-associated ARF.

Time to Initiation of Antiretroviral Therapy Among Patients With HIV-Associated Tuberculosis in Cape Town, South Africa

We studied the time interval between starting tuberculosis treatment and commencing antiretroviral treatment (ART) in HIV-infected patients (n = 1433; median CD4 count 71 cells per microliter, interquartile range: 32-132) attending 3 South African township ART services between 2002 and 2008. The overall median delay was 2.66 months (interquartile range: 1.58-4.17). In adjusted analyses, delays varied between treatment sites but were shorter for patients with lower CD4 counts and those treated in more recent calendar years. During the most recent period (2007-2008), 4.7%, 19.7%, and 51.1% of patients started ART within 2, 4, and 8 weeks of tuberculosis treatment, respectively. Operational barriers must be tackled to permit further acceleration of ART initiation as recommended by 2010 WHO ART guidelines.

Total protein, albumin and low-molecular-weight protein excretion in HIV-positive patients

BackgroundChronic kidney disease is common in HIV positive patients and renal tubular dysfunction has been reported in those receiving combination antiretroviral therapy (cART). Tenofovir (TFV) in particular has been linked to severe renal tubular disease as well as proximal tubular dysfunction. Markedly elevated urinary concentrations of retinal-binding protein (RBP) have been reported in patients with severe renal tubular disease, and low-molecular-weight proteins (LMWP) such as RBP may be useful in clinical practice to assess renal tubular function in patients receiving TFV. We analysed 3 LMWP as well as protein and albumin in the urine of a sample of HIV positive patients.MethodsIn a cross-sectional fashion, total protein, albumin, RBP, cystatin C, and neutrophil gelatinase-associated lipocalin (NGAL) were quantified in random urine samples of 317 HIV positive outpatients and expressed as the ratio-to-creatinine (RBPCR, CCR and NGALCR). Exposure to cART was categorised as none, cART without TFV, and cART containing TFV and a non-nucleoside reverse-transcriptase-inhibitor (TFV/NNRTI) or TFV and a protease-inhibitor (TFV/PI).ResultsProteinuria was present in 10.4 % and microalbuminuria in 16.7 % of patients. Albumin accounted for approximately 10 % of total urinary protein. RBPCR was within the reference range in 95 % of patients while NGALCR was elevated in 67 % of patients. No overall differences in urine protein, albumin, and LMWP levels were observed among patients stratified by cART exposure, although a greater proportion of patients exposed to TFV/PI had RBPCR >38.8 μg/mmol (343 μg/g) (p = 0.003). In multivariate analyses, black ethnicity (OR 0.43, 95 % CI 0.24, 0.77) and eGFR <75 mL/min/1.73 m2 (OR 3.54, 95 % CI 1.61, 7.80) were independently associated with upper quartile (UQ) RBPCR. RBPCR correlated well to CCR (r2 = 0.71), but not to NGALCR, PCR or ACR.ConclusionsIn HIV positive patients, proteinuria was predominantly of tubular origin and microalbuminuria was common. RBPCR in patients without overt renal tubular disease was generally within the reference range, including those receiving TFV. RBP therefore appears a promising biomarker for monitoring renal tubular function in patients receiving TFV and for distinguishing patients with normal tubular function or mild tubular dysfunction from those with severe renal tubular disease or Fanconi syndrome.

Effects of renal tubular dysfunction on bone in tenofovir-exposed HIV-positive patients

Objectives:Tenofovir disoproxil fumarate (TDF) may cause renal tubular dysfunction (RTD) and reduce bone mineral density (BMD). We examined the relationship between RTD and BMD in TDF-exposed HIV-positive men. Design and methods:We analysed urinary retinol-binding protein/creatinine ratio (RBPCR) and fractional excretion of phosphate (FEPO4) to quantify RTD in a cross-sectional sample of randomly selected HIV-positive men at a single tertiary outpatient clinic. BMD at the lumbar spine and hip was measured by dual-energy X-ray absorptiometry. Multivariate logistic regression was used to analyse factors associated with RTD, and linear regression to examine the relationship between RTD and BMD. Results:Of 293 men (mean age 48 years, 94% White ethnicity, median TDF exposure 2.1 years), 22.5% had RBPCR-defined RTD and 12.3% had FEPO4-defined RTD. We observed a negative correlation between RBPCR and BMD at the spine (&bgr; −0.2, P = 0.002) and hip (total: &bgr; −0.1, P = 0.02; femoral neck: &bgr; −0.1, P = 0.02), but not between FePO4 and BMD. In multivariable analyses, RTD defined by more than five-fold elevations in RBPCR was associated with significantly lower BMD of the spine. Conclusion:In HIV-positive patients receiving TDF-containing antiretroviral therapy, RTD was associated with lower BMD of the spine in HIV-positive men. RBPCR quantification may identify patients at increased risk of TDF-associated BMD loss.

Late HIV diagnosis is a major risk factor for intensive care unit admission in HIV-positive patients: a single centre observational cohort study

BackgroundHIV positive patients are at risk of infectious and non-infectious complications that may necessitate intensive care unit (ICU) admission. While the characteristics of patients requiring ICU admission have been described previously, these studies did not include information on the denominator population from which these cases arose.MethodsWe conducted an observational cohort study of ICU admissions among 2751 HIV positive patients attending King’s College Hospital, South London, UK. Poisson regression models were used to identify factors associated with ICU admission.ResultsThe overall incidence rate of ICU admission was 1.0 [95% CI 0.8, 1.2] per 100 person-years of follow up, and particularly high early (during the first 3 months) following HIV diagnosis (12.4 [8.7, 17.3] per 100 person-years compared to 0.37 [0.27, 0.50] per 100 person-years thereafter; incidence rate ratio 33.5 [23.4, 48.1], p < 0.001). In time-updated analyses, AIDS and current CD4 cell counts of less than 200 cells/mm3 were associated with an increased incidence of ICU admission while receipt of combination antiretroviral therapy (cART) was associated with a reduced incidence of ICU admission. Late HIV diagnosis (initial CD4 cell count <350 or AIDS within 3 months of HIV diagnosis) applied to 81% of patients who were first diagnosed HIV positive during the study period and who required ICU admission. Late HIV diagnosis was significantly associated with ICU admission in the first 3 months following HIV diagnosis (adjusted incidence rate ratio 8.72, 95% CI 2.76, 27.5).ConclusionsLate HIV diagnosis was a major risk factor for early ICU admission in our cohort. Earlier HIV diagnosis allowing cART initiation at CD4 cell counts of 350 cells/mm3 is likely to have a significant impact on the need for ICU care.

Abacavir and increased risk of myocardial infarction

This project was initiated as part of the Uganda Women’s Health Initiative (UWHI) involving the University College London Institute for Women’s Health, Mulago Hospital, Makerere University, and Hospice Africa, Uganda. We are grateful to Graham Evans (Project Manager UWHI) for his support and guidance. The UWHI and this project were supported by generous donations from Lee and Roger Myers and Ann-Margaret and John Walton. These funding sources had no involvement in study design, collection, analysis, and interpretation of data in the writing of report or the decision to submit the letter for publication. We declare that we have no confl ict of interest.