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1.  Kidney and liver organ transplantation in persons with human immunodeficiency virus 
Executive Summary
Objective
The objective of this analysis is to determine the effectiveness of solid organ transplantation in persons with end stage organ failure (ESOF) and human immunodeficiency virus (HIV+)
Clinical Need: Condition and Target Population
Patients with end stage organ failure who have been unresponsive to other forms of treatment eventually require solid organ transplantation. Similar to persons who are HIV negative (HIV−), persons living with HIV infection (HIV+) are at risk for ESOF from viral (e.g. hepatitis B and C) and non-viral aetiologies (e.g. coronary artery disease, diabetes, hepatocellular carcinoma). Additionally, HIV+ persons also incur risks of ESOF from HIV-associated nephropathy (HIVAN), accelerated liver damage from hepatitis C virus (HCV+), with which an estimated 30% of HIV positive (HIV+) persons are co-infected, and coronary artery disease secondary to antiretroviral therapy. Concerns that the need for post transplant immunosuppression and/or the interaction of immunosuppressive drugs with antiretroviral agents may accelerate the progression of HIV disease, as well as the risk of opportunistic infections post transplantation, have led to uncertainty regarding the overall benefit of transplantation among HIV+ patients. Moreover, the scarcity of donor organs and their use in a population where the clinical benefit of transplantation is uncertain has limited the availability of organ transplantation to persons living with ESOF and HIV.
With the development of highly active anti retroviral therapy (HAART), which has been available in Canada since 1997, there has been improved survival and health-related quality of life for persons living with HIV. HAART can suppress HIV replication, enhance immune function, and slow disease progression. HAART managed persons can now be expected to live longer than those in the pre-HAART era and as a result many will now experience ESOF well before they experience life-threatening conditions related to HIV infection. Given their improved prognosis and the burden of illness they may experience from ESOF, the benefit of solid organ transplantation for HIV+ patients needs to be reassessed.
Evidence-Based Analysis Methods
Research Questions
What are the effectiveness and cost effectiveness of solid organ transplantation in HIV+ persons with ESOF?
Literature Search
A literature search was performed on September 22, 2009 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 1996 to September 22, 2009.
Inclusion Criteria
Systematic review with or without a Meta analysis, RCT, Non-RCT with controls
HIV+ population undergoing solid organ transplantation
HIV+ population managed with HAART therapy
Controls include persons undergoing solid organ transplantation who are i) HIV− ii) HCV+ mono-infected, and iii) HIV+ persons with ESOF not transplanted.
Studies that completed and reported results of a Kaplan-Meier Survival Curve analysis.
Studies with a minimum (mean or medium) follow up of 1-year.
English language citations
Exclusion Criteria
Case reports and case series were excluded form this review.
Outcomes of Interest
i) Risk of Death after transplantation
ii) Death censored graft survival (DCGS)
iii) HIV disease progression defined as the post transplant incidence of:
- opportunistic infections or neoplasms,
- CD4+ T-cell count < 200mm3, and
- any detectable level of plasma HIV viral load.
iv) Acute graft rejection,
v) Return to dialysis,
vi) Recurrence of HCV infection
Summary of Findings
No direct evidence comparing an HIV+ cohort undergoing transplantation with the same not undergoing transplantation (wait list) was found in the literature search.
The results of this review are reported for the following comparison cohorts undergoing transplantation:
i) Kidney Transplantation: HIV+ cohort compared with HIV− cohort
ii) Liver Transplantation: HIV+ cohort compared with HIV− negative cohort
iii) Liver Transplantation: HIV+ HCV+ (co-infected) cohort compared with HCV+ (mono-infected) cohort
Kidney Transplantation: HIV+ vs. HIV−
Based on a pooled HIV+ cohort sample size of 285 patients across four studies, the risk of death after kidney transplantation in an HIV+ cohort does not differ to that of an HIV− cohort [hazard ratio (HR): 0.90; 95% CI: 0.36, 2.23]. The quality of evidence supporting this outcome is very low.
Death censored graft survival was reported in one study with an HIV+ cohort sample size of 100, and was statistically significantly different (p=.03) to that in the HIV− cohort (n=36,492). However, the quality of evidence supporting this outcome was determined to be very low. There was also uncertainty in the rate of return to dialysis after kidney transplantation in both the HIV+ and HIV− groups and the effect, if any, this may have on patient survival. Because of the very low quality evidence rating, the effect of kidney transplantation on HIV-disease progression is uncertain.
The rate of acute graft rejection was determined using the data from one study. There was a nonsignificant difference between the HIV+ and HIV− cohorts (OR 0.13; 95% CI: 0.01, 2.64), although again, because of very low quality evidence there is uncertainty in this estimate of effect.
Liver Transplantation: HIV+ vs. HIV−
Based on a combined HIV+ cohort sample size of 198 patient across five studies, the risk of death after liver transplantation in an HIV+ cohort (with at least 50% of the cohort co-infected with HCV+) is statistically significantly 64% greater compared with an HIV− cohort (HR: 1.64; 95% CI: 1.32, 2.02). The quality of evidence supporting this outcome is very low.
Death censored graft survival was reported for an HIV+ cohort in one study (n=11) however the DCGS rate of the contemporaneous control HIV− cohort was not reported. Because of sparse data the quality of evidence supporting this outcome is very low indicating death censored graft survival is uncertain.
Both the CD4+ T-cell count and HIV viral load appear controlled post transplant with an incidence of opportunistic infection of 20.5%. However, the quality of this evidence for these outcomes is very low indicating uncertainty in these effects. Similarly, because of very low quality evidence there is uncertainty in the rate of acute graft rejection among both the HIV+ and HIV− groups
Liver Transplantation: HIV+/HCV+ vs. HCV+
Based on a combined HIV+/HCV+ cohort sample size of 156 from seven studies, the risk of death after liver transplantation is significantly greater (2.8 fold) in a co-infected cohort compared with an HCV+ mono-infected cohort (HR: 2.81; 95% CI: 1.47, 5.37). The quality of evidence supporting this outcome is very low. Death censored graft survival evidence was not available.
Regarding disease progression, based on a combined sample size of 71 persons in the co-infected cohort, the CD4+ T-cell count and HIV viral load appear controlled post transplant; however, again the quality of evidence supporting this outcome is very low. The rate of opportunistic infection in the co-infected cohort was 7.2%. The quality of evidence supporting this estimate is very low, indicating uncertainty in these estimates of effect.
Based on a combined HIV+/HCV+ cohort (n=57) the rate of acute graft rejection does not differ to that of an HCV+ mono-infected cohort (OR: 0.88; 95% CI: 0.44, 1.76). Also based on a combined HIV+/HCV+ cohort (n=83), the rate of HCV+ recurrence does not differ to that of an HCV+ mono-infected cohort (OR: 0.66; 95% CI: 0.27, 1.59). In both cases, the quality of the supporting evidence was very low.
Overall, because of very low quality evidence there is uncertainty in the effect of kidney or liver transplantation in HIV+ persons with end stage organ failure compared with those not infected with HIV. Examining the economics of this issue, the cost of kidney and liver transplants in an HIV+ patient population are, on average, 56K and 147K per case, based on both Canadian and American experiences.
PMCID: PMC3377507  PMID: 23074407
2.  Urinary NGAL is a useful clinical biomarker of HIV-associated nephropathy 
Nephrology Dialysis Transplantation  2011;26(7):2387-2390.
Background. Urinary neutrophil gelatinase-associated lipocalin (uNGAL) is expressed by kidney tubules that are acutely damaged, but few studies have investigated the association of neutrophil gelatinase-associated lipocalin (NGAL) with different forms of chronic kidney disease (CKD). HIV-associated nephropathy (HIVAN) is a progressive form of CKD characterized by collapsing focal segmental glomerulosclerosis and microcytic tubular dilatation that typically leads to end-stage renal disease (ESRD).
Methods. Previously, we reported that microcystic tubular dilatations specifically expressed NGAL RNA, implying that the detection of uNGAL protein could mark advanced HIVAN. To test this idea, we performed a comparative study of diverse proteinuric glomerulopathies in 25 patients who were HIV positive.
Results. Eighteen patients had HIVAN and seven had other glomerulopathies (four membranoproliferative glomerulonephritis, one membranous glomerulonephritis, one amyloid and one malarial GN). HIVAN and non-HIVAN patients did not differ with respect to age, ethnicity, serum creatinine, estimated GFR, proteinuria or the prevalence of hypocomplementemia (6 versus 29%, P = 0.18), but HIVAN patients were less likely to have HCV infections. HIVAN patients expressed 4-fold higher levels of uNGAL than the patients with other glomerulopathies [387 ± 338 versus 94 ± 101 μg/g urine creatinine (uCr), P = 0.02]. A cutpoint of 121.5 μg uNGAL/g uCr demonstrated 94% sensitivity and 71% specificity for the diagnosis of HIVAN, with an area under the receiver operator characteristic curve of 0.88.
Conclusion. In summary, while HIVAN disease is currently diagnosed only by kidney biopsy, uNGAL can distinguish HIVAN from other proteinuric glomerulopathies in the HIV-infected patient, likely because of its specific expression from characteristic microcysts.
doi:10.1093/ndt/gfr258
PMCID: PMC3164447  PMID: 21555394
biomarker; HIV-associated nephropathy; progressive chronic kidney disease; tubular injury; urinary neutrophil gelatinase-associated lipocalin
3.  Gene-Gene and Gene-Environment Interactions in HIV-Associated Nephropathy: a Focus on the MYH9 Nephropathy Susceptibility Gene 
Human immunodeficiency virus-associated nephropathy (HIVAN) is a leading cause of end-stage renal disease in African Americans. The HIV-1 virus infects podocytes, cells integral to formation of the glomerular filtration barrier, often leading to focal segmental glomerulosclerosis. HIVAN is typically a complication of late-stage HIV infection, associated with low CD4 cell counts and elevated serum HIV RNA levels. Highly active antiretroviral therapy (HAART) is partially protective and has altered the natural history of HIV-associated kidney disease. Nonetheless, HIVAN remains an important public health concern among HIV-infected African Americans. Although polymorphisms in the MYH9 gene on chromosome 22 are strongly associated with HIVAN, as well as with idiopathic focal segmental glomerulosclerosis and global glomerulosclerosis (historically labeled "hypertensive nephrosclerosis"), the majority of HIV-infected patients who are genetically at risk from MYH9 do not appear to develop severe kidney disease. Therefore, we postulate that additional environmental exposures and/or inherited factors are necessary to initiate human HIVAN. Gene-environment interactions have also been proposed as necessary for initiation of HIVAN in murine models. It is important that these novel risk factors be identified, as prevention of environmental exposures and targeting of additional gene products may reduce the risk for HIVAN, even among those harboring two risk alleles in MYH9.
doi:10.1053/j.ackd.2009.08.002
PMCID: PMC2814053  PMID: 20005488
African Americans; FSGS; HIV-associated nephropathy; kidney disease; MYH9
4.  The New Epidemiology of HIV-Related Kidney Disease 
HIV-related kidney disease has been associated with significant morbidity and mortality in the HIV population. It is clear that the epidemiology of HIV-related kidney disease has changed dramatically since the first case reports in 1984. During these early years, the predominant etiology of kidney disease in HIV was recognized as HIV-associated nephropathy (HIVAN), an aggressive form of kidney disease with a high rate of progression to end-stage renal disease (ESRD). Subsequently, with the widespread use of combination antiretroviral therapy (cART), there was a dramatic decrease in the incidence of ESRD attributed to HIV/AIDS. Although the incidence of HIV-related ESRD has plateaued in the last 15 years, the prevalence has continued to increase because of improved survival. Available prevalence estimates do not include HIV-infected individuals with comorbid ESRD, although there is growing evidence that the epidemiology of kidney disease in the HIV-infected population has changed. This article reviews the impact of risk factors such as race, diabetes mellitus, hypertension, hepatitis C virus coinfection, and the chronic use of cART on the changing epidemiology of HIV-related kidney disease. Additionally in this review, we propose potential areas of translational research that will help to further characterize HIV-related kidney disease in the 21st century.
doi:10.4172/2155-6113.S4-001
PMCID: PMC4190040  PMID: 25309811
HIV; AIDS; HCV
5.  HIVAN and medication use in chronic dialysis patients in the United States: analysis of the USRDS DMMS Wave 2 study 
BMC Nephrology  2003;4:5.
Background
The use and possible effects of factors known to improve outcomes in patients with human immunodeficiency virus associated nephropathy (HIVAN), namely of angiotensin converting enzyme inhibitors (ACE) and antiretroviral therapy, has not been reported for a national sample of dialysis patients.
Methods
We conducted a historical cohort study of the United States Renal Data System (USRDS) Dialysis Morbidity and Mortality Study (DMMS) Wave 2 to identify risk factors associated with increased mortality in these patients. Data were available for 3374 patients who started dialysis and were followed until March 2000. Cox Regression analysis was used to model adjusted hazard ratios (AHR) with HIVAN as a cause of end stage renal disease (ESRD) and its impact on mortality during the study period, adjusted for potential confounders.
Results
Of the 3374 patients who started dialysis, 36 (1.1%) had ESRD as a result of HIVAN. Only 22 (61%) of patients with HIVAN received antiretroviral agents, and only nine patients (25%) received combination antiretroviral therapy, and only 14% received ACE inhibitors. Neither the use of multiple antiretroviral drugs (AHR, 0.62, 95% CI, 0.10, 3.86, p = 0.60), or ACE inhibitors were associated with a survival advantage. Patients with HIVAN had an increased risk of mortality (adjusted hazard ratio, 4.74, 95% Confidence Interval, 3.12, 7.32, p < 0.01) compared to patients with other causes of ESRD.
Conclusions
Medications known to improve outcomes in HIV infected patients were underutilized in patients with HIVAN. Adjusted for other factors, a primary diagnosis of HIVAN was associated with increased mortality compared with other causes of ESRD.
doi:10.1186/1471-2369-4-5
PMCID: PMC166168  PMID: 12837135
HIV; antiretroviral; angiotensin converting enzyme inhibitors; dialysis; end-stage renal disease; calcium channel blockers; dihydropyridine; USRDS; heart failure; hyperparathyroidism
6.  Nephropathy in human immunodeficiency virus-1 transgenic mice is due to renal transgene expression. 
HIV-associated nephropathy (HIVAN) is a progressive glomerular and tubular disease that is increasingly common in AIDS patients and one of the leading causes of end stage renal disease in African Americans. A major unresolved issue in the pathogenesis of HIVAN is whether the kidney disease is due to renal cell infection or a "bystander" phenomenon mediated by systemically dysregulated cytokines. To address this issue, we have used two different experimental approaches and an HIV-1 transgenic mouse line that develops a progressive renal disease histologically similar to HIVAN in humans. In the murine model, kidney tissue expresses the transgene and in heterozygous adults, renal disease develops shortly thereafter. We demonstrate by terminal deoxynucleotide transferase-mediated dUTP-biotin nick-end labeling assay that similar to the disease in humans, apoptosis of renal tubular epithelial cells is a component of the molecular pathogenesis. To determine whether apoptosis is due to transgene expression or environmental factors, we treated fetal kidney explants (normal and transgenic) with UV light to induce transgene expression. Apoptosis occurred in transgenic but not normal littermates after stimulation of transgene expression. To confirm a direct effect of HIV expression on the production of HIVAN, we transplanted kidneys between normal and transgenic mice. HIVAN developed in transgenic kidneys transplanted into nontransgenic littermates. Normal kidneys remained disease free when transplanted into transgenic littermates. Thus, the renal disease in the murine model is intrinsic to the kidney. Using two different experimental approaches, we demonstrate a direct effect of transgene expression on the development of HIVAN in the mouse. These studies suggest that in humans, a direct effect of HIV-1 expression is likely the essential cause of HIVAN, rather than an indirect effect of cytokine dysregulation.
PMCID: PMC508168  PMID: 9202060
7.  Risk Factors for ESRD in HIV-Infected Individuals: Traditional and HIV-Related Factors 
Background
Despite improvements in survival with HIV infection, kidney disease remains an important complication. Few studies have evaluated risk factors associated with development of end-stage renal disease (ESRD) in HIV-infected individuals. We sought to identify traditional and HIV-related risk factors for ESRD in HIV-infected individuals, and to compare ESRD risk by eGFR and proteinuria levels.
Study design
Retrospective cohort study.
Setting and Participants
22,156 HIV-infected veterans without preexisting ESRD receiving healthcare in the Veterans’ Affairs medical system between 1996 and 2004.
Predictors
Hypertension, diabetes, cardiovascular disease, hypoalbuminemia (serum albumin<3.5mg/dL), CD4 lymphocyte count, HIV viral load, hepatitis C virus coinfection, proteinuria, and estimated glomerular filtration rate (eGFR) were identified using the Veterans’ Affairs electronic record system.
Outcomes
ESRD was ascertained by the United States Renal Data System.
Results
366 cases of ESRD occurred, corresponding to 3 cases per 1,000 person-years. Hypertension (HR, 1.9; 95% CI, 1.5–2.4), diabetes (HR, 1.7; 95% CI, 1.3–2.2), and cardiovascular disease (HR, 2.2; 95% CI, 1.7–2.7) were independently associated with ESRD risk in multivariate-adjusted models, as were CD4 lymphocyte count <200 cells/mm3 (HR, 1.5; 95% CI, 1.2–2.0), HIV viral load ≥30,000 copies/mL (HR, 2.0; 95% CI, 1.5–2.8), hepatitis C virus coinfection (HR, 1.9; 95% CI, 1.5–2.4), and hypoalbuminemia (HR, 2.1; 95% CI, 1.8–2.5). Compared to persons without chronic kidney disease (CKD), defined as eGFR>60mg/min/1.73m2 and no proteinuria, lower eGFR and higher proteinuria categories were jointly associated with exponentially higher ESRD rates, ranging from 6.6 per 1000 person-years for persons with proteinuria 30–100 mg/dL and eGFR>60ml/min/1.73m2, to 193 per 1000 person-years for persons with proteinuria ≥300mg/dL and eGFR<30ml/min/1.73m2.
Limitations
Results may not be generalizable to female and nonveteran populations.
Conclusions
In HIV-infected persons, ESRD risk appears attributable to a combination of traditional and HIV-related risk factors for kidney disease. Combining eGFR and proteinuria for CKD staging is most effective for stratifying risk for ESRD.
doi:10.1053/j.ajkd.2011.10.050
PMCID: PMC3324595  PMID: 22206742
End-stage renal disease; HIV; chronic kidney disease; risk factors
8.  Advances in our understanding of the pathogenesis of HIV-1 associated nephropathy in children 
Future virology  2011;6(7):883-894.
Childhood HIV-1 associated nephropathy (HIVAN) is a clinical and renal histological disease characterized by heavy proteinuria associated with focal and segmental glomerular sclerosis and/or mesangial hyperplasia in combination with microcystic tubular dilatation. These lesions lead to renal enlargement and rapid progression to kidney failure. Children of African ancestry have a unique susceptibility to developing HIVAN. It is estimated that approximately 300,000 HIV-infected children living in the sub-Saharan Africa could develop HIVAN if they do not receive appropriate antiretroviral therapy. This article discusses recent developments and controversies related to the pathogenesis of childhood HIVAN. The role of host genetic factors, including the newly identified variants in the APOL1 gene, is discussed in the context of previous studies that established the pathological paradigm for HIVAN, and our current understanding of the functional genomics analysis. Hopefully, these advances will provide new research opportunities to generate better treatments for children with HIVAN.
doi:10.2217/fvl.11.57
PMCID: PMC3232000  PMID: 22162721
African–American; APOL1; autophagic cell death; autophagy; Duffy antigen; genetic susceptibility; HIVAN; kidney failure; nonsynonymous SNP
9.  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
10.  Glomerular lesions in HIV-infected patients: a Yale University Department of Medicine Residency Peer-Teaching Conference. 
HIV-associated nephropathy (HIVAN) is a clinicopathologic entity characterized by heavy proteinuria, absence of edema and an irreversible decline in renal function. Findings on renal biopsy include: collapsed glomerular capillaries; visceral glomerular epitheliosis; microcystic tubules; mesangial prominence; and endothelial tubuloreticular inclusions. Early in the AIDS epidemic, HIVAN was the predominant glomerular lesion observed in HIV-infected patients. It is being increasingly recognized, especially in Caucasian populations, that a variety of immune complex-mediated lesions such as membranoproliferative glomerulonephritis, proliferative glomerulonephritis and IgA nephropathy are associated with HIV infection. In this review we present two cases: one patient whose first presentation of AIDS was end-stage renal disease, who on biopsy was found to have HIVAN, and the second, who was infected with HIV, and on biopsy was found to have hepatitis C-related hepatitis C related membranoproliferative glomerulonephritis. We also review the current literature on HIVAN and HIV-associated immune complex diseases (HIVICDs). Each case illustrates an important clinical point. The first that renal disease can be the first manifestation of HIV infection and the second that HIV-infected patients may develop immune complex related renal diseases, some of which may be potentially treatable.
Images
PMCID: PMC2589068  PMID: 9493848
11.  HIV-1 vpr inhibits cytokinesis in human proximal tubule cells 
Kidney international  2008;74(8):1049-1058.
HIV associated nephropathy (HIVAN) afflicts an estimated 1–3 million people worldwide and is a major cause of morbidity and mortality. Murine transgenic models have demonstrated that expression of HIV-1 genes in kidney cells results in characteristic HIVAN pathology: collapsing FSGS and microcystic tubular disease. While we have gained significant understanding of the podocyte disease, less is known about the tubular epithelial responses to infection.
HIV-1 vpr plays an important role in the FSGS of HIVAN particularly in association with nef expression in podocytes. In addition, Vpr is reported to exacerbate tubular pathology. Therefore, we explored the effect of vpr expression on renal tubular epithelial cell function.
Proximal tubule epithelial cells (PTEC) were transduced in vitro using a pseudotyped lentivirus vector carrying HIV-1 vpr and control genes. HIV-1 vpr expression in cultured PTECs impaired cytokinesis causing cell enlargement and multinucleation. Because the in vitro phenotype was so profound, we re-examined the HIVAN murine model and human HIVAN biopsies to see if similar changes could be seen in vivo.
Surprisingly, both the transgenic murine HIVAN model and human HIVAN biopsies showed abundant hypertrophic tubule cells consistent with the in vitro findings. The extent of the tubular cell hypertrophy was particularly impressive and represents a previously unappreciated aspect of the disease. Additionally, multinucleated tubular cells were identified in the murine HIVAN model and increased chromosome number was detected in tubular cells in HIVAN biopsies.
This study provides evidence of a new clinical phenotype in HIVAN that may result from Vpr’s ability to impair cytokinesis.
doi:10.1038/ki.2008.303
PMCID: PMC4039560  PMID: 18614999
HIVAN; Proximal Tubule; HIV; Vpr; hypertrophy; multinucleation; cytokinesis; apoptosis
12.  Chronic kidney disease and estimates of kidney function in HIV infection: a cross-sectional study in the Multicenter AIDS Cohort Study 
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1097/QAI.0b013e318222f461
PMCID: PMC3159728  PMID: 21646913
HIV; kidney disease; serum creatinine; cystatin C; glomerular filtration rate; Multicenter AIDS Cohort Study
13.  HIV-1 and Kidney Cells: Better Understanding of Viral Interaction 
Nephron. Experimental Nephrology  2010;115(2):e15-e21.
HIV-associated nephropathy (HIVAN) is the most common disease affecting untreated seropositive patients of African descent. Besides genetic (African descent) and HIV-1 infection (environmental), specific host factors such as activation of renin-angiotensin-aldosterone system (RAAS) have also been demonstrated to play a role in the manifestation of HIVAN. The recent identification of MYH9 as susceptible allele is a key step forward in our understanding for the pathogenesis of focal glomerulosclerosis in people of African-American descent. HIV-1 transgenic models have significantly advanced our knowledge base in terms of role of HIV-1 genes in general and individual gene in particular in the development of renal lesions mimicking HIVAN. These studies suggest that viral replication is not needed for the development of renal lesions. Renal biopsy data from HIVAN patients suggest that renal epithelial cells express HIV-1 genes and thus it may be sufficient to invoke HIVAN phenotype in the presence of specific host and genetic factors. On the other hand, immune response to infection may be required to induce HIV-1 associated immune complex kidney disease (HIVICK). Since renal cell lack conventional HIV-1 receptors, HIV-1 entry into renal cells has been a mystery. Recently, non-conventional pathways have been demonstrated to facilitate HIV-1 entry into renal cells in in vitro studies. These include presence of DEC-205 receptors in renal tubular cells and lipid rafts in podocytes. However, HIV-1 entry through these pathways only allows non-productive infection. It appears that the presence of specific genetic and host factors in in vivo conditions may be facilitating the development of the productive HIV-1 infection in kidney cells.
doi:10.1159/000312882
PMCID: PMC2889261  PMID: 20407278
HIV-associated nephropathy (HIVAN); HIV-associated immune complex kidney disease (HIVICK); Tubular cells; Podocytes; DEC-205
14.  Determining the prevalence of Human Immunodeficiency Virus–Associated nephropathy (HIVAN) using proteinuria and ultrasound findings in a Nigerian paediatric HIV population 
Background
HIV associated nephropathy (HIVAN) is the most common form of chronic kidney disease resulting directly from HIV infection. The true prevalence of HIVAN in the paediatric population of West Africa is unknown, largely due to lack of surveillance and reporting of kidney disease in HIV positive patients.
Methods
This was a prospective study over a six month period( July to December 2008) conducted in the Infectious Disease Unit of the Department of Paediatrics, University of Uyo Teaching Hospital, Uyo, Nigeria involving all confirmed cases of paediatric HIV infection. Urine microalbuminuria using calculated urine albumin – creatinine ratio was determined and repeated in 4 weeks interval. CD4 count and renal ultrasonography was done for all the patients. The correlation of urine albumin – creatinine ratio with CD4 count, duration of treatment with highly active antiretroviral therapy (HAART) and association with clinical staging of the disease was also examined.
Results
Fifty – nine (60.2%) were males, thirty – nine (39.8%) were females with male to female ratio of 1.5:1. The prevalence rate of 31.6% HIVAN was found, out of which 3.1% had abnormal ultrasound findings. There was a significant correlation between CD4 count and urine albumin – creatinine ratio (r=−0.22, p=0.03). There was no correlation between urine albumin – creatinine ratio and duration on HAART (r=−0.10, p=0.31).
Conclusion
Screening for microalbuminuria is essential for the early diagnosis and treatment of HIVAN in this age group.
PMCID: PMC3283028  PMID: 22368756
HIVAN; microalbuminuria; HIV; HAART; proteinuria; paediatrics; Nigeria
15.  Expert Opinion on Pharmacotherapy of Kidney Disease in HIV-Infected Patients 
Expert opinion on pharmacotherapy  2011;12(5):691-704.
Importance of the field
Human immunodeficiency virus (HIV) infection is associated with the development of a wide spectrum of kidney diseases. HIV-associated nephropathy (HIVAN) is the most common cause of chronic kidney disease (CKD) in HIV-infected individuals and predominantly affects patients of African ancestry. HIVAN is a leading cause of end-stage renal disease (ESRD) among African-Americans.
Areas covered in this review
an overview of the spectrum of kidney disease in patients with HIV; current pharmacologic interventions to treat kidney disease in HIV.
What the reader will gain
Knowledge regarding the most common causes of kidney disease in HIV-infected patients and principals related to pharmacotherapy in HIV-infected patients with kidney disease.
Take home message
Kidney disease is an important cause of morbidity and mortality in HIV-infected patients and the most common cause of chronic kidney disease in this population is HIV-associated nephropathy, which is caused by viral infection of the renal epithelium. Several medications that are commonly used in HIV-infected patients can have adverse effects on the kidneys and the doses of many antiretroviral medications need to be adjusted in patients with impaired renal function.
doi:10.1517/14656566.2011.535518
PMCID: PMC3059255  PMID: 21250871
HIV associated nephropathy; HIVAN; collapsing glomerulopathy; FSGS; antiretroviral therapy
16.  Association of Family History of ESRD, Prevalent Albuminuria, and Reduced GFR With Incident ESRD 
Background
The contribution of albuminuria to the increased risk of incident end-stage renal disease (ESRD) in individuals with a family history of ESRD has not been well studied.
Study Design
Prospective cohort study.
Study Setting & Participants
We analyzed data for family history of ESRD collected from 19,409 participants of the Renal REGARDS (Reasons for Geographic and Racial Differences in Stroke) cohort study.
Predictor
Family history of ESRD was ascertained by asking “Has anyone in your immediate family ever been told that he or she had kidney failure? This would be someone who is on or had been on dialysis or someone who had a kidney transplant.”
Study Outcomes
Incidence rate for ESRD.
Measurements
Morning urine albumin-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR). Incident cases of ESRD were identified through the US Renal Data System.
Results
A family history of ESRD was reported by 11.1% of participants. Mean eGFRs for those with and without a family history of ESRD were 87.5 ± 22.2 (SD) and 86.5 ± 19.3 mL/min/1.73 m2, respectively (P = 0.05) and the respective geometric mean ACRs were 12.2 and 9.7 mg/g (P < 0.001). ESRD incidence rates for those with and without a family history of ESRD were 244.3 and 106.1/100,000 person-years, respectively. After adjusting for age, sex, and race, the ESRD HR for those with versus those without a family history of ESRD was 2.13 (95% CI, 1.18-3.83). Adjustment for comorbid conditions and socioeconomic status attenuated this association (HR, 1.82; 95% CI, 1.00-3.28), and further adjustment for baseline eGFR and ACR completely attenuated the association between family history of ESRD and incident ESRD (HR, 1.12; 95% CI, 0.69-1.80).
Limitations
The report of a family history of ESRD was not validated.
Conclusion
Family history of ESRD is common in older Americans and the increased risk of ESRD associated with a family history reflects lower GFR, higher albuminuria, and comorbid conditions.
doi:10.1053/j.ajkd.2011.09.018
PMCID: PMC3725825  PMID: 22078058
Race; albuminuria; end-stage renal disease; chronic kidney disease
17.  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.
doi:10.1053/j.ackd.2009.07.014
PMCID: PMC2818858  PMID: 20005486
HIV infection; proteinuria; estimated GFR; MDRD equation; cystatin C
18.  Chronic Kidney Disease Associated with Perinatal HIV infection in Children and Adolescents 
Background
This study describes the incidence, clinical and demographic characteristics, and spectrum of chronic kidney disease (CKD) in youths with perinatal HIV-1 infection.
Methods
Retrospective analysis between May 1993 and December 2006 of subjects with renal disease followed in the Pediatric AIDS Clinical Trials Group 219/219C multicenter study examining long-term consequences of perinatal HIV infection. Diagnosis confirmation was made utilizing a questionnaire mailed to research sites. Participants with CKD of other etiology than HIV were excluded. Outcome measures were biopsy-diagnosed CKD and, in absence of biopsy, HIV-associated nephropathy (HIVAN) using established clinical criteria.
Results
Questionnaires on 191 of 2,102 participants identified 27 cases of CKD: 14 biopsy-diagnosed and six clinical cases of HIVAN, and seven biopsy-diagnosed cases of immune complex-mediated kidney disease (lupus-like nephritis, three; IgA nephropathy, two; membranous nephropathy, two). Incidence rates for CKD associated with HIV in pre-HAART (1993–1997) and HAART (1998–2002, 2003–2006) eras were 0.43, 2.84 and 2.79 events per 1000 person years, respectively. In multivariable analysis, Black race and viral load ≥ 100,000 copies/ml (rate ratios 3.28 and 5.05, p ≤ 0.02) were associated with CKD.
Conclusions
A variety of immune complex-mediated glomerulonephritides and HIVAN occurs in this population. Black race and uncontrolled viral replication are risk factors for CKD associated with HIV.
doi:10.1007/s00467-011-2097-1
PMCID: PMC3715373  PMID: 22366874
HIVAN; HIV immune complex kidney disease; FSGS; renal; youth; proteinuria; biopsy
19.  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
20.  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
21.  Kidney disease in children and adolescents with perinatal HIV-1 infection 
Introduction
Involvement of the kidney in children and adolescents with perinatal (HIV-1) infection can occur at any stage during the child's life with diverse diagnoses, ranging from acute kidney injury, childhood urinary tract infections (UTIs), electrolyte imbalances and drug-induced nephrotoxicity, to diseases of the glomerulus. The latter include various immune-mediated chronic kidney diseases (CKD) and HIV-associated nephropathy (HIVAN).
Discussion
The introduction of highly active anti-retroviral therapy (HAART) has dramatically reduced the incidence of HIVAN, once the commonest form of CKD in children of African descent living with HIV, and also altered its prognosis from eventual progression to end-stage kidney disease to one that is compatible with long-term survival. The impact of HAART on the outcome of other forms of kidney diseases seen in this population has not been as impressive. Increasingly important is nephrotoxicity secondary to the prolonged use of anti-retroviral agents, and the occurrence of co-morbid kidney disease unrelated to HIV infection or its treatment. Improved understanding of the molecular pathogenesis and genetics of kidney diseases associated with HIV will result in better screening, prevention and treatment efforts, as HIV specialists and nephrologists coordinate clinical care of these patients. Both haemodialysis (HD) and peritoneal dialysis (PD) are effective as renal replacement therapy in HIV-infected patients with end-stage kidney disease, with PD being preferred in resource-limited settings. Kidney transplantation, once contraindicated in this population, has now become the most effective renal replacement therapy, provided rigorous criteria are met. Given the attendant morbidity and mortality in HIV-infected children and adolescents with kidney disease, routine screening for kidney disease is recommended where resources permit.
Conclusions
This review focuses on the pathogenesis and genetics, clinical presentation and management of kidney disease in children and adolescents with perinatal HIV-1 infection.
doi:10.7448/IAS.16.1.18596
PMCID: PMC3687339  PMID: 23782479
human immunodeficiency virus; kidney; children; adolescents; anti-retroviral drug toxicity
22.  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
23.  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
24.  HIV Associated Lupus Like Nephropathy 
Background
Human immunodeficiency virus type 1 (HIV-1)-seropositive patients are at a high risk for the development of a variety of acute and chronic renal diseases. Most patients with HIVAN are of African descent, presenting late in the course of their HIV-1 infection. The only reliable test to establish or rule out the presence of HIVAN (HIV associated nephropathy) is renal biopsy. The most common lesion associated with HIV is a focal segmental glomeruloscelerosis, but several times, other biopsy findings may also be seen. Our patient had lupus nephritis like pathology picture. The therapeutic agents with the most promise are angiotensin-converting enzyme inhibitors and antiretroviral medications. Role of steroids are less well-defined although they have been used with success many times.
Case Details
Our patient was a young male who presented with a pulmonary renal syndrome like picture and wasting. On evaluation, he was found to be HIV-1 positive, and renal biopsy showed lupus nephritis like pathological picture. The patient was treated with HAART (Highly active anti retroviral therapy) , steroids and ACE inhibitors and showed an excellent response.
Conclusion
The case highlights the fact that immune mediated glomerulonephritis, although rare, can be the presenting feature of HIV infection and can be controlled, if not cured, with proper treatment.
PMCID: PMC4141233  PMID: 25183936
HIV; Glomerulonephritis; HIV associated nephropathy
25.  A urinary biomarker profile for children with HIV-associated renal diseases 
Kidney international  2009;76(2):207-214.
Human immunodeficiency virus (HIV)-infected children are at risk of developing several types of renal diseases, including HIV-associated nephropathy (HIVAN), which is usually seen during late stages of infection in children with a high viral load. This disease is defined by the presence of proteinuria associated with mesangial hyperplasia and/or global–focal segmental glomerulosclerosis combined with microcystic transformation of the renal tubules. Because HIVAN can have an insidious clinical onset, renal biopsy is the only definitive way of establishing a diagnosis. Given the risk of performing this procedure in HIV-infected children with other AIDS-defining illness, we sought to identify informative biomarkers such as growth factors in the urine of 55 HIV-infected children that might be predictive of the extent and activity of the renal lesions characteristic of HIVAN. We found that the levels of epidermal growth factor were lower in the urine of children with renal disease, whereas levels of fibroblast growth factor-2 and metalloproteinase-2 were higher as compared with those levels in infected children without renal disease. Similar changes were observed in HIV-Tg26 mice correlating with the progression of renal disease in this model of HIVAN. Our findings suggest that this urinary growth factor profile may be useful in facilitating the diagnosis of HIV-infected children at risk of developing HIVAN when interpreted in the appropriate clinical setting.
doi:10.1038/ki.2009.115
PMCID: PMC2778294  PMID: 19357719
growth factors; HIV-associated nephropathy; HIV-transgenic mice; progression of pediatric renal diseases

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