Long-term impact of immediate versus deferred antiretroviral therapy on kidney health in people with HIV.

People with human immunodeficiency virus (HIV) are at risk for chronic kidney disease (CKD) due to HIV and antiretroviral therapy (ART) nephrotoxicity. Immediate ART initiation reduces mortality and is now the standard of care, but the long-term impact of prolonged ART exposure on CKD is unknown. To evaluate this, the Strategic Timing of Antiretroviral Treatment (START) trial randomized 4,684 ART-naïve adults with CD4 cell count under 500 cells/mm3 to immediate versus deferred ART. We previously reported a small but statistically significantly greater decline in estimated glomerular filtration rate (eGFR) over a median of 2.1 years in participants randomized to deferred versus immediate ART. Here, we compare the incidence of CKD events and changes in eGFR and urine albumin/creatinine ratio (UACR) in participants randomized to immediate versus deferred ART during extended follow-up. Over a median of 9.3 years, eight participants experienced kidney failure or kidney-related death, three in the immediate and five in the deferred ART arms, respectively. Over a median of five years of more comprehensive follow-up, the annual rate of eGFR decline was 1.19 mL/min/1.73m2/year, with no significant difference between treatment arms (difference deferred - immediate arm 0.055; 95% confidence interval -0.106, 0.217 mL/min/1.73m2). Results were similar in models adjusted for baseline covariates associated with CKD, including UACR and APOL1 genotype. Similarly, there was no significant difference between treatment arms in incidence of confirmed UACR 30 mg/g or more (odds ratio 1.13; 95% confidence interval 0.85, 1.51). Thus, our findings provide the most definitive evidence to date in support of the long-term safety of early ART with respect to kidney health.

Kidney disease characteristics, prevalence, and risk factors in León, Nicaragua: a population-based study.

BACKGROUND: CKD of unknown etiology (CKDu) disproportionately affects young people in Central America who lack traditional CKD risk factors (diabetes and hypertension) and has instead been variably linked to heat stress, occupational and environmental exposures, nephrotoxic medications, and/or genetic susceptibility. This study aimed to estimate the prevalence of CKD and identify risk factors for traditional CKD and CKDu in Nicaragua. METHODS: Surveys and assessment for CKD markers in urine and serum were performed in 15-59 year olds in households of the León municipality of Nicaragua. The survey included questions on demographics, health behaviors, occupation, and medical history. Participants with CKD were subdivided into traditional CKD and suspected CKDu based on history of diabetes, hypertension, or other specified conditions. A multinomial logistic regression model was used to identify factors associated with traditional CKD and suspected CKDu, compared to the non-CKD reference group. RESULTS: In 1795 study participants, CKD prevalence was 8.6%. Prevalence in males was twofold higher than females (12% vs 6%). Of those with CKD, 35% had suspected CKDu. Both traditional CKD and CKDu were associated with male sex and increasing age. Traditional CKD was associated with a family history of CKD, history of urinary tract infections, and lower socioeconomic status, while CKDu was associated with drinking well water and a lower body mass index. CONCLUSIONS: Both traditional CKD and CKDu are significant burdens in this region. Our study supports previous hypotheses of CKDu etiology and emphasizes the importance of CKD screening.

Association of HIV and viral suppression status with hospital acute kidney injury in the era of antiretroviral therapy.

In the modern era, it is unknown if people that are virally suppressed with HIV (PWH) are at increased risk for acute kidney injury (AKI) compared to people without HIV and no studies have compared the risk of AKI by viral suppression status. Here, we determined the associations of HIV status and AKI among PWH with and without viral suppression compared to people without HIV. An observational cohort study of PWH and people without HIV hospitalized in a large New York City health system between 2010-2019 was conducted. Multivariable Cox proportional hazards models were used to determine associations between HIV status and risk of AKI, severe AKI and development of chronic kidney disease (CKD). Among 173,884 hospitalized patients, 4,718 had HIV; 2,532 (53.7%) were virally suppressed and 2,186 (46.3%) were not suppressed. Compared to people without HIV, PWH with and without viral suppression were at increased risk of AKI (adjusted hazard ratio 1.27, 95% confidence interval 1.15, 1.40 and 1.73, 1.58, 1.90, respectively) and AKI requiring kidney replacement therapy (1.89, 1.27, 2.84 and 1.87, 1.23, 2.84, respectively). Incremental, graded associations were observed between HIV status and Stage 2 or 3 AKI, and among AKI survivors, and incident CKD. The elevated risk of AKI across ages of PWH was similar in magnitude to older people without HIV. Thus, regardless of virologic control, HIV is an independent risk factor for AKI among hospitalized patients. Future studies should determine the mechanisms by which HIV increases susceptibility to AKI and identify strategies to prevent AKI in PWH.

Environmental exposures are important risk factors for advanced liver fibrosis in African American adults.

Background & Aims: The prevalence and aetiology of liver fibrosis vary over time and impact racial/ethnic groups unevenly. This study measured time trends and identified factors associated with advanced liver fibrosis in the United States. Methods: Standardised methods were used to analyse data on 47,422 participants (≥20 years old) in the National Health and Nutrition Examination Survey (1999-2018). Advanced liver fibrosis was defined as Fibrosis-4 ≥2.67 and/or Forns index ≥6.9 and elevated alanine aminotransferase. Results: The estimated number of people with advanced liver fibrosis increased from 1.3 million (95% CI 0.8-1.9) to 3.5 million (95% CI 2.8-4.2), a nearly threefold increase. Prevalence was higher in non-Hispanic Black and Mexican American persons than in non-Hispanic White persons. In multivariable logistic regression analysis, cadmium was an independent risk factor in all racial/ethnic groups. Smoking and current excessive alcohol use were risk factors in most. Importantly, compared with non-Hispanic White persons, non-Hispanic Black persons had a distinctive set of risk factors that included poverty (odds ratio [OR] 2.09; 95% CI 1.44-3.03) and susceptibility to lead exposure (OR 3.25; 95% CI 1.95-5.43) but did not include diabetes (OR 0.88; 95% CI 0.61-1.27; p =0.52). Non-Hispanic Black persons were more likely to have high exposure to lead, cadmium, polychlorinated biphenyls, and poverty than non-Hispanic White persons. Conclusions: The number of people with advanced liver fibrosis has increased, creating a need to expand the liver care workforce. The risk factors for advanced fibrosis vary by race/ethnicity. These differences provide useful information for designing screening programmes. Poverty and toxic exposures were associated with the high prevalence of advanced liver fibrosis in non-Hispanic Black persons and need to be addressed. Impact and Implications: Because liver disease often produces few warning signs, simple and inexpensive screening tests that can be performed by non-specialists are needed to allow timely diagnosis and linkage to care. This study shows that non-Hispanic Black persons have a distinctive set of risk factors that need to be taken into account when designing liver disease screening programs. Exposure to exogenous toxins may be especially important risk factors for advanced liver fibrosis in non-Hispanic Black persons.

Depression and PrEP uptake, interruption, and adherence among young women in Uganda.

Depression is a common cause of morbidity globally and can impact adherence to medications, posing challenges to medication-based HIV prevention. The objectives of this work are to describe the frequency of depression symptoms in a cohort of 499 young women in Kampala, Uganda and to determine the association of depression symptoms with use of HIV pre-exposure prophylaxis (PrEP). Mild or greater depression, assessed by the patient health questionnaire (PHQ-9), was experienced by 34% of participants at enrollment. Participants with mild depression symptoms tended to uptake PrEP, request PrEP refills, and adhere to PrEP with similar frequency to women with no/minimal signs of depression. These findings highlight opportunities to leverage existing HIV prevention programs to identify women who may benefit from mental health services and may not otherwise be screened.Trial registration: ClinicalTrials.gov identifier: NCT03464266..

The urinary proteome infers dysregulation of mitochondrial, lysosomal, and protein reabsorption processes in chronic kidney disease of unknown etiology (CKDu).

Chronic kidney disease (CKD) of uncertain etiology (CKDu) is a global health concern affecting tropical farming communities. CKDu is not associated with typical risk factors (e.g., diabetes) and strongly correlates with environmental drivers. To gain potential insights into disease etiology and diagnosis, here we report the first urinary proteome comparing patients with CKDu and non-CKDu controls from Sri Lanka. We found 944 differentially abundant proteins. In silico analyses identified 636 proteins of likely kidney and urogenital origin. As expected, renal tubular injury in patients with CKDu was evinced by increases in albumin, cystatin C, and ß2-microglobulin. However, several proteins typically elevated under CKD, including osteopontin and α-N-acetylglucosaminidase, were decreased in patients with CKDu. Furthermore, urinary excretion of aquaporins found higher in CKD was lower in CKDu. Comparisons with previous CKD urinary proteome datasets revealed a unique proteome for CKDu. Notably, the CKDu urinary proteome was relatively similar to that of patients with mitochondrial diseases. Furthermore, we report a decrease in endocytic receptor proteins responsible for protein reabsorption (megalin and cubilin) that correlated with an increase in abundance of 15 of their cognate ligands. Functional pathway analyses identified kidney-specific differentially abundant proteins in patients with CKDu denoted significant changes in the complement cascade and coagulation systems, cell death, lysosomal function, and metabolic pathways. Overall, our findings provide potential early detection markers to diagnose and distinguish CKDu and warrant further analyses on the role of lysosomal, mitochondrial, and protein reabsorption processes and their link to the complement system and lipid metabolism in CKDu onset and progression.NEW & NOTEWORTHY CKDu is a global health concern debilitating a number of tropical rural farming communities. In the absence of typical risk factors like diabetes and hypertension and the lack of molecular markers, it is crucial to identify potential early disease markers. Here, we detail the first urinary proteome profile to distinguish CKDu from CKD. Our data and in silico pathway analyses infer the roles of mitochondrial, lysosomal, and protein reabsorption processes in disease onset and progression.

The effect of daily oral PrEP use during pregnancy on bone mineral density among adolescent girls and young women in Uganda.

Introduction: Oral pre-exposure prophylaxis (PrEP) is recommended during pregnancy for at-risk cisgender women. Pregnancy is known to impede bone growth and tenofovir-based PrEP may also yield detrimental changes to bone health. Thus, we evaluated the effect of PrEP use during pregnancy on bone mineral density (BMD). Methods: We used data from a cohort of women who were sexually active, HIV-negative, ages 16-25 years, initiating DMPA or choosing condoms for contraception and enrolled in the Kampala Women's Bone Study. Women were followed quarterly with rapid testing for HIV and pregnancy, PrEP dispensation, and adherence counseling. Those who became pregnant were counseled on PrEP use during pregnancy per national guidelines. BMD of the neck of the hip, total hip, and lumbar spine was measured using dual-energy x-ray absorptiometry at baseline and annually. We compared the mean percent change in BMD from baseline to month 24. Results: Among 499 women enrolled in the study, 105 pregnancies occurred in 90 women. At enrollment, the median age was 20 years (IQR: 19-21) and 89% initiated PrEP. During pregnancy, 67% of women continued using PrEP and PrEP was dispensed in 64% of visits. BMD declined significantly in women using PrEP during pregnancy compared to women who were not pregnant nor used PrEP: relative BMD change was -2.26% (95% CI: -4.63 to 0.11, p = 0.06) in the femoral neck, -2.57% (95% CI: -4.48 to -0.66, p = 0.01) in total hip, -3.06% (95% CI: -5.49 to -0.63, p = 0.001) lumbar spine. There was no significant difference in BMD loss when comparing PrEP-exposed pregnant women to pregnant women who never used PrEP. Women who became pregnant were less likely to continue PrEP at subsequent study visits than women who did not become pregnant (adjOR: 0.25, 95% CI: 0.16-0.37, p < 0.001). Based on pill counts, there was a 62% reduction in the odds of high PrEP adherence during pregnancy (adjOR = 0.38, 95% CI: 0.27-0.58, p < 0.001). Conclusion: Women who used PrEP during pregnancy experienced a similar reduction in BMD as pregnant women with no PrEP exposure, indicating that BMD loss in PrEP-using pregnant women is largely driven by pregnancy and not PrEP.

Bone mineral density, nutrient intake, and physical activity among young women from Uganda.

Few studies have characterized bone mineral density (BMD) among health young African women. In our study of 496 Ugandan women age ≤25 years, we found that women had healthy BMD that were lower on average than the standard reference ranges. Reference ranges available for BMD measurements need greater precision. PURPOSE: Data describing bone mineral density (BMD), nutrient intake, and body composition among healthy, young women in sub-Saharan Africa are limited. Using baseline data from a cohort of young, healthy Ugandan women, we summarize bone health and associated risk factors for reduced bone mass. METHODS: Using baseline data from Ugandan women ages 16-25 years who enrolled in an ongoing cohort study of bone health with concurrent use of injectable contraception and oral HIV pre-exposure prophylaxis, we describe the distribution of BMD, nutrient intake, physical activity, and body composition. The association of low BMD (1 or more standard deviations below the age, sex, and race-matched reference range from the USA) and calcium intake, vitamin D intake, physical activity, and body composition was estimated using multivariable logistic regression. RESULTS: In 496 healthy, Ugandan women with median age of 20 years (interquartile range [IQR] 19-21) and median fat:lean mass ratio of 0.55 (IQR 0.46-0.64), median lumbar spine and total hip BMD was 0.9g/cm2 (IQR 0.9-1.0) each. For lumbar spine, Z-score distributions were lower overall than the reference population and 9.3% and 36.3% of women had Z-score >2 and >1 standard deviations below the reference range, respectively. For total hip, Z-scores were similar to the reference population and 1.0% and 12.3% of women had Z-score >2 and >1 standard deviations below the reference range, respectively. In the week prior to enrollment, 41.1% of women consumed >7 servings of calcium, 56.5% had >7 servings of vitamin D, and 98.6% reported ≥2.5 h of physical activity. Having greater body fat was associated with greater frequency of low lumbar spine BMD (p<0.01 for fat:lean mass ratio, total body fat percentage, waist circumference, and BMI). CONCLUSION: Young Ugandan women exhibited healthy levels of BMD that were lower than the reference range population.

Polypharmacy and medical intensive care unit (MICU) admission and 10-year all-cause mortality risk among hospitalized patients with and without HIV.

OBJECTIVE: Medical intensive care unit (MICU) admissions have been declining in people with HIV infection (PWH), but frequency of outpatient polypharmacy (prescription of ≥5 chronic medications) has increased. Among those hospitalized, we examined whether outpatient polypharmacy is associated with subsequent 1-year MICU admission or 10-year all-cause mortality, and if the association varies by HIV status. DESIGN: Retrospective cohort study. METHODS: Using a national electronic health record cohort of Veterans in care, we ascertained outpatient polypharmacy during fiscal year (FY) 2009 and followed patients for 1-year MICU admission and 10-year mortality. We assessed associations of any polypharmacy (yes/no and categorized ≤4, 5-7, 8-9, and ≥10 medications) with 1-year MICU admission and 10-year mortality using logistic and Cox regressions, respectively, adjusted for demographics, HIV status, substance use, and severity of illness. RESULTS: Among 9898 patients (1811 PWH) hospitalized in FY2010, prior outpatient polypharmacy was common (51%). Within 1 year, 1532 (15%) had a MICU admission and within 10 years, 4585 (46%) died. Polypharmacy was associated with increased odds of 1-year MICU admission, in both unadjusted (odds ratio (OR) 1.36 95% CI: (1.22, 1.52)) and adjusted models, aOR (95% CI) = 1.28 (1.14, 1.43) and with 10-year mortality in unadjusted, hazard ratio (HR) (95% CI) = 1.40 (1.32, 1.48), and adjusted models, HR (95% CI) = 1.26 (1.19, 1.34). Increasing levels of polypharmacy demonstrated a dose-response with both outcomes and by HIV status, with a stronger association among PWH. CONCLUSIONS: Among hospitalized patients, prior outpatient polypharmacy was associated with 1-year MICU admission and 10-year all-cause mortality after adjusting for severity of illness in PWH and PWoH.

Associations between female birth sex and risk of chronic kidney disease development among people with HIV in the USA: A longitudinal, multicentre, cohort study.

Background: Women represent a meaningful proportion of new HIV diagnoses, with Black women comprising 58% of new diagnoses among women. As HIV infection also increases risk of chronic kidney disease (CKD), understanding CKD risk among women with HIV (WWH), particularly Black women, is critical. Methods: In this longitudinal cohort study of people with HIV (PWH) enrolled in CFAR Network of Integrated Clinical Systems (CNICS), a multicentre study comprised of eight academic medical centres across the United States from Jan 01, 1996 and Nov 01, 2019, adult PWH were excluded if they had ≤2 serum creatinine measurements, developed CKD prior to enrollment, or identified as intersex or transgendered, leaving a final cohort of 33,998 PWH. The outcome was CKD development, defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1·73 m2 calculated using the CKD-EPI equation, for ≥90 days with no intervening higher values. Findings: Adjusting for demographic and clinical characteristics, WWH were 61% more likely to develop CKD than men (adjusted hazard ratio [aHR]: 1·61, 95% CI: 1·46-1·78, p<0·001). This difference persisted after further adjustment for APOL1 risk variants (aHR female sex: 1·92, 95% CI: 1·63-2·26, p<0·001) and substance abuse (aHR female sex: 1·70, 95% CI: 1·54-1·87, p<0·001). Interpretation: WWH experienced increased risk of CKD. Given disparities in care among patients with end-stage kidney disease, efforts to engage WWH in nephrology care to improve chronic disease management are critical. Funding: US National Institutes of Health.

The association of lupus nephritis with adverse pregnancy outcomes among women with lupus in North America.

OBJECTIVES: We evaluated the association of lupus nephritis (LN) and adverse pregnancy outcomes in prospective cohorts of pregnant women with SLE (systemic lupus erythematosus). METHODS: We conducted a patient-level pooled analysis of data from three cohorts of pregnant women with SLE. Pooled logistic regression models were used to evaluate the association of LN and adverse pregnancy outcomes. Odds ratios and 95% confidence intervals were calculated using a fixed effect model by enrolling cohort. RESULTS: The pooled cohort included 393 women who received care at clinics in the United States and Canada from 1995 to 2015. There were 144 (37%) women with a history of LN. Compared to women without LN, those with LN had higher odds of fetal loss (OR: 1.90; 95% CI: 1.01, 3.56) and preeclampsia (OR: 2.04; 95% CI: 1.01, 4.13). Among the 31 women with active nephritis (defined as urine protein ≥ 0.5 g/24 h) there was a higher odds of poor pregnancy outcome (OR: 3.08; 95% CI: 1.31, 7.23) and fetal loss (OR: 6.29; 95% CI: 2.52, 15.70) compared to women without LN. CONCLUSIONS: In this pooled cohort of women with SLE, a history of LN was associated with fetal loss and preeclampsia. Active nephritis was associated with poor pregnancy outcome and fetal loss.

Risk Factors for Incident Hypertension Within 1 Year of Initiating Antiretroviral Therapy Among People with HIV.

Hypertension (HTN) is a common comorbidity among people with HIV and associated with an increased risk for atherosclerotic cardiovascular disease and chronic kidney disease. The relationship of antiretroviral therapy (ART) initiation to incident HTN remains a clinical question. We determined HTN incidence at 48 weeks of follow-up among ART-naive participants without HTN and not taking antihypertensive medications at ART initiation through randomized clinical trials through the AIDS Clinical Trial Group between 1999 and 2011. We assessed the association of baseline characteristics, including randomized ART agents with HTN incidence at 48 weeks using Poisson regression models. Incident HTN was defined as blood pressure ≥130/80 mmHg, or use of antihypertensive medication. Among 2,614 participants, mean age was 37 ± 10 years, 79% male sex, and 36% African American race. After 48 weeks, 839 participants (32%) developed HTN. Receiving a non-nucleoside reverse transcriptase inhibitor (NNRTI) was associated with an increased relative risk (RR) of incident HTN, while the risk was lower for protease inhibitor use. Stavudine and efavirenz were associated with an increased RR of developing HTN, while tenofovir disoproxil fumarate, darunavir/ritonavir, and atazanavir/ritonavir were associated with a decreased risk of developing HTN. Additionally, older age, higher body mass index (BMI), and having hepatitis C were associated with an increased risk for developing HTN, while women and participants with a higher baseline CD4 count were at a decreased risk of developing HTN at 48 weeks. One third of these ART naive participants developed HTN after ART initiation. NNRTIs, notably efavirenz, and stavudine were associated with an increased risk of HTN. Additional factors associated with HTN included traditional factors like older age and higher BMI, and advanced HIV disease (lower CD4 count). (Clinicaltrials.gov: NCT00001137).

HIV at 40: kidney disease in HIV treatment, prevention, and cure.

Four decades after the first cases of HIV were reported, kidney disease remains an important comorbidity in people with HIV (PWH). Both HIV-associated nephropathy and immune complex kidney disease were recognized as complications of HIV infection in the early years before treatment was available. Although the introduction of effective antiretroviral therapy in the late 1990s resulted in dramatic improvements in survival and health in PWH, several commonly used antiretroviral agents have been associated with kidney injury. HIV infection and treatment may also promote the progression of comorbid chronic kidney disease due to traditional risk factors such as diabetes, and HIV is one of the strongest "second hits" for the high-risk APOL1 genotype. Unique considerations in the management of chronic kidney disease in PWH are largely related to the need for lifelong antiretroviral therapy, with potential for toxicity, drug-drug interactions, and polypharmacy. PWH who develop progressive chronic kidney disease are candidates for all modalities of kidney replacement therapy, including kidney transplantation, and at some centers, PWH may be candidates to serve as donors for recipients with HIV. Transplantation of kidney allografts from donors with HIV also offers a unique opportunity to study viral dynamics in the kidney, with implications for kidney health and for research toward HIV cure. In addition, HIV-transgenic animal models have provided important insights into kidney disease pathogenesis beyond HIV, and experience with HIV and HIV-related kidney disease has provided important lessons for future pandemics.

Etiology of Persistent Microalbuminuria in Nigeria (P_MICRO study): protocol and study design.

BACKGROUND: Microalbuminuria is an independent risk factor for cardiovascular and kidney disease and a predictor of end organ damage, both in the general population and in persons with HIV (PWH). Microalbuminuria is also an important risk factor for mortality in PWH treated with antiretroviral therapy (ART). In the ongoing Renal Risk Reduction (R3) study in Nigeria, we identified a high prevalence of microalbuminuria confirmed by two measurements 4-8 weeks apart in ART-experienced, virologically suppressed PWH. Although Stage 1 or 2 hypertension and exposure to potentially nephrotoxic antiretroviral medications were common in R3 participants, other traditional risk factors for albuminuria and kidney disease, including diabetes, APOL1 high-risk genotype, and smoking were rare. Co-infection with endemic pathogens may also be significant contributors to albuminuria, but co-infections were not evaluated in the R3 study population. METHODS: In Aim 1, we will cross-sectionally compare the prevalence of albuminuria and established kidney disease risk factors in a cohort of PWH to age- and sex-matched HIV-negative adults presenting for routine care at the Aminu Kano Teaching Hospital in Kano, Nigeria. We will leverage stored specimens from 2500 R3 participants and enroll an additional 500 PLWH recently initiated on ART (≤ 24 months) and 750 age- and sex-matched HIV-negative adults to determine the contribution of HIV, hypertension, and other comorbid medical conditions to prevalent albuminuria. In Aim 2, we will follow a cohort of 1000 HIV-positive, ART-treated and 500 HIV-negative normoalbuminuric adults for 30 months to evaluate the incidence and predictors of albuminuria. DISCUSSION: The findings from this study will support the development of interventions to prevent or address microalbuminuria in PWH to reduce kidney and cardiovascular morbidity and mortality. Such interventions might include more intensive monitoring and treatment of traditional risk factors, the provision of renin-angiotensin aldosterone system or sodium-glucose cotransporter-2 inhibitors, consideration of changes in ART regimen, and screening and treatment for relevant co-infections.

Staphylococcus aureus Bacteremia Among Patients Receiving Maintenance Hemodialysis: Trends in Clinical Characteristics and Outcomes.

RATIONALE & OBJECTIVE: Staphylococcus aureus (Saureus) bacteremia (SAB) is associated with morbidity and mortality in patients receiving maintenance hemodialysis (HD). We evaluated changes in clinical and bacterial characteristics, and their associations with clinical outcomes with SAB in this population over a 21-year period. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 453 hospitalized, non-neutropenic adults receiving maintenance HD who developed monomicrobial SAB between 1995 and 2015. EXPOSURE: Clinical characteristics and bacterial genotype. OUTCOME: All-cause and SAB-attributable mortality, persistent bacteremia, and metastatic complications. ANALYTICAL APPROACH: Proportions of participants experiencing each outcome were calculated overall and by calendar year. Secular trends were estimated using binomial risk regression, a generalized linear model with the log link function for a binomial outcome. Associations with outcomes were estimated using logistic regression. RESULTS: Over the 21-year study period, patients receiving maintenance HD experienced significant increases in age- and diabetes-adjusted SAB-attributable mortality (0.45% [95% CI, 0.36%-0.46%] per year), persistent bacteremia (0.86% [95% CI, 0.14%-1.55%] per year), metastatic complications (0.84% [95% CI, 0.11%-1.56%] per year), and infection with the virulent Saureus clone USA300 (1.47% [95% CI, 0.33%-2.52%] per year). Over time, the suspected source of SAB was less likely to be a central venous catheter (-1.32% [95% CI, -2.05 to-0.56%] per year) or arteriovenous graft (-1.08% [95% CI, -1.54 to-0.56] per year), and more likely to be a nonvascular access source (1.89% [95% CI, 1.29%-2.43%] per year). Patients with a nonvascular access suspected source of infection were more likely to die as a result of their S aureus infection (OR, 3.20 [95% CI, 1.36-7.55]). The increase in USA300 infections may have contributed to the observed increase in persistent bacteremia (OR, 2.96 [95% CI, 1.12-7.83]) but did not explain the observed increases in SAB-attributable mortality (OR, 0.83 [95% CI, 0.19-3.61]) or metastatic complications (OR, 1.34 [95% CI, 0.53-3.41]). LIMITATIONS: Single-center, inpatient cohort. CONCLUSIONS: The clinical and molecular epidemiology of SAB in patients receiving maintenance HD has changed over time, with an increase in SAB-attributable mortality and morbidity despite a decline in catheter-related infections.

Randomized Placebo-Controlled Trial of Reloxaliase in Enteric Hyperoxaluria.

Reloxaliase in Enteric HyperoxaluriaPatients with enteric hyperoxaluria received reloxaliase or placebo with food for 4 weeks. Urinary oxalate excretion decreased from 83.2 to 67.4 mg/24 hr during weeks 1 to 4 with reloxaliase compared with 84.2 to 78.1 mg/24 hr with placebo (P=0.004). Adverse events occurred for 69% of reloxaliase-treated patients versus 53% of those receiving placebo.

Mechanisms of Proteinuria in HIV.

Proteinuria is common in the setting of HIV infection, and may reflect comorbid kidney disease, treatment-related nephrotoxicity, and HIV-related glomerular diseases. The mechanisms of podocyte and tubulointerstial injury in HIV-associated nephropathy (HIVAN) have been the subject of intense investigation over the past four decades. The pathologic contributions of viral gene expression, dysregulated innate immune signaling, and ancestry-driven genetic risk modifiers have been explored in sophisticated cellular and whole animal models of disease. These studies provide evidence that injury-induced podocyte dedifferentiation, hyperplasia, cytoskeletal dysregulation, and apoptosis may cause the loss of glomerular filtration barrier integrity and slit diaphragm performance that facilitates proteinuria and tuft collapse in HIVAN. Although the incidence of HIVAN has declined with the introduction of antiretroviral therapy, the collapsing FSGS lesion has been observed in the context of other viral infections and chronic autoimmune disorders, and with the use of interferon-based therapies in genetically susceptible populations. This highlights the fact that the lesion is not specific to HIVAN and that the role of the immune system in aggravating podocyte injury warrants further exploration. This review will summarize our progress in characterizing the molecular mechanisms of podocyte dysfunction in HIVAN and other forms of HIV-associated kidney disease.

Regional and Racial Disparities in HIV-Related Kidney Disease.

Clinical Background and Epidemiology: Worldwide, an estimated 38 million people are living with HIV infection. The classic kidney disease of HIV infection, commonly known as HIV-associated nephropathy, is a collapsing form of focal segmental glomerulosclerosis that almost exclusively affects individuals of African descent with advanced HIV disease. People living with HIV are also at risk for immune-complex kidney diseases, antiretroviral nephrotoxicity, and kidney disease due to co-infections and comorbidities. Challenges: The burden of HIV-related kidney disease is greatest in traditionally disadvantaged populations in resource-limited settings in sub-Saharan Africa and the Caribbean and among minority populations in the United States and Europe. Factors contributing to these disparities include a higher prevalence of HIV infection, limited access to optimal antiretroviral therapy, and genetic susceptibility to kidney disease. Treatment and Prevention: Current treatment guidelines recommend the initiation of life-long antiretroviral therapy in all people living with HIV to prevent AIDS and non-AIDS complications, including kidney disease. People living with HIV who progress to end-stage kidney disease despite treatment are candidates for dialysis and kidney transplant, including the possibility of accepting organs from HIV-positive donors in some settings. Although HIV prevention is currently the only definitive solution, expanding access to antiretroviral therapy, dialysis, and kidney transplantation in people living with HIV are important intermediate steps to address the global burden of HIV-related kidney disease.