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.
African Americans; FSGS; HIV-associated nephropathy; kidney disease; MYH9
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.
African–American; APOL1; autophagic cell death; autophagy; Duffy antigen; genetic susceptibility; HIVAN; kidney failure; nonsynonymous SNP
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.
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.
HIV infection; proteinuria; estimated GFR; MDRD equation; cystatin C
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.
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.
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).
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.
renal dysfunction; HIV; antiretroviral therapy; sub-Saharan Africa
Highly active antiretroviral therapy (HAART) and other medical therapies for HIV-related infections have been associated with toxicities. Antiretroviral therapy can contribute to renal dysfunction directly by inducing acute tubular necrosis, acute interstitial nephritis, crystal nephropathy, and renal tubular disorders or indirectly via drug interactions. With the increase in HAART use, clinicians must screen patients for the development of kidney disease especially if the regimen employed increases risk of kidney injury. It is also important that patients with chronic kidney disease (CKD) are not denied the best combinations, especially since most drugs can be adjusted based on the estimated GFR. Early detection of risk factors, systematic screening for chronic causes of CKD, and appropriate referrals for kidney disease management should be advocated for improved patient care. The interaction between immunosuppressive therapy and HAART in patients with kidney transplants and the recent endorsement of tenofovir/emtricitabine by the Centers for Disease Control (CDC) for preexposure prophylaxis bring a new dimension for nephrotoxicity vigilance. This paper summarizes the common antiretroviral drugs associated with nephrotoxicity with particular emphasis on tenofovir and protease inhibitors, their risk factors, and management as well as prevention strategies.
HIV-1 associated nephropathy (HIVAN) is a clinical and renal histological disease characterized by the presence of heavy proteinuria associated with focal segmental glomerulosclerosis and microcystic tubular dilatation. These renal lesions lead to renal enlargement and rapid progression to kidney failure. People from African ancestry show a unique susceptibility to develop HIVAN. The study by Wearne and colleagues, which includes the largest group of patients of African ancestry with HIVAN studied so far, describes a novel renal histological variant of HIVAN, and suggests that antiretroviral therapies improve the clinical outcome of all HIV-associated renal diseases. These findings, when interpreted in the context of recent advances in our understanding of the molecular pathogenesis and genetics of HIVAN, will facilitate the recognition of all clinical variants of HIVAN as well the planning of better screening, prevention, and treatment programs for all HIV nephropathies.
APOL-1; collapsing glomerulopathy; FSGS; HIV-1
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.
To determine the prevalence and associated factors with chronic kidney disease (CKD) in a cohort of HIV-positive individuals with undetectable viral load on HAART.
From March, 2009 to September 2009, 213 individuals between 18-70 years, period on HAART ≥12 months, viral load < 50 copies/mm3, and CD4 ≥ 200 cells/mm3, were consecutively enrolled at the outpatient clinic of Hospital de Clínicas, Porto Alegre, Brazil. Exclusion criteria were obesity, malnourishment, amputee, paraplegic, previous history of renal disease, pregnancy and hepatic insufficiency. Renal function was determined by estimated glomerular filtration rate (eGFR) assessed by the modification of diet in renal disease. CKD was defined as an eGFR less or equal than 60 ml/min/1.73 m2, for a period of at least 3 months. Poisson regression was used to determine factors associated with CKD.
CKD was diagnosed in 8.4% of the population, and after adjustment, the risk factors were hypertension (RR = 3.88, 95%CI, 1.84 - 8.16), time on HAART (RR = 1.15, 95%CI,1.03–1.27) and tenofovir exposure (RR = 2.25, 95%CI, 1.04–4.95). Higher weight (RR = ,0.88 95%CI, 0.82–0.96) was associated to normal function.
CKD was a common finding in this cohort of patients and was related to hypertension, time on HAART and tenofovir exposure. We suggest a more frequent monitoring of renal function, especially for those with risk factors to early identify renal impairment.
Kidney disease is a common complication of human immunodeficiency virus (HIV) infection even in the era of antiretroviral therapy, with kidney function being abnormal in up to 30% of HIV-infected patients. We determined the predictors of impaired renal function in HIV-infected adults initiating highly active antiretroviral therapy (HAART) in Nigeria.
Materials and Methods:
This was a retrospective study among HIV-1 infected patients attending the antiretroviral clinic at the Jos University Teaching Hospital (JUTH), between November 2005 and November 2007. Data were analysed for age, gender, weight, WHO clinical stage, CD4 count, HIV-1 RNA viral load, HBsAg and anti-HCV antibody status. Estimated glomerular filtration rate (eGFR) was calculated using the Cockcroft-Gault equation. Statistical analysis was done using Epi Info 3.5.1.
Data for 491 (294 females and 197 males) eligible patients were abstracted. The mean age of this population was 38.8±8.87 years. One hundred and seventeen patients (23.8%; 95% CI, 20.2-27.9%) had a reduced eGFR (defined as <60 mL/min), with more females than males (28.6% vs. 16.8%; P=0.02) having reduced eGFR. Age and female sex were found to have significant associations with reduced eGFR. Adjusted odds ratios were 1.07 (95% CI, 1.04, 1.10) and 1.96 (95% CI, 1.23, 3.12) for age and female sex, respectively.
Older age and female sex are independently associated with a higher likelihood of having lower eGFRs at initiation of HAART among our study population. We recommend assessment of renal function of HIV-infected patients prior to initiation of HAART to guide the choice and dosing of antiretroviral drugs.
Highly active antiretroviral therapy; human immunodeficiency virus; predictors; renal function; serum creatinine
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.
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.
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.
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).
Screening for microalbuminuria is essential for the early diagnosis and treatment of HIVAN in this age group.
HIVAN; microalbuminuria; HIV; HAART; proteinuria; paediatrics; Nigeria
Chronic kidney disease (CKD) is an important cause of morbidity and mortality in HIV-positive individuals. Hepatitis C (HCV) co-infection has been associated with increased risk of CKD, but prior studies lack information on potential mechanisms. We evaluated the association between HCV or hepatitis B (HBV) co-infection and progressive CKD among 3,441 antiretroviral-treated clinical trial participants. Progressive CKD was defined as the composite of end-stage renal disease, renal death, or significant glomerular filtration rate (eGFR) decline (25% decline to eGFR <60 mL/min/1.73 m2 or 25% decline with a baseline <60). Generalized Estimating Equations were used to model the odds of progressive CKD. At baseline, 13.8% and 3.3% of participants were co-infected with HCV and HBV, respectively. Median eGFR was 111, and 3.7% developed progressive CKD. After adjustment, the odds of progressive CKD were increased in participants with HCV (OR 1.72, 95% CI 1.07–2.76) or HBV (OR 2.26, 95% CI 1.15–4.44). Participants with undetectable or low HCV-RNA had similar odds of progressive CKD as HCV seronegative participants, while participants with HCV-RNA >800,000 IU/ml had increased odds (OR 3.07; 95% CI 1.60–5.90). Interleukin-6, hyaluronic acid, and the FIB-4 hepatic fibrosis index were higher among participants who developed progressive CKD, but were no longer associated with progressive CKD after adjustment. Future studies should validate the relationship between HCV viremia and CKD.
ClinicalTrials.gov NCT00027352; NCT00004978
Direct effects of HIV-1 infection on the kidney combine with immune and genetic factors, comorbidities, coinfections, and medication toxicities to induce a spectrum of kidney disorders in HIV disease. The most dramatic of these, HIV associated nephropathy (HIVAN), emerges almost exclusively in persons of African descent and is associated with rapid progression to end-stage renal disease in the absence of antiretroviral therapy (ART). ART modifies the natural history of HIVAN, but the renal benefits of ART may not be limited to HIVAN. ART is often under prescribed or incorrectly dosed in persons with kidney disease, and kidney disease is a marker of accelerated HIV disease progression. Vigilant attention to kidney function and an understanding of the complex associations involving the kidneys is necessary for optimal care of these patients.
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.
HIV-associated nephropathy (HIVAN); HIV-associated immune complex kidney disease (HIVICK); Tubular cells; Podocytes; DEC-205
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.
growth factors; HIV-associated nephropathy; HIV-transgenic mice; progression of pediatric renal diseases
Kidney disease is an important complication in HIV infected people, and this may be related to infection or antiretroviral therapy (ART). Our aim is to assess renal function in HIV infected paediatric patients, who may be particularly affected and are likely to take ART for longer than adults, and investigate the long term role of Tenofovir Disoproxil Fumarate (TDF) alone or co-administered with Ritonavir-boosted Protease Inhibitors (PI).
Serum creatinine, phosphate and potassium levels, with estimated Glomerular Filtration Rate (eGFR), had been prospectively evaluated for 2 years in a cohort of HIV infected children and adolescents (age 9-18) on ART, and data analyzed according to the exposure to TDF or simultaneous TDF and PI.
Forty-nine patients were studied (57% female, mean age 14). Sixty-three percent were treated with ART containing TDF (Group A), and 37% without TDF (Group B); 47% with concomitant use of TDF and PI (Group C) and 53% without this combination (Group D). The groups didn't differ for age, gender or ethnicity. The median creatinine increased in the entire cohort and in all the groups analyzed; eGFR decreased from 143.6 mL/min/1.73 m2 at baseline to 128.9 after 2 years (p = 0.006) in the entire cohort. Three patients presented a mild eGFR reduction, all were on TDF+PI. Phosphatemia decreased significantly in the entire cohort (p = 0.0003) and in TDF+PI group (p = 0.0128) after 2 years. Five patients (10%) developed hypophosphatemia (Division of Acquired Immune Deficiency AE grade 1 or 2), and four of them were on TDF+PI.
Renal function decrease and hypophosphatemia occur over time in HIV infected children and adolescents on ART. The association with co-administration of TDF and PI appears weak, and further studies are warranted.
To compare the rate of decline of renal function in tenofovir- and abacavir-based antiretroviral therapy (ART) in low-body weight treatment-naïve patients with HIV infection.
We conducted a single-center retrospective cohort study of 503 Japanese patients who commenced on either tenofovir- or abacavir-based initial ART.
The incidence of renal dysfunction, defined as more than 25% fall in estimated glomerular filtration rate (eGFR) from the baseline, was determined in each group. The effect of tenofovir on renal dysfunction was estimated by univariate and multivariate Cox hazards models as the primary exposure. Changes in eGFR until 96 weeks were estimated in both groups with a repeated measures mixed model.
The median body weight of the cohort was 64 kg. The estimated incidence of renal dysfunction in the tenofovir and the abacavir arm was 9.84 per 100 and 4.55 per 100 person-years, respectively. Tenofovir was significantly associated with renal dysfunction by univariate and multivariate analysis (HR = 1.747; 95% CI, 1.152–2.648; p = 0.009) (adjusted HR = 2.080; 95% CI, 1.339–3.232; p<0.001). In subgroup analysis of the patients stratified by intertertile baseline body weight, the effect of tenofovir on renal dysfunction was more evident in patients with lower baseline body weight by multivariate analysis (≤60 kg: adjusted HR = 2.771; 95%CI, 1.494–5.139; p = 0.001) (61–68 kg: adjusted HR = 1.908; 95%CI, 0.764–4.768; p = 0.167) (>68 kg: adjusted HR = 0.997; 95%CI, 0.318–3.121; p = 0.995). The fall in eGFR was significantly greater in the tenofovir arm than the abacavir arm after starting ART (p = 0.003).
The incidence of renal dysfunction in low body weight patients treated with tenofovir was twice as high as those treated with abacavir. Close monitoring of renal function is recommended for patients with small body weight especially those with baseline body weight <60 kg treated with tenofovir.
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.
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).
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.
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.
nephropathy; antiretroviral therapy; comorbidities; tenofovir; African American; Hispanic
HIV-1–associated nephropathy (HIVAN) is a common complication of HIV-1 infection, and its skewed incidence in certain ethnic groups suggests that there is a genetic basis to HIVAN susceptibility. In their study reported in this issue of the JCI, Papeta and colleagues used a combination of gene expression profiling and linkage analysis to identify three genomic loci that regulate a network of genes expressed by podocytes — cells that are crucial to the filtration of fluid and waste by the kidney (see the related article beginning on page 1178). Surprisingly, two of these loci confer disease susceptibility in a transgenic mouse model of HIVAN. This report confirms the central role of podocytes in the pathogenesis of HIVAN and demonstrates the power of this combination of genomic analysis techniques in elucidating the pathogenesis of glomerular disease.
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.
HIV associated nephropathy; HIVAN; collapsing glomerulopathy; FSGS; antiretroviral therapy
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.
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.
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.
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.
Antiretroviral therapy (ART) preserves kidney function in patients with human immunodeficiency virus (HIV)-associated nephropathy (HIVAN). Emerging data also document substantial renal benefits of ART in the general HIV-infected population, which is associated in part with suppression of HIV-1 viral replication. The extent to which the response to ART differs in persons with HIVAN, compared to those with other HIV-associated kidney disorders, is unknown. Beneficial effects of corticosteroids and angiotensin-converting enzyme (ACE) inhibitors on kidney function also are suggested by retrospective cohort studies and uncontrolled trials of patients with HIVAN. Underexposure to ART, or inadequate ART dosing in HIV-infected patients with CKD, may curtail the optimal benefits that may be derived from this therapy.
antiretroviral therapy; HIVAN; angiotensin-converting enzyme inhibitors; prednisone; chronic kidney disease
Childhood human immunodeficiency virus-associated nephropathy (HIVAN) is defined by the presence of proteinuria associated with mesangial hyperplasia and/or global-focal segmental glomerulosclerosis, in combination with the microcystic transformation of renal tubules. This review discusses the pathogenesis of childhood HIVAN and explores how the current pathological paradigm for HIVAN in adults can be applied to children. The Human Immunodeficiency virus-1 (HIV-1) induces renal epithelial injury in African American children with a genetic susceptibility to develop HIVAN. The mechanism is not well understood, since renal epithelial cells harvested from children with HIVAN do not appear to be productively infected. Children with HIVAN show a renal up-regulation of heparan sulphate proteoglycans and a recruitment of circulating heparin-binding growth factors, chemokines, and mononuclear cells. Macrophages appear to establish a renal HIV-reservoir and transfer viral particles to renal epithelial cells. All of these changes seem to trigger an aberrant and persistent renal epithelial proliferative response. The paradigm that viral products produced by infected renal epithelial cells per se induce the proliferation of these cells is not supported by data available in children with HIVAN. More research is needed to elucidate how HIV-1 induces renal epithelial injury and proliferation in HIV-infected children.
Heparin-binding growth factors; HIV-associated nephropathy; Infection of renal tubular epithelial cells; Pediatric AIDS; Renal disease
Diabetic nephropathy is the kidney disease that occurs as a result of diabetes. Cardiovascular and renal complications share common risk factors such as blood pressure, blood lipids, and glycemic control. Thus, chronic kidney disease may predict cardiovascular disease in the general population. The impact of diabetes on renal impairment changes with increasing age. Serum markers of glomerular filtration rate and microalbuminuria identify renal impairment in different segments of the diabetic population, indicating that serum markers as well as microalbuminuria tests should be used in screening for nephropathy in diabetic older people. The American Diabetes Association and the National Institutes of Health recommend Estimated glomerular filtration rate (eGFR) calculated from serum creatinine at least once a year in all people with diabetes for detection of kidney dysfunction. eGFR remains an independent and significant predictor after adjustment for conventional risk factors including age, sex, duration of diabetes, smoking, obesity, blood pressure, and glycemic and lipid control, as well as presence of diabetic retinopathy. Cystatin-C (Cys C) may in future be the preferred marker of diabetic nephropathy due differences in measurements of serum creatinine by various methods. The appropriate reference limit for Cys C in geriatric clinical practice must be defined by further research. Various studies have shown the importance of measurement of albuminuria, eGFR, serum creatinine and hemoglobin level to further enhance the prediction of end stage renal disease.
Chronic kidney disease; End stage renal disease; Glomerular filtration rate; Estimated glomerular filtration rate; Microalbumin; Cockcroft-Gault formula; Modification of diet; Renal disease; Cystatin-C