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Rationale & objectiveTubulointerstitial damage is a feature of early chronic kidney disease (CKD), but current clinical tests capture it poorly. Urine biomarkers of tubulointerstitial health may identify risk of CKD.Study designProspective cohort (Atherosclerosis Risk in Communities [ARIC]) and case-cohort (Multi-Ethnic Study of Atherosclerosis [MESA] and Reasons for Geographic and Racial Differences in Stroke [REGARDS]).Setting & participantsAdults with estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 and without diabetes in the ARIC, REGARDS, and MESA studies.ExposuresBaseline urine monocyte chemoattractant protein-1 (MCP-1), alpha-1-microglobulin (α1m), kidney injury molecule-1, epidermal growth factor, and chitinase-3-like protein 1.OutcomeIncident CKD or end-stage kidney disease.Analytical approachMultivariable Cox proportional hazards regression for each cohort; meta-analysis of results from all 3 cohorts.Results872 ARIC participants (444 cases of incident CKD), 636 MESA participants (158 cases), and 924 REGARDS participants (488 cases) were sampled. Across cohorts, mean age ranged from 60 ± 10 to 63 ± 8 years, and baseline eGFR ranged from 88 ± 13 to 91 ± 14 mL/min/1.73 m2. In ARIC, higher concentrations of urine MCP-1, α1m, and kidney injury molecule-1 were associated with incident CKD. In MESA, higher concentration of urine MCP-1 and lower concentration of epidermal growth factor were each associated with incident CKD. In REGARDS, none of the biomarkers were associated with incident CKD. In meta-analysis of all 3 cohorts, each 2-fold increase α1m concentration was associated with incident CKD (HR, 1.19; 95% CI, 1.08-1.31).LimitationsObservational design susceptible to confounding; competing risks during long follow-up period; meta-analysis limited to 3 cohorts.ConclusionsIn 3 combined cohorts of adults without prevalent CKD or diabetes, higher urine α1m concentration was independently associated with incident CKD. 4 biomarkers were associated with incident CKD in at least 1 of the cohorts when analyzed individually. Kidney tubule health markers might inform CKD risk independent of eGFR and albuminuria.

BACKGROUNDLongitudinal investigations of murine acute kidney injury (AKI) suggest that injury and inflammation may persist long after the initial insult. However, the evolution of these processes and their prognostic values are unknown in patients with AKI.METHODSIn a prospective cohort of 656 participants hospitalized with AKI, we measured 7 urine and 2 plasma biomarkers of kidney injury, inflammation, and tubular health at multiple time points from the diagnosis to 12 months after AKI. We used linear mixed-effect models to estimate biomarker changes over time, and we used Cox proportional hazard regressions to determine their associations with a composite outcome of chronic kidney disease (CKD) incidence and progression. We compared the gene expression kinetics of biomarkers in murine models of repair and atrophy after ischemic reperfusion injury (IRI).RESULTSAfter 4.3 years, 106 and 52 participants developed incident CKD and CKD progression, respectively. Each SD increase in the change of urine KIM-1, MCP-1, and plasma TNFR1 from baseline to 12 months was associated with 2- to 3-fold increased risk for CKD, while the increase in urine uromodulin was associated with 40% reduced risk for CKD. The trajectories of these biological processes were associated with progression to kidney atrophy in mice after IRI.CONCLUSIONSustained tissue injury and inflammation, and slower restoration of tubular health, are associated with higher risk of kidney disease progression. Further investigation into these ongoing biological processes may help researchers understand and prevent the AKI-to-CKD transition.FUNDINGNIH and NIDDK (grants U01DK082223, U01DK082185, U01DK082192, U01DK082183, R01DK098233, R01DK101507, R01DK114014, K23DK100468, R03DK111881, K01DK120783, and R01DK093771).

Acute kidney injury (AKI) is a growing epidemic and is independently associated with increased risk of death, chronic kidney disease (CKD) and cardiovascular events. Randomized-controlled trials (RCTs) in this domain are notoriously challenging and many clinical studies in AKI have yielded inconclusive findings. Underlying this conundrum is the inherent heterogeneity of AKI in its etiology, presentation and course. AKI is best understood as a syndrome and identification of AKI subphenotypes is needed to elucidate the disease's myriad etiologies and to tailor effective prevention and treatment strategies. Conventional RCTs are logistically cumbersome and often feature highly selected patient populations that limit external generalizability and thus alternative trial designs should be considered when appropriate. In this narrative review of recent developments in AKI trials based on the Kidney Disease Clinical Trialists (KDCT) 2020 meeting, we discuss barriers to and strategies for improved design and implementation of clinical trials for AKI patients, including predictive and prognostic enrichment techniques, the use of pragmatic trials and adaptive trials.

ObjectivesThe epidemiology of hospitalized acute kidney injury (AKI) among people living with HIV (PLWH) in the era of modern antiretroviral therapy (ART) for all PLWH is not well characterized. We evaluated the incidence of and risk factors for hospitalized AKI from 2005 to 2015 among PLWH on ART.MethodsWe conducted a retrospective analysis of PLWH from the Johns Hopkins HIV Clinical Cohort. We defined hospitalized AKI as a rise of ≥ 0.3 mg/dL in serum creatinine (SCr) within any 48-h period or a 50% increase in SCr from baseline and assessed associations of risk factors with incident AKI using multivariate Cox regression models.ResultsMost participants (75%) were black, 34% were female, and the mean age was 43 years. The incidence of AKI fluctuated annually, peaking at 40 per 1000 person-years (PY) [95% confidence interval (CI) 22-69 per 1000 PY] in 2007, and reached a nadir of 20 per 1000 PY (95% CI 11-34 per 1000 PY) in 2010. There was no significant temporal trend (-3.3% change per year; 95% CI -8.6 to 2.3%; P = 0.24). After multivariable adjustment, characteristics independently associated with AKI included black race [hazard ratio (HR) 2.44; 95% CI 1.42-4.20], hypertension (HR 1.62; 95% CI 1.09-2.38), dipstick proteinuria > 1 (HR 1.86; 95% CI 1.07-3.23), a history of AIDS (HR 1.82; 95% CI 1.29-2.56), CD4 count

IntroductionBiomarkers of acute kidney injury (AKI) are often indexed to urine creatinine (UCr) or urine osmolarity (UOsm) to control for urine concentration. We evaluated how these approaches affect the biomarker-outcome association in patients with AKI.MethodsThe Assessment, Serial Evaluation, and Subsequent Sequelae in Acute Kidney Injury Study was a cohort of hospitalized patients with and without AKI between 2009 and 2015. Using Cox proportional hazards regression, we assessed the associations and predictions (C-statistics) of urine biomarkers with a composite outcome of incident chronic kidney disease (CKD) and CKD progression. We used 4 approaches to account for urine concentration: indexing and adjusting for UCr and UOsm.ResultsAmong 1538 participants, 769 (50%) had AKI and 300 (19.5%) developed composite CKD outcome at median follow-up of 4.7 years. UCr and UOsm during hospitalization were inversely associated with the composite CKD outcome. The associations and predictions with CKD were significantly strengthened after indexing or adjusting for UCr or UOsm for urine kidney injury molecule-1 (KIM-1), interleukin-18 (IL-18), and monocyte chemoattractant protein-1 (MCP-1) in patients with AKI. There was no significant improvement with indexing or adjusting UCr or UOsm for albumin, neutrophil gelatinase-associated lipocalin (NGAL), and chitinase 3-like 1 (YKL-40). Uromodulin's (UMOD) inverse association with the outcome was significantly blunted after indexing but not adjusting for UCr or UOsm.ConclusionUCr and UOsm during hospitalization are inversely associated with development and progression of CKD. Indexing or adjusting for UCr or UOsm strengthened associations and improved predictions for CKD for only some biomarkers. Incorporating urinary concentration should be individualized for each biomarker in research and clinical applications.

BackgroundMechanisms by which AKI leads to CKD progression remain unclear. Several urine biomarkers have been identified as independent predictors of progressive CKD. It is unknown whether AKI may result in long-term changes in these urine biomarkers, which may mediate the effect of AKI on CKD progression.MethodsWe selected 198 episodes of hospitalized AKI (defined as peak/nadir inpatient serum creatinine values ≥ 1.5) among adult participants in the Chronic Renal Insufficiency Cohort (CRIC) Study. We matched the best non-AKI hospitalization (unique patients) for each AKI hospitalization using pre-hospitalization characteristics including eGFR and urine protein/creatinine ratio. Biomarkers were measured in banked urine samples collected at annual CRIC study visits.ResultsUrine biomarker measurements occurred a median of 7 months before and 5 months after hospitalization. There were no significant differences in the change in urine biomarker-to-creatinine ratio between the AKI and non-AKI groups: KIM-1/Cr + 9% vs + 7%, MCP-1/Cr + 4% vs + 1%, YKL-40/Cr + 7% vs -20%, EGF/Cr -11% vs -8%, UMOD/Cr -2% vs -7% and albumin/Cr + 17% vs + 13% (all p > 0.05).ConclusionIn this cohort of adults with CKD, AKI did not associate with long-term changes in urine biomarkers.

Although immunoassays are the most widely used protein measurement method, aptamer-based methods such as the SomaScan platform can quantify up to 7000 proteins per biosample, creating new opportunities for unbiased discovery. However, there is limited research comparing the consistency of biomarker-disease associations between immunoassay and aptamer-based platforms. In a substudy of the TRIBE-AKI cohort, preoperative and postoperative plasma samples from 294 patients with previous immunoassay measurements were analyzed using the SomaScan platform. Inter-platform Spearman correlations (rs) and biomarker-AKI associations were compared across 30 preoperative and 34 postoperative immunoassay-aptamer pairs. Possible factors contributing to inter-platform differences were examined including target protein characteristics, immunoassay, and SomaScan coefficients of variation, other assay characteristics, and sample storage time. The median rs was 0.54 (interquartile range [IQR] 0.34-0.83) in postoperative samples and 0.41 (IQR 0.21-0.69) in preoperative samples. We observed a trend of greater rs in biomarkers with greater concentrations; the Spearman correlation between the concentration of protein and the inter-platform correlation was 0.64 in preoperative pairs and 0.53 in postoperative pairs. Of proteins measured by immunoassays, we observed significant biomarker-AKI associations for 13 proteins preop and 24 postop; of all corresponding aptamers, 8 proteins preop and 12 postop. All proteins significantly associated with AKI as measured by SomaScan were also significantly associated with AKI as measured by immunoassay. All biomarker-AKI odds ratios were significantly different (P < 0.05) between platforms in 14% of aptamer-immunoassay pairs, none of which had high (rs > 0.50) inter-platform correlations. Although similar biomarker-disease associations were observed overall, biomarkers with high physiological concentrations tended to have the highest-confidence inter-platform operability in correlations and biomarker-disease associations. Aptamer assays provide excellent precision and an unprecedented coverage and promise for disease associations but interpretation of results should keep in mind a broad range of correlations with immunoassays.

BackgroundNovel urine biomarkers have enabled the characterization of kidney tubular dysfunction and injury among persons living with HIV, a population at an increased risk of kidney disease. Even though several urine biomarkers predict progressive kidney function decline, antiretroviral toxicity, and mortality in the setting of HIV infection, the relationships among the risk factors for chronic kidney disease (CKD) and urine biomarkers are unclear.MethodsWe assessed traditional and infection-related CKD risk factors and measured 14 urine biomarkers at baseline and at follow-up among women living with HIV in the Women's Interagency Health Study (WIHS). We then used simultaneously adjusted multivariable linear regression models to evaluate the associations of CKD risk factors with longitudinal changes in biomarker levels.ResultsOf the 647 women living with HIV in this analysis, the majority (67%) were Black, the median age was 45 years and median follow-up time was 2.5 years. Each traditional and infection-related CKD risk factor was associated with a unique set of changes in urine biomarkers. For example, baseline hemoglobin a1c was associated with worse tubular injury (higher interleukin [IL]-18), proximal tubular reabsorptive dysfunction (higher α1-microglobulin), tubular reserve (lower uromodulin) and immune response to injury (higher chitinase-3-like protein-1 [YKL-40]). Furthermore, increasing hemoglobin a1c at follow-up was associated with further worsening of tubular injury (higher kidney injury molecule-1 [KIM-1] and IL-18), as well as higher YKL-40. HCV co-infection was associated with worsening proximal tubular reabsorptive dysfunction (higher β2-microglobulin [β2m]), and higher YKL-40, whereas HIV viremia was associated with worsening markers of tubular and glomerular injury (higher KIM-1 and albuminuria, respectively).ConclusionsCKD risk factors are associated with unique patterns of biomarker changes among women living with HIV, suggesting that serial measurements of multiple biomarkers may help in detecting and monitoring kidney disease in this setting.

BackgroundAcute kidney injury (AKI) and obesity are independent risk factors for chronic kidney disease (CKD). This study aimed to determine if obesity modifies risk for CKD outcomes after AKI.MethodsThis prospective multisite cohort study followed adult survivors after hospitalization, with or without AKI. The primary outcome was a combined CKD event of incident CKD, progression of CKD and kidney failure, examined using time-to-event Cox proportional hazards models, adjusted for diabetes status, age, pre-existing CKD, cardiovascular disease status and intensive care unit admission, and stratified by study center. Body mass index (BMI) was added as an interaction term to examine effect modification by body size.ResultsThe cohort included 769 participants with AKI and 769 matched controls. After median follow-up of 4.3 years, among AKI survivors, the rate of the combined CKD outcome was 84.7 per1000-person-years with BMI ≥30 kg/m2, 56.4 per 1000-person-years with BMI 25-29.9 kg/m2, and 72.6 per 1000-person-years with BMI 20-24.9 kg/m2. AKI was associated with a higher risk of combined CKD outcomes; adjusted-HR 2.43 (95%CI 1.87-3.16), with no evidence that this was modified by BMI (p for interaction = 0.3). After adjustment for competing risk of death, AKI remained associated with a higher risk of the combined CKD outcome (subdistribution-HR 2.27, 95%CI 1.76-2.92) and similarly, there was no detectable effect of BMI modifying this risk.ConclusionsIn this post-hospitalization cohort, we found no evidence for obesity modifying the association between AKI and development or progression of CKD.

BackgroundThere has recently been considerable interest in better understanding how blood pressure should be managed after an episode of hospitalized AKI, but there are scant data regarding the associations between blood pressure measured after AKI and subsequent adverse outcomes. We hypothesized that among AKI survivors, higher blood pressure measured three months after hospital discharge would be associated with worse outcomes. We also hypothesized these associations between blood pressure and outcomes would be similar among those who survived non-AKI hospitalizations.MethodsWe quantified how systolic blood pressure (SBP) observed three months after hospital discharge was associated with risks of subsequent hospitalized AKI, loss of kidney function, mortality, and heart failure events among 769 patients in the prospective ASSESS-AKI cohort study who had hospitalized AKI. We repeated this analysis among the 769 matched non-AKI ASSESS-AKI enrollees. We then formally tested for AKI interaction in the full cohort of 1538 patients to determine if these associations differed among those who did and did not experience AKI during the index hospitalization.ResultsAmong 769 patients with AKI, 42 % had subsequent AKI, 13 % had loss of kidney function, 27 % died, and 18 % had heart failure events. SBP 3 months post-hospitalization did not have a stepwise association with the risk of subsequent AKI, loss of kidney function, mortality, or heart failure events. Among the 769 without AKI, there was also no stepwise association with these risks. In formal interaction testing using the full cohort of 1538 patients, hospitalized AKI did not modify the association between post-discharge SBP and subsequent risks of adverse clinical outcomes.ConclusionsContrary to our first hypothesis, we did not observe that higher stepwise blood pressure measured three months after hospital discharge with AKI was associated with worse outcomes. Our data were consistent with our second hypothesis that the association between blood pressure measured three months after hospital discharge and outcomes among AKI survivors is similar to that observed among those who survived non-AKI hospitalizations.

BackgroundThere has recently been considerable interest in better understanding how blood pressure should be managed after an episode of hospitalized AKI, but there are scant data regarding the associations between blood pressure measured after AKI and subsequent adverse outcomes. We hypothesized that among AKI survivors, higher blood pressure measured three months after hospital discharge would be associated with worse outcomes. We also hypothesized these associations between blood pressure and outcomes would be similar among those who survived non-AKI hospitalizations.MethodsWe quantified how systolic blood pressure (SBP) observed three months after hospital discharge was associated with risks of subsequent hospitalized AKI, loss of kidney function, mortality, and heart failure events among 769 patients in the prospective ASSESS-AKI cohort study who had hospitalized AKI. We repeated this analysis among the 769 matched non-AKI ASSESS-AKI enrollees. We then formally tested for AKI interaction in the full cohort of 1538 patients to determine if these associations differed among those who did and did not experience AKI during the index hospitalization.ResultsAmong 769 patients with AKI, 42 % had subsequent AKI, 13 % had loss of kidney function, 27 % died, and 18 % had heart failure events. SBP 3 months post-hospitalization did not have a stepwise association with the risk of subsequent AKI, loss of kidney function, mortality, or heart failure events. Among the 769 without AKI, there was also no stepwise association with these risks. In formal interaction testing using the full cohort of 1538 patients, hospitalized AKI did not modify the association between post-discharge SBP and subsequent risks of adverse clinical outcomes.ConclusionsContrary to our first hypothesis, we did not observe that higher stepwise blood pressure measured three months after hospital discharge with AKI was associated with worse outcomes. Our data were consistent with our second hypothesis that the association between blood pressure measured three months after hospital discharge and outcomes among AKI survivors is similar to that observed among those who survived non-AKI hospitalizations.

Rationale & objectiveSingle measurements of urinary biomarkers reflecting kidney tubule health are associated with chronic kidney disease (CKD) risk in HIV infection, but the prognostic value of repeat measurements over time is unknown.Study designCohort study.Setting & participants647 women living with HIV infection enrolled in the Women's Interagency Health Study.Exposures14 urinary biomarkers of kidney tubule health measured at 2 visits over a 3-year period.OutcomeIncident CKD, defined as estimated glomerular filtration rate (eGFR)

BackgroundUromodulin modulates the sodium-potassium-two-chloride transporter in the thick ascending limb of the loop of Henle, and its overexpression in murine models leads to salt-induced hypertension. We hypothesized that individuals with higher baseline levels of urine uromodulin would have a greater increase in systolic blood pressure (SBP) for the same increase in sodium compared with those with lower uromodulin levels.MethodsWe used data from 157 subjects randomized to the control diet of the Dietary Approaches to Stop Hypertension (DASH)-Sodium trial who were assigned to 30 days of low (1,500 mg/d), medium (2,400 mg/d), and high salt (3,300 mg/d) diets in random order. Blood pressure was measured prerandomization and then weekly during each feeding period. We evaluated the association of prerandomization urine uromodulin with change in SBP between diets, as measured at the end of each feeding period, using multivariable linear regression.ResultsBaseline urine uromodulin stratified by tertiles was ≤17.64, 17.65-31.97, and ≥31.98 µg/ml. Across the tertiles, there were no significant differences in SBP at baseline, nor was there a differential effect of sodium diet on SBP across tertiles (low to high, P = 0.81). After adjusting for age, sex, body mass index, and race, uromodulin levels were not significantly associated with SBP change from low to high sodium diet (P = 0.42).ConclusionsIn a randomized trial of different levels of salt intake, higher urine uromodulin levels were not associated with a greater increase in blood pressure in response to high salt intake.

Chronic kidney disease (CKD) and acute kidney injury (AKI) are common, heterogeneous, and morbid diseases. Mechanistic characterization of CKD and AKI in patients may facilitate a precision-medicine approach to prevention, diagnosis, and treatment. The Kidney Precision Medicine Project aims to ethically and safely obtain kidney biopsies from participants with CKD or AKI, create a reference kidney atlas, and characterize disease subgroups to stratify patients based on molecular features of disease, clinical characteristics, and associated outcomes. An additional aim is to identify critical cells, pathways, and targets for novel therapies and preventive strategies. This project is a multicenter prospective cohort study of adults with CKD or AKI who undergo a protocol kidney biopsy for research purposes. This investigation focuses on kidney diseases that are most prevalent and therefore substantially burden the public health, including CKD attributed to diabetes or hypertension and AKI attributed to ischemic and toxic injuries. Reference kidney tissues (for example, living-donor kidney biopsies) will also be evaluated. Traditional and digital pathology will be combined with transcriptomic, proteomic, and metabolomic analysis of the kidney tissue as well as deep clinical phenotyping for supervised and unsupervised subgroup analysis and systems biology analysis. Participants will be followed prospectively for 10 years to ascertain clinical outcomes. Cell types, locations, and functions will be characterized in health and disease in an open, searchable, online kidney tissue atlas. All data from the Kidney Precision Medicine Project will be made readily available for broad use by scientists, clinicians, and patients.

Rationale & objectiveUnderlying kidney disease is an emerging risk factor for more severe coronavirus disease 2019 (COVID-19) illness. We examined the clinical courses of critically ill COVID-19 patients with and without pre-existing chronic kidney disease (CKD) and investigated the association between the degree of underlying kidney disease and in-hospital outcomes.Study designRetrospective cohort study.Settings & participants4,264 critically ill patients with COVID-19 (143 patients with pre-existing kidney failure receiving maintenance dialysis; 521 patients with pre-existing non-dialysis-dependent CKD; and 3,600 patients without pre-existing CKD) admitted to intensive care units (ICUs) at 68 hospitals across the United States.Predictor(s)Presence (vs absence) of pre-existing kidney disease.Outcome(s)In-hospital mortality (primary); respiratory failure, shock, ventricular arrhythmia/cardiac arrest, thromboembolic events, major bleeds, and acute liver injury (secondary).Analytical approachWe used standardized differences to compare patient characteristics (values>0.10 indicate a meaningful difference between groups) and multivariable-adjusted Fine and Gray survival models to examine outcome associations.ResultsDialysis patients had a shorter time from symptom onset to ICU admission compared to other groups (median of 4 [IQR, 2-9] days for maintenance dialysis patients; 7 [IQR, 3-10] days for non-dialysis-dependent CKD patients; and 7 [IQR, 4-10] days for patients without pre-existing CKD). More dialysis patients (25%) reported altered mental status than those with non-dialysis-dependent CKD (20%; standardized difference=0.12) and those without pre-existing CKD (12%; standardized difference=0.36). Half of dialysis and non-dialysis-dependent CKD patients died within 28 days of ICU admission versus 35% of patients without pre-existing CKD. Compared to patients without pre-existing CKD, dialysis patients had higher risk for 28-day in-hospital death (adjusted HR, 1.41 [95% CI, 1.09-1.81]), while patients with non-dialysis-dependent CKD had an intermediate risk (adjusted HR, 1.25 [95% CI, 1.08-1.44]).LimitationsPotential residual confounding.ConclusionsFindings highlight the high mortality of individuals with underlying kidney disease and severe COVID-19, underscoring the importance of identifying safe and effective COVID-19 therapies in this vulnerable population.

INTRODUCTIONAcute kidney injury and chronic kidney disease (CKD) are common in hospitalized patients. To inform clinical decision making, more accurate information regarding risk of long-term progression to kidney failure is required.METHODSWe enrolled 1538 hospitalized patients in a multicenter, prospective cohort study. Monocyte chemoattractant protein 1 (MCP-1/CCL2), uromodulin (UMOD), and YKL-40 (CHI3L1) were measured in urine samples collected during outpatient follow-up at 3 months. We followed patients for a median of 4.3 years and assessed the relationship between biomarker levels and changes in estimated glomerular filtration rate (eGFR) over time and the development of a composite kidney outcome (CKD incidence, CKD progression, or end-stage renal disease). We paired these clinical studies with investigations in mouse models of renal atrophy and renal repair to further understand the molecular basis of these markers in kidney disease progression.RESULTSHigher MCP-1 and YKL-40 levels were associated with greater eGFR decline and increased incidence of the composite renal outcome, whereas higher UMOD levels were associated with smaller eGFR declines and decreased incidence of the composite kidney outcome. A multimarker score increased prognostic accuracy and reclassification compared with traditional clinical variables alone. The mouse model of renal atrophy showed greater Ccl2 and Chi3l1 mRNA expression in infiltrating macrophages and neutrophils, respectively, and evidence of progressive renal fibrosis compared with the repair model. The repair model showed greater Umod expression in the loop of Henle and correspondingly less fibrosis.CONCLUSIONSBiomarker levels at 3 months after hospitalization identify patients at risk for kidney disease progression.FUNDINGNIH.

Acute kidney injury (AKI) has been reported to be associated with excess risks of death, kidney disease progression and cardiovascular events although previous studies have important limitations. To further examine this, we prospectively studied adults from four clinical centers surviving three months and more after hospitalization with or without AKI who were matched on center, pre-admission CKD status, and an integrated priority score based on age, prior cardiovascular disease or diabetes mellitus, preadmission estimated glomerular filtration rate (eGFR) and treatment in the intensive care unit during the index hospitalization between December 2009-February 2015, with follow-up through November 2018. All participants had assessments of kidney function before (eGFR) and at three months and annually (eGFR and proteinuria) after the index hospitalization. Associations of AKI with outcomes were examined after accounting for pre-admission and three-month post-discharge factors. Among 769 AKI (73% Stage 1, 14% Stage 2, 13% Stage 3) and 769 matched non-AKI adults, AKI was associated with higher adjusted rates of incident CKD (adjusted hazard ratio 3.98, 95% confidence interval 2.51-6.31), CKD progression (2.37,1.28-4.39), heart failure events (1.68, 1.22-2.31) and all-cause death (1.78, 1.24-2.56). AKI was not associated with major atherosclerotic cardiovascular events in multivariable analysis (0.95, 0.70-1.28). After accounting for degree of kidney function recovery and proteinuria at three months after discharge, the associations of AKI with heart failure (1.13, 0.80-1.61) and death (1.29, 0.84-1.98) were attenuated and no longer significant. Thus, assessing kidney function recovery and proteinuria status three months after AKI provides important prognostic information for long-term clinical outcomes.

Acute kidney injury (AKI) has been reported to be associated with excess risks of death, kidney disease progression and cardiovascular events although previous studies have important limitations. To further examine this, we prospectively studied adults from four clinical centers surviving three months and more after hospitalization with or without AKI who were matched on center, pre-admission CKD status, and an integrated priority score based on age, prior cardiovascular disease or diabetes mellitus, preadmission estimated glomerular filtration rate (eGFR) and treatment in the intensive care unit during the index hospitalization between December 2009-February 2015, with follow-up through November 2018. All participants had assessments of kidney function before (eGFR) and at three months and annually (eGFR and proteinuria) after the index hospitalization. Associations of AKI with outcomes were examined after accounting for pre-admission and three-month post-discharge factors. Among 769 AKI (73% Stage 1, 14% Stage 2, 13% Stage 3) and 769 matched non-AKI adults, AKI was associated with higher adjusted rates of incident CKD (adjusted hazard ratio 3.98, 95% confidence interval 2.51-6.31), CKD progression (2.37,1.28-4.39), heart failure events (1.68, 1.22-2.31) and all-cause death (1.78, 1.24-2.56). AKI was not associated with major atherosclerotic cardiovascular events in multivariable analysis (0.95, 0.70-1.28). After accounting for degree of kidney function recovery and proteinuria at three months after discharge, the associations of AKI with heart failure (1.13, 0.80-1.61) and death (1.29, 0.84-1.98) were attenuated and no longer significant. Thus, assessing kidney function recovery and proteinuria status three months after AKI provides important prognostic information for long-term clinical outcomes.

BackgroundHIV-positive persons bear an excess burden of chronic kidney disease (CKD); however, conventional methods to assess kidney health are insensitive and non-specific for detecting early kidney injury. Urinary biomarkers can detect early kidney injury, and may help mitigate the risk of overt CKD.MethodsCross-sectional study of HIV-positive persons in the Multicenter AIDS Cohort Study and the Women's Interagency HIV Study. We measured levels of 14 biomarkers, capturing multiple dimensions of kidney injury. We then evaluated associations of known CKD risk factors with urine biomarkers using separate multivariable adjusted models for each biomarker.ResultsOf the 198 participants, one third were on HAART and virally suppressed. The vast majority (95%) had preserved kidney function as assessed by serum creatinine, with a median eGFR of 103 ml/min/1.73 m2 (interquartile range (IQR): 88, 116). In our multivariable analyses, the associations of each CKD risk factor with urinary biomarker levels varied in magnitude. For example, HIV viral load was predominantly associated with elevations in interleukin(IL)-18, and albuminuria, while higher CD4 levels were associated with lower monocyte chemoattractant protein-1 (MCP-1) and β2-microglobulin. In contrast, older age was significantly associated with elevations in α1-microglobulin, kidney injury marker-1, clusterin, MCP-1, and chitinase-3-like protein-1 levels, as well as lower epidermal growth factor, and uromodulin levels.ConclusionsAmong HIV-positive persons, CKD risk factors are associated with unique and heterogeneous patterns of changes in urine biomarkers levels. Additional work is needed to develop parsimonious algorithms that integrate multiple biomarkers and clinical data to discern the risk of overt CKD and its progression.

BackgroundChronic kidney disease (CKD) occurs commonly among HIV-infected persons. Statins may delay CKD onset and progression through their cholesterol-lowering and pleiotropic effects.MethodsAmong 850 HIV-infected men from the Multicenter AIDS Cohort Study with stored urine samples (2009-2011), we evaluated cross-sectional associations of statin use with urine biomarkers of kidney damage [albumin-to-creatinine ratio (ACR), alpha-1-microglobulin, interleukin-18, kidney injury molecule-1, and procollagen type III N-terminal propeptide] using multivariable linear regression. We evaluated the longitudinal associations of statin use with annual change in estimated glomerular filtration rate by creatinine (eGFR) using linear mixed models, and with incident proteinuria and incident CKD (eGFR

Urine markers can quantify tubular function including reabsorption (α-1 microglobulin [α1m]) and β-2-microglobulin [β2m]) and protein synthesis (uromodulin). Individuals with tubular dysfunction may be less able to compensate to insults than those without, despite similar estimated glomerular filtration rate (eGFR) and albuminuria. Among Systolic Blood Pressure Intervention Trial (SPRINT) participants with an eGFR under 60 ml/min/1.73m2, we measured urine markers of tubular function and injury (neutrophil gelatinase-associated lipocalin [NGAL], kidney injury molecule-1 [KIM-1], interleukin-18 [IL-18], monocyte chemoattractant protein-1, and chitinase-3-like protein [YKL-40]) at baseline. Cox models evaluated associations with subsequent acute kidney injury (AKI) risk, adjusting for clinical risk factors, baseline eGFR and albuminuria, and the tubular function and injury markers. In a random subset, we remeasured biomarkers after four years, and compared changes in biomarkers in those with and without intervening AKI. Among 2351 participants, 184 experienced AKI during 3.8 years mean follow-up. Lower uromodulin (hazard ratio per two-fold higher (0.68, 95% confidence interval [0.56, 0.83]) and higher α1m (1.20; [1.01, 1.44]) were associated with subsequent AKI, independent of eGFR and albuminuria. None of the five injury markers were associated with eventual AKI. In the random subset of 947 patients with repeated measurements, the 59 patients with intervening AKI versus without had longitudinal increases in urine NGAL, IL-19, and YKL-40 and only 1 marker of tubule function (α1m). Thus, joint evaluation of tubule function and injury provided novel insights to factors predisposing to AKI, and responses to kidney injury.

Rationale & objectiveThe process of angiogenesis after kidney injury may determine recovery and long-term outcomes. We evaluated the association of angiogenesis markers with acute kidney injury (AKI) and mortality after cardiac surgery.Study designProspective cohort.Setting & participants1,444 adults undergoing cardiac surgery in the TRIBE-AKI (Translational Research Investigating Biomarker Endpoints for Acute Kidney Injury) cohort.ExposuresPlasma concentrations of 2 proangiogenic markers (vascular endothelial growth factor A [VEGF] and placental growth factor [PGF]) and 1 antiangiogenic marker (soluble VEGF receptor 1 [VEGFR1]), measured pre- and postoperatively within 6 hours after surgery.OutcomesAKI, long AKI duration (≥7 days), and 1-year all-cause mortality.Analytical approachMultivariable logistic regression.ResultsFollowing cardiac surgery, plasma VEGF concentrations decreased 2-fold, and PGF and VEGFR1 concentrations increased 1.5- and 8-fold, respectively. There were no meaningful associations of preoperative concentrations of angiogenic markers with outcomes of AKI and mortality. Higher postoperative VEGF and PGF concentrations were independently associated with lower odds of AKI (adjusted ORs of 0.89 [95% CI, 0.82-0.98] and 0.69 [95% CI, 0.55-0.87], respectively), long AKI duration (0.65 [95% CI, 0.49-0.87] and 0.48 [95% CI, 0.28-0.82], respectively), and mortality (0.74 [95% CI, 0.62-0.89] and 0.46 [95% CI, 0.31-0.68], respectively). In contrast, higher postoperative VEGFR1 concentrations were independently associated with higher odds of AKI (1.56; 95% CI, 1.31-1.87), long AKI duration (1.75; 95% CI, 1.09-2.82), and mortality (2.28; 95% CI, 1.61-3.22).LimitationsAngiogenesis markers were not measured after hospital discharge, so we were unable to determine long-term trajectories of angiogenesis marker levels during recovery and follow-up.ConclusionsHigher levels of postoperative proangiogenic markers, VEGF and PGF, were associated with lower AKI and mortality risk, whereas higher postoperative antiangiogenic VEGFR1 levels were associated with higher risk for AKI and mortality.

ObjectivesUrinary biomarkers of kidney injury may have potential to identify subclinical injury attributable to tenofovir disoproxil fumarate (TDF) toxicity.DesignThis observational study included 198 HIV-infected participants from the Multicenter AIDS Cohort Study and the Women's Interagency HIV Study, who initiated TDF between 2009 and 2015 and had urine samples collected at baseline before and after TDF initiation.MethodsWe used linear mixed-effects models controlling for urine creatinine and time on TDF to evaluate the effects of TDF initiation on changes in 14 urinary biomarkers.ResultsWithin 1 year after TDF initiation, concentrations of trefoil factor 3 [+78%; 95% confidence interval (CI) +38%, +129%), alpha-1 microglobulin (α1m) (+32%; 95% CI +13%, +55%), clusterin (+21%; 95% CI +6%, +38%), uromodulin (+19%; 95% CI +4%, +36%), and kidney injury molecule-1 (KIM-1) (+13%; 95% CI +1%, +26%) significantly increased, whereas interleukin-18 (IL-18) significantly decreased (-13%, 95% CI -7%, -25%). Subsequent to the first year of TDF use, biomarker concentrations stabilized, and these changes were not statistically significant. When stratifying by baseline viremia (HIV-1 RNA < vs. ≥80 copies/ml), concentration changes for most biomarkers during the first year of TDF use were greater among aviremic vs. viremic participants, with significant differences in α1m (+80 vs. +22%), KIM-1 (+43 vs. +10%), beta-2 microglobulin (+83 vs. -10%), YKL-40 (+33 vs. -5%), and IL-18 (+20 vs. -27%).ConclusionsTDF initiation was associated with substantial changes in urinary biomarkers of kidney injury within the first year of use, particularly among aviremic participants. A urinary biomarker panel may be a clinically useful tool to detect and monitor the heterogeneous effects of TDF on the kidney.

BackgroundHIV-positive persons bear an excess burden of chronic kidney disease (CKD); however, conventional methods to assess kidney health are insensitive and non-specific for detecting early kidney injury. Urinary biomarkers can detect early kidney injury, and may help mitigate the risk of overt CKD.MethodsCross-sectional study of HIV-positive persons in the Multicenter AIDS Cohort Study and the Women's Interagency HIV Study. We measured levels of 14 biomarkers, capturing multiple dimensions of kidney injury. We then evaluated associations of known CKD risk factors with urine biomarkers using separate multivariable adjusted models for each biomarker.ResultsOf the 198 participants, one third were on HAART and virally suppressed. The vast majority (95%) had preserved kidney function as assessed by serum creatinine, with a median eGFR of 103 ml/min/1.73 m2 (interquartile range (IQR): 88, 116). In our multivariable analyses, the associations of each CKD risk factor with urinary biomarker levels varied in magnitude. For example, HIV viral load was predominantly associated with elevations in interleukin(IL)-18, and albuminuria, while higher CD4 levels were associated with lower monocyte chemoattractant protein-1 (MCP-1) and β2-microglobulin. In contrast, older age was significantly associated with elevations in α1-microglobulin, kidney injury marker-1, clusterin, MCP-1, and chitinase-3-like protein-1 levels, as well as lower epidermal growth factor, and uromodulin levels.ConclusionsAmong HIV-positive persons, CKD risk factors are associated with unique and heterogeneous patterns of changes in urine biomarkers levels. Additional work is needed to develop parsimonious algorithms that integrate multiple biomarkers and clinical data to discern the risk of overt CKD and its progression.

BACKGROUND:HIV-infected (HIV+) persons are at increased risk of chronic kidney disease, but serum creatinine does not detect early losses in kidney function. We hypothesized that urine biomarkers of kidney damage would be associated with subsequent changes in kidney function in a contemporary cohort of HIV+ and HIV-uninfected (HIV-) men. METHODS:In the Multicenter AIDS Cohort Study, we measured baseline urine concentrations of 5 biomarkers from 2009 to 2011 in 860 HIV+ and 337 HIV- men: albumin, alpha-1-microglobulin (α1m), interleukin-18 (IL-18), kidney injury molecule-1 (KIM-1), and procollagen type III N-terminal propeptide (PIIINP). We evaluated associations of urine biomarker concentrations with annual changes in estimated glomerular filtration rate (eGFR) using multivariable linear mixed models adjusted for demographics, traditional kidney disease risk factors, HIV-related risk factors, and baseline eGFR. RESULTS:Over a median follow-up of 4.8 years, the average annual eGFR decline was 1.42 mL/min/1.73 m2/year in HIV+ men and 1.22 mL/min/1.73 m2/year in HIV- men. Among HIV+ men, the highest vs. lowest tertiles of albumin (-1.78 mL/min/1.73 m2/year, 95% CI -3.47 to -0.09) and α1m (-2.43 mL/min/1.73 m2/year, 95% CI -4.14 to -0.73) were each associated with faster annual eGFR declines after multivariable adjustment. Among HIV- men, the highest vs. lowest tertile of α1m (-2.49 mL/min/1.73 m2/year, 95% CI -4.48 to -0.50) was independently associated with faster annual eGFR decline. Urine IL-18, KIM-1, and PIIINP showed no independent associations with eGFR decline, regardless of HIV serostatus. CONCLUSIONS:Among HIV+ men, higher urine albumin and α1m are associated with subsequent declines in kidney function, independent of eGFR.

Rationale & objectiveRandom assignment to intensive blood pressure (BP) lowering (systolic BP

BackgroundRandom assignment to the intensive systolic blood pressure (SBP) arm (

BackgroundWhether the increased incidence of chronic kidney disease (CKD) during intensive systolic blood pressure (SBP) lowering is accompanied by intrinsic kidney injury is unknown.ObjectiveTo compare changes in kidney damage biomarkers between incident CKD case participants and matched control participants as well as between case participants in the intensive (

Rationale & objectiveNovel urinary biomarkers have enabled earlier detection of kidney tubular damage, but their prognostic value for adverse cardiovascular outcomes is uncertain. We hypothesized that tubular damage, measured by urine α1-microglobulin (A1M), amino-terminal propeptide of type III procollagen (PIIINP), and neutrophil gelatinase-associated lipocalin (NGAL), would be associated with higher risks for cardiovascular events and mortality among elders.Study designCase-cohort study.Setting & participantsThis study included a randomly selected subcohort (n=502), cardiovascular disease (CVD) cases (n=245), and heart failure cases (n=220) from the Health, Aging, and Body Composition (Health ABC) Study.PredictorsBaseline urine A1M, PIIINP, and NGAL concentrations.OutcomesIncident CVD, heart failure, and all-cause mortality.Analytical approachCox proportional hazards models were used to evaluate biomarker associations with each outcome.ResultsAt baseline, mean age was 74 years and estimated glomerular filtration rate was 73mL/min/1.73m2. After adjustment for demographics, estimated glomerular filtration rate, albumin-creatinine ratio, and other cardiovascular risk factors, each doubling in biomarker concentration was associated with the following adjusted HRs for CVD: A1M, 1.51 (95% CI, 1.16-1.96); PIIINP, 1.21 (95% CI, 1.00-1.46); and NGAL, 1.12 (95% CI, 1.05-1.20). There were 248 deaths in the subcohort during a median follow-up of 12.4 years. Adjusted associations of each biomarker (HR per doubling) with all-cause mortality were: A1M, 1.29 (95% CI, 1.10-1.51); PIIINP, 1.05 (95%, 0.94-1.18); and NGAL, 1.07 (95% CI, 1.02-1.12). Biomarker concentrations did not have statistically significant associations with heart failure after multivariable adjustment.LimitationsUrine biomarkers were measured at a single time point; no validation cohort available.ConclusionsKidney tubular damage is an independent risk factor for CVD and death among elders. Future studies should investigate mechanisms by which kidney tubular damage may adversely affect cardiovascular risk.

BackgroundPrevious studies in HIV-infected individuals have demonstrated serum albumin to be strongly associated with kidney function decline, independent of urine albumin and inflammatory markers. Lower serum albumin concentrations may be an under-appreciated risk factor for kidney function decline in elders.MethodsWe performed a cohort analysis in the Health Aging and Body Composition Study, a cohort of well-functioning, bi-racial, community-dwelling elders between the age of 70 and 79 years. We examined the associations of serum albumin concentration with longitudinal kidney function decline by estimated glomerular filtration rate (eGFR). Outcomes included linear eGFR decline, rapid kidney function decline defined as >30% decrease in eGFR, defined as a final eGFR 60 mL/min/1.73 m2 at baseline. Cystatin C-based eGFR was calculated at baseline, Year 3 and Year 10.ResultsMean age was 74 years, and mean eGFR was 73 mL/min/1.73 m2 at baseline. The mean rate of eGFR change was 1.81 mL/min/1.73 m2 per year. After multivariate adjustment, lower serum albumin concentrations were strongly and independently associated with kidney function decline (-0.11 mL/min/1.73 m2 per year for each standard deviation decrease serum albumin; -0.01 to - 0.20) with no attenuation after adjustment for urine albumin and inflammatory markers (-0.12, -0.03 to - 0.22). When divided into quartiles, serum albumin levels ≤3.80 g/dL were associated with increased odds of rapid kidney function decline (odds ratio 1.59; 1.12-2.26) and increased risk of incident chronic kidney disease (incident rate ratio 1.29; 1.03-1.62) relative to levels >4.21g/dL. Urine albumin to creatinine ratio (ACR) was also significantly and independently associated with kidney function decline (-0.08 mL/min/1.73 m2 per year for urine ACR >30 mg/g; -0.82 to - 0.13).ConclusionsLower serum albumin levels are strongly and independently associated with kidney function decline in elders, independent of clinical risk factors, urine albumin and measured inflammatory markers.

BackgroundPre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) is becoming increasingly adopted for HIV prevention. Tenofovir can cause proximal tubular damage and chronic kidney disease in HIV-infected persons, but little is known regarding its nephrotoxic potential among HIV-uninfected persons. In this study, we evaluated the effects of PrEP on urine levels of the following: α1-microglobulin (α1m), a marker of impaired tubular reabsorption; albuminuria, a measure of glomerular injury; and total proteinuria.SettingThe Iniciativa Profilaxis Pre-Exposicion (iPrEx) study randomized HIV-seronegative men and transgender women who have sex with men to oral TDF/FTC or placebo. The iPrEx open-label extension (iPrEx-OLE) study enrolled former PrEP trial participants to receive open-label TDF/FTC.MethodsA cross-sectional analysis compared urine biomarker levels by study arm in iPrEx (N = 100 treatment arm, N = 100 placebo arm). Then, urine biomarker levels were compared before and after PrEP initiation in 109 participants of iPrEx-OLE.ResultsIn iPrEx, there were no significant differences in urine α1m, albuminuria, or proteinuria by treatment arm. In iPrEx-OLE, after 24 weeks on PrEP, urine α1m and proteinuria increased by 21% [95% confidence interval (CI): 10 to 33] and 18% (95% CI: 8 to 28), respectively. The prevalence of detectable α1m increased from 44% to 65% (P < 0.001) and estimated glomerular filtration rate declined by 4 mL/min/1.73 m (P < 0.001). There was no significant change in albuminuria (6%; 95% CI: -7% to 20%).ConclusionPrEP with TDF/FTC was associated with a statistically significant rise in urine α1m and proteinuria after 6 months, suggesting that PrEP may result in subclinical tubule dysfunction.

AIM:To investigate early postoperative biomarkers for risk discrimination of advanced acute kidney injury (AKI). MATERIALS & METHODS:Postoperative plasma biomarkers including NGAL, h-FABP, CK-MB, hsTNT, NT-proBNP, IL-6, IL-10 and VEGF were analyzed using group-based method among 426 patients with AKI after cardiac surgery. RESULTS:Six patient groups with distinct biomarker patterns were identified. Individual biomarker displayed significant difference across the groups. The groups showed better discrimination for advanced AKI than any single biomarker either with or without adjusting for clinical variables. Average concentration of a single biomarker within each group, mortality and risk of a secondary outcome all demonstrated an approximately U-shaped relationship with proportion of advanced AKI within each group. CONCLUSION:The group-based analysis revealed that the order of the patient groups with an increasing likelihood of advanced AKI had a nonlinear relationship with average concentration of an individual biomarker, mortality and risk of other outcomes.

BackgroundChronic kidney disease (CKD) is common among HIV-infected individuals but serum creatinine is insensitive for detecting kidney damage at early stages. We hypothesized that HIV infection would be associated with elevations in subclinical markers of kidney injury and fibrosis in a contemporary cohort of men.MethodsIn this cross-sectional study, we measured urine levels of interleukin-18 (IL-18), kidney injury molecule-1 (KIM-1), pro-collagen type III N-terminal pro-peptide (PIIINP) and albumin-creatinine ratio (ACR) in 813 HIV-infected and 331 uninfected men enrolled in the Multicenter AIDS Cohort Study.ResultsMedian eGFR was 95 ml/min/1.73 m2 among African-Americans (n=376) and 87 ml/min/1.73 m2 among Caucasians (n=768). Among HIV-infected men, the median CD4 lymphocyte count was 572 cells/mm3 and 76% of men had undetectable HIV RNA levels. After multivariable adjustment for traditional CKD risk factors including eGFR, HIV infection was associated with 52% higher urine IL-18 (95% CI, 33%, 73%), 44% higher KIM-1 (27%, 64%), 30% higher PIIINP (15%, 47%) and 84% higher ACR (54%, 120%), with similar effect sizes among African-Americans and Caucasians (P>0.2 for tests of interaction by race). These associations remained statistically significant in analyses that excluded persons with detectable HIV RNA levels and in models that adjusted for cumulative exposure to tenofovir disoproxil fumarate.ConclusionsCompared with uninfected men, HIV-infected men had more extensive glomerular and tubulointerstitial damage, as assessed by urine biomarkers. Future studies should evaluate whether combinations of biomarkers can be used to monitor stages of kidney injury and to predict CKD risk in HIV-infected individuals.

BackgroundUrine uromodulin (uUMOD) is a protein secreted by the kidney tubule. Recent studies have suggested that higher uUMOD may be associated with improved kidney and mortality outcomes.MethodsUsing a case-cohort design, we evaluated the association between baseline uUMOD levels and ≥ 30% estimated glomerular filtration rate (eGFR) decline, incident chronic kidney disease (CKD), rapid kidney function decline, and mortality using standard and modified Cox proportional hazards regression.ResultsThe median value of uUMOD was 25.8 µg/mL, mean age of participants was 74 years, 48% were women, and 39% were black. Persons with higher uUMOD had lower prevalence of diabetes and coronary artery disease (CAD), and had lower systolic blood pressure. Persons with higher uUMOD also had higher eGFR, lower urinary albumin to creatinine ratio (ACR), and lower C-reactive protein (CRP). There was no association of uUMOD with > 30% eGFR decline. In comparison to those in the lowest quartile of uUMOD, those in the highest quartile had a significantly (53%) lower risk of incident CKD (CI 73%, 18%) and a 51% lower risk of rapid kidney function decline (CI 76%, 1%) after multivariable adjustment. Higher uUMOD was associated with lower risk of mortality in demographic adjusted models, but not after multivariable adjustment.ConclusionHigher levels of uUMOD are associated with lower risk of incident CKD and rapid kidney function decline. Additional studies are needed in the general population and in persons with advanced CKD to confirm these findings.
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BackgroundUrine uromodulin (uUMOD) is a protein secreted by the kidney tubule. Recent studies have suggested that higher uUMOD may be associated with improved kidney and mortality outcomes.MethodsUsing a case-cohort design, we evaluated the association between baseline uUMOD levels and ≥ 30% estimated glomerular filtration rate (eGFR) decline, incident chronic kidney disease (CKD), rapid kidney function decline, and mortality using standard and modified Cox proportional hazards regression.ResultsThe median value of uUMOD was 25.8 µg/mL, mean age of participants was 74 years, 48% were women, and 39% were black. Persons with higher uUMOD had lower prevalence of diabetes and coronary artery disease (CAD), and had lower systolic blood pressure. Persons with higher uUMOD also had higher eGFR, lower urinary albumin to creatinine ratio (ACR), and lower C-reactive protein (CRP). There was no association of uUMOD with > 30% eGFR decline. In comparison to those in the lowest quartile of uUMOD, those in the highest quartile had a significantly (53%) lower risk of incident CKD (CI 73%, 18%) and a 51% lower risk of rapid kidney function decline (CI 76%, 1%) after multivariable adjustment. Higher uUMOD was associated with lower risk of mortality in demographic adjusted models, but not after multivariable adjustment.ConclusionHigher levels of uUMOD are associated with lower risk of incident CKD and rapid kidney function decline. Additional studies are needed in the general population and in persons with advanced CKD to confirm these findings.
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BackgroundUrine biomarkers have helped identify persons at risk for progressing to kidney disease in the setting of HIV infection. We explored factors associated with changes in 3 urine biomarkers over 10 years among women living with HIV.MethodsProspective cohort of 294 HIV-infected women from the multicenter Women's Interagency HIV Study. Predictors included HIV viral and immunological parameters, comorbid conditions, and health-related behaviors. Outcomes were patterns of changes of urine interleukin-18 (IL-18), albumin-to-creatinine ratio (ACR), and alpha-1-microglobulin (α1m) over 10 years. We used quantile regression to examine patterns of change in each urine biomarker during follow-up and multivariable analysis of variance regression to identify predictors of biomarker changes.ResultsOver 10 years, the median concentrations of IL-18 declined from 120 to 64 pg/mL, α1m rose from 0.7 to 1.5 ng/mL, and ACR remained stable (9-8 mg/g). In multivariate analyses, the strongest predictors of increases in IL-18 were higher baseline body mass index, increase in waist circumference, higher follow-up HIV viral load, lower follow-up CD4 cell count, hepatitis C virus (HCV) coinfection, and higher follow-up high density lipoprotein cholesterol. Predictors of increasing concentration of α1m were lower CD4 cell counts, higher diastolic blood pressure, HCV coinfection, and smoking. Finally, determinants of ACR increases during follow-up were higher follow-up diastolic blood pressure, HCV coinfection, higher follow-up HIV viral load, and triglyceride concentration.ConclusionsOver 10 years, HIV disease status had different associations with each urine biomarker under study. Overall, the associations with changes in each biomarker support research into their use for longitudinal monitoring of kidney health.

Tenofovir disoproxil fumarate (TDF) can cause kidney damage, but current clinical tests are insensitive for detecting toxicity. Among 884 HIV-infected men enrolled in the Multicenter AIDS Cohort Study, we measured urine biomarkers specific for tubular damage (interleukin-18, kidney injury molecule-1, procollagen type III N-terminal propeptide) and albuminuria. In adjusted analyses, each year of TDF exposure was independently associated with 3.3% higher interleukin-18 (95% CI: 0.8% to 5.8%), 3.4% higher kidney injury molecule-1 (1.1% to 5.7%), and 3.1% higher procollagen type III N-terminal propeptide (0.8% to 5.5%), but not with albuminuria (2.8%; -0.6% to 6.2%). Biomarkers of tubular damage may be more sensitive than albuminuria for detecting toxicity from TDF and other medications.

BackgroundTenofovir disoproxil fumarate (TDF) can cause proximal tubular damage and chronic kidney disease in human immunodeficiency virus (HIV)-infected individuals. Urine α1-microglobulin (A1M), a low-molecular-weight protein indicative of proximal tubular dysfunction, may enable earlier detection of TDF-associated tubular toxicity.Study designCross-sectional.Setting & participants883 HIV-infected and 350 -uninfected men enrolled in the Multicenter AIDS Cohort Study.PredictorsHIV infection and TDF exposure.OutcomeUrine A1M level.ResultsUrine A1M was detectable in 737 (83%) HIV-infected and 202 (58%) -uninfected men (P

BackgroundAlthough individual urine biomarkers are associated with chronic kidney disease (CKD) incidence and all-cause mortality in the setting of HIV infection, their combined utility for prediction remains unknown.MethodsWe measured eight urine biomarkers shown previously to be associated with incident CKD and mortality risk among 902 HIV-infected women in the Women's Interagency HIV Study: N-acetyl-β-d-glucosaminidase (NAG), kidney injury molecule-1 (KIM-1), alpha-1 microglobulin (α1m), interleukin 18, neutrophil gelatinase-associated lipocalin, albumin-to-creatinine ratio, liver fatty acid-binding protein and α-1-acid-glycoprotein. A group-based cluster method classified participants into three distinct clusters using the three most distinguishing biomarkers (NAG, KIM-1 and α1m), independent of the study outcomes. We then evaluated associations of each cluster with incident CKD (estimated glomerular filtration rate

BackgroundAcute kidney injury is a risk factor for death in cardiac surgical patients. Plasma cystatin C and creatinine have different temporal profiles in the postoperative setting, but the associations of simultaneous changes in both filtration markers compared with change in only one marker with prognosis after hospital discharge are not well described.MethodsThis is a longitudinal study of 1,199 high-risk adult cardiac surgical patients in the TRIBE-AKI (Translational Research Investigating Biomarker Endpoints for Acute Kidney Injury) Consortium who survived hospitalization. We examined in-hospital peak changes of cystatin C and creatinine in the 3 days after cardiac operations. We evaluated associations of these filtration markers with death, adjusting for demographics, operative characteristics, medical comorbidities, preoperative estimated glomerular filtration rate, preoperative urinary albumin-to-creatinine ratio, and site.ResultsDuring the first 3 days of hospitalization, nearly twice as many patients had a 25% or higher rise in creatinine (30%) compared with a 25% or higher peak rise in cystatin C (15%). The risk of death was higher in those with elevations in cystatin C (adjusted hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.4 to 2.37) or creatinine (adjusted HR, 1.90; 95% CI, 1.32 to 2.72) compared with patients who experienced a postoperative decrease in either filtration marker. Patients who had simultaneous elevations of 25% or higher in cystatin C and creatinine were at similar adjusted risk for 3-year mortality (HR, 1.79; 95% CI, 1.03 to 3.1) as those with a 25% or higher increase in cystatin C alone (HR, 2.2; 95% CI, 1.09 to 4.47).ConclusionsElevations in creatinine postoperatively are more common than elevations in cystatin C. However, elevations in cystatin C appeared to be associated with a higher risk of death after hospital discharge.

BackgroundStudies suggest that in patients with heart failure (HF), high serum erythropoietin is associated with risk of recurrent HF and mortality. Trials of erythropoietin-stimulating agents in persons with kidney disease have also suggested an increased incidence of adverse clinical events. No large studies of which we are aware have evaluated the association of endogenous erythropoietin levels with clinical outcomes in the community-living older adults.Methods and resultsErythropoietin concentration was measured in 2488 participants aged 70-79 years in the Health, Aging and Body Composition Study. Associations of erythropoietin with incident HF, coronary heart disease, stroke, mortality, and ≥ 30% decline in estimated glomerular filtration rate were examined using Cox proportional hazards and logistic regression over 10.7 years of follow-up. Mean (SD) age was 75 (3) years and median (quartile 1, quartile 3) erythropoietin was 12.3 (9.0, 17.2) mIU/mL. There were 503 incident HF events, and each doubling of serum erythropoietin was associated with a 25% increased risk of incident HF 1.25 (95% confidence interval 1.13, 1.48) after adjusting for demographics, prevalent cardiovascular disease, cardiovascular disease risk factors, kidney function, and serum hemoglobin. There was no interaction of serum erythropoietin with chronic kidney disease or anemia (P > 0.50). There were 330 incident coronary heart disease events, 161 strokes, 1112 deaths, and 698 outcomes of ≥ 30% decline in estimated glomerular filtration rate. Serum erythropoietin was not significantly associated with these outcomes.ConclusionsHigher levels of endogenous erythropoietin are associated with incident HF in older adults. Studies need to elucidate the mechanisms through which endogenous erythropoietin levels associate with specific outcomes.

BackgroundThe interaction between baseline kidney function and the performance of biomarkers of acute kidney injury (AKI) on the development of AKI is unclear.Study designPost hoc analysis of prospective cohort study.Setting & participantsThe 1,219 TRIBE-AKI Consortium adult cardiac surgery cohort participants.PredictorUnadjusted postoperative urinary biomarkers of AKI measured within 6 hours of surgery.OutcomeAKI was defined as AKI Network stage 1 (any AKI) or higher, as well as a doubling of serum creatinine level from the preoperative value or the need for post-operative dialysis (severe AKI).MeasurementsStratified analyses by preoperative estimated glomerular filtration rate (eGFR) ≤ 60 versus > 60mL/min/1.73m(2).Results180 (42%) patients with preoperative eGFRs≤60mL/min/1.73m(2) developed clinical AKI compared with 246 (31%) of those with eGFRs>60mL/min/1.73m(2) (P

BackgroundAPOL1 genotype is associated with advanced kidney disease in African Americans, but the pathogenic mechanisms are unclear. Here, associations of APOL1 genotype with urine biomarkers of glomerular and tubular injury and kidney function decline were evaluated.Study designObservational study.Setting & participants431 human immunodeficiency virus (HIV)-infected African American women enrolled in Women's Interagency HIV Study (WIHS).PredictorAPOL1 genotype.OutcomesAlbumin-creatinine ratio (ACR), 4 tubular injury biomarkers (interleukin 18 [IL-18], kidney injury molecule 1 [KIM-1], neutrophil gelatinase-associated lipocalin [NGAL], and α1-microglobulin [A1M]), and kidney function estimated using the CKD-EPI cystatin C equation.MeasurementsParticipants were genotyped for APOL1 single-nucleotide polymorphisms rs73885319 (G1 allele) and rs71785313 (G2 allele). Urine biomarkers were measured using stored samples from 1999-2000. Cystatin C was measured using serum collected at baseline and 4- and 8-year follow-ups.ResultsAt baseline, ACRs were higher among 47 women with 2 APOL1 risk alleles versus 384 women with 0/1 risk allele (median, 24 vs 11mg/g; P30 (95% CI, 1.17-3.44) mg/g after multivariable adjustment. APOL1 genotype showed little association with urine IL-18:Cr ratio, KIM-1:Cr ratio, and NGAL:Cr ratio (estimates of -5% [95% CI, -24% to 18%], -20% [95% CI, -36% to -1%], and 10% [95% CI, -26% to 64%], respectively) or detectable urine A1M (prevalence ratio, 1.13; 95% CI, 0.65-1.97) in adjusted analyses. Compared with women with 0/1 allele, women with 2 risk alleles had faster eGFR decline, by 1.2 (95% CI, 0.2 to 2.2) mL/min/1.73m(2) per year, and 1.7- and 3.4-fold greater rates of incident chronic kidney disease (95% CI, 1.1 to 2.5) and 10% annual eGFR decline (95% CI, 1.7 to 6.7), respectively, with minimal attenuation after adjustment for glomerular and tubular injury biomarker levels.LimitationsResults may not be generalizable to men.ConclusionsAmong HIV-infected African American women, APOL1-associated kidney injury appears to localize to the glomerulus, rather than the tubules.

BackgroundHuman immunodeficiency virus (HIV)-infected adults, particularly those of black race, are at high-risk for end-stage renal disease (ESRD), but contributing factors are evolving. We hypothesized that improvements in HIV treatment have led to declines in risk of ESRD, particularly among HIV-infected blacks.MethodsUsing data from the North American AIDS Cohort Collaboration for Research and Design from January 2000 to December 2009, we validated 286 incident ESRD cases using abstracted medical evidence of dialysis (lasting >6 months) or renal transplant. A total of 38 354 HIV-infected adults aged 18-80 years contributed 159 825 person-years (PYs). Age- and sex-standardized incidence ratios (SIRs) were estimated by race. Poisson regression was used to identify predictors of ESRD.ResultsHIV-infected ESRD cases were more likely to be of black race, have diabetes mellitus or hypertension, inject drugs, and/or have a prior AIDS-defining illness. The overall SIR was 3.2 (95% confidence interval [CI], 2.8-3.6) but was significantly higher among black patients (4.5 [95% CI, 3.9-5.2]). ESRD incidence declined from 532 to 303 per 100 000 PYs and 138 to 34 per 100 000 PYs over the time period for blacks and nonblacks, respectively, coincident with notable increases in both the prevalence of viral suppression and the prevalence of ESRD risk factors including diabetes mellitus, hypertension, and hepatitis C virus coinfection.ConclusionsThe risk of ESRD remains high among HIV-infected individuals in care but is declining with improvements in virologic suppression. HIV-infected black persons continue to comprise the majority of cases, as a result of higher viral loads, comorbidities, and genetic susceptibility.

BackgroundSerum albumin concentrations are a strong predictor of mortality and cardiovascular disease in human immunodeficiency virus (HIV)-infected individuals. We studied the longitudinal associations between serum albumin levels and kidney function decline in a population of HIV-infected women.Study designRetrospective cohort analysis.Setting & participantsStudy participants were recruited from the Women's Interagency HIV Study (WIHS), a large observational study designed to understand risk factors for the progression of HIV infection in women living in urban communities. 908 participants had baseline assessment of kidney function and 2 follow-up measurements over an average of 8 years.PredictorThe primary predictor was serum albumin concentration.OutcomesWe examined annual change in kidney function. Secondary outcomes included rapid kidney function decline and incident reduced estimated glomerular filtration rate (eGFR).MeasurementsKidney function decline was determined by cystatin C-based (eGFR(cys)) and creatinine-based eGFR (eGFR(cr)) at baseline and follow-up. Each model was adjusted for kidney disease and HIV-related risk factors using linear and relative risk regression.ResultsAfter multivariate adjustment, each 0.5-g/dL decrement in baseline serum albumin concentration was associated with a 0.56-mL/min faster annual decline in eGFR(cys) (P < 0.001), which was attenuated only slightly to 0.55 mL/min/1.73 m(2) after adjustment for albuminuria. Results were similar whether using eGFR(cys) or eGFR(cr). In adjusted analyses, each 0.5-g/dL lower baseline serum albumin level was associated with a 1.71-fold greater risk of rapid kidney function decline (P < 0.001) and a 1.72-fold greater risk of incident reduced eGFR (P < 0.001).LimitationsThe cohort is composed of only female participants from urban communities within the United States.ConclusionsLower serum albumin levels were associated strongly with kidney function decline and incident reduced eGFRs in HIV-infected women independent of HIV disease status, body mass index, and albuminuria.

BackgroundKidney damage and reduced kidney function are potent risk factors for heart failure, but existing studies are limited to assessing albuminuria or estimated glomerular filtration rate (eGFR). We evaluated the associations of levels of urinary biomarkers of kidney tubular injury (interleukin 18 [IL-18] and kidney injury molecule 1 [KIM-1]) with future risk of heart failure.Study designRetrospective cohort study.Setting & participants2,917 participants without heart failure in the Health, Aging, and Body Composition (Health ABC) cohort.PredictorsRatios of urine KIM-1, IL-18, and albumin to creatinine (KIM-1:Cr, IL-18:Cr, and ACR, respectively).OutcomesIncident heart failure over a median follow-up of 12 years.ResultsMedian values of each marker at baseline were 812 (IQR, 497-1,235)pg/mg for KIM-1:Cr, 31 (IQR, 19-56)pg/mg for IL-18:Cr, and 8 (IQR, 5-19) mg/g for ACR. 596 persons developed heart failure during follow-up. The top quartile of KIM-1:Cr was associated with risk of incident heart failure after adjustment for baseline eGFR, heart failure risk factors, and ACR (HR, 1.32; 95% CI, 1.02-1.70) in adjusted multivariate proportional hazards models. The top quartile of IL-18:Cr also was associated with heart failure in a model adjusted for risk factors and eGFR (HR, 1.35; 95% CI, 1.05-1.73), but was attenuated by adjustment for ACR (HR, 1.15; 95% CI, 0.89-1.48). The top quartile of ACR had a stronger adjusted association with heart failure (HR, 1.96; 95% CI, 1.53-2.51).LimitationsGeneralizability to other populations is uncertain.ConclusionsHigher urine KIM-1 concentrations were associated independently with incident heart failure risk, although the associations of higher ACR were of stronger magnitude.

BackgroundAcute kidney injury (AKI) is a serious complication of cardiac operations for which there remains no specific therapy. Animal data and several observational studies suggest that statins prevent AKI, but the results are not conclusive, and many studies are retrospective in nature.MethodsWe conducted a multicenter prospective cohort study of 625 adult patients undergoing elective cardiac operations. All patients were taking statins and were grouped according to whether statins were continued or held in the 24 hours before operation. The primary outcome was AKI as defined by a doubling of serum creatinine or dialysis. The secondary outcome was the peak level of several kidney injury biomarkers. The results were adjusted for demographic and clinical factors.ResultsContinuing (vs holding) a statin before operation was not associated with a lower risk of AKI, as defined by a doubling of serum creatinine or dialysis (adjusted relative risk [RR] 1.09; 95% confidence interval [CI] 0.44, 2.70). However, continuing a statin was associated with a lower risk of elevation of the following AKI biomarkers: urine interleukin-18, urine neutrophil gelatinase-associated lipocalin, urine kidney injury molecule-1, and plasma neutrophil gelatinase-associated lipocalin (adjusted RR 0.34; 95% CI 0.18, 0.62), (adjusted RR 0.41; 95% CI 0.22, 0.76), (adjusted RR 0.37; 95% CI 0.20, 0.76), (adjusted RR 0.62; 95% CI 0.39, 0.98), respectively.ConclusionsStatins may prevent kidney injury after cardiac operations, as evidenced by lower levels of kidney injury biomarkers.

BackgroundThe study of novel urinary biomarkers of acute kidney injury has expanded exponentially. Effective interpretation of data and meaningful comparisons between studies require awareness of factors that can adversely affect measurement. We examined how variations in short-term storage and processing might affect the measurement of urine biomarkers.Study designCross-sectional prospective.Setting & participantsHospitalized patients from 2 sites: Yale New Haven Hospital (n=50) and University of California, San Francisco Medical Center (n=36).PredictorsWe tested the impact of 3 urine processing conditions on these biomarkers: (1) centrifugation and storage at 4°C for 48 hours before freezing at -80°C, (2) centrifugation and storage at 25°C for 48 hours before freezing at -80°C, and (3) uncentrifuged samples immediately frozen at -80°C.OutcomesUrine concentrations of 5 biomarkers: neutrophil gelatinase-associated lipocalin (NGAL), interleukin 18 (IL-18), kidney injury molecule 1 (KIM-1), liver-type fatty acid-binding protein (L-FABP), and cystatin C.MeasurementsWe measured urine biomarkers by established enzyme-linked immunosorbent assay methods. Biomarker values were log-transformed, and agreement with a reference standard of immediate centrifugation and storage at -80°C was compared using concordance correlation coefficients (CCCs).ResultsNeither storing samples at 4°C for 48 hours nor centrifugation had a significant effect on measured levels, with CCCs higher than 0.9 for all biomarkers tested. For samples stored at 25°C for 48 hours, excellent CCC values (>0.9) also were noted between the test sample and the reference standard for NGAL, cystatin C, L-FABP and KIM-1. However, the CCC for IL-18 between samples stored at 25°C for 48 hours and the reference standard was 0.81 (95% CI, 0.66-0.96).LimitationsNo comparisons to fresh, unfrozen samples; no evaluation of the effect of protease inhibitors.ConclusionsAll candidate markers tested using the specified assays showed high stability with both short-term storage at 4°C and without centrifugation prior to freezing. For optimal fidelity, urine for IL-18 measurement should not be stored at 25°C before long-term storage or analysis.

BackgroundIn HIV-infected women, urine concentrations of novel tubulointerstitial injury markers, interleukin-18 (IL-18) and kidney injury marker-1 (KIM-1), are associated with kidney function decline and all-cause mortality. We hypothesized that HIV-infected individuals with preserved kidney filtration function would have more extensive kidney injury, as determined by urine injury markers, compared to the uninfected controls, and that risk factors for tubulointerstitial injury would differ from risk factors for albuminuria.MethodsIn this cross-sectional study, we compared urine concentrations of IL-18, KIM-1 and albumin-to-creatinine ratio (ACR) in 908 HIV-infected and 289 HIV-uninfected women enrolled in the Women's Interagency HIV Study, utilizing stored urine specimens from visits between 1999 and 2000.ResultsAfter multivariate-adjusted linear regression analysis, mean urine concentrations were higher in HIV-infected individuals by 38% for IL-18 (P

BackgroundCystatin C could improve chronic kidney disease (CKD) classification in HIV-infected women relative to serum creatinine.DesignRetrospective cohort analysis.MethodsCystatin C and creatinine were measured from specimens taken and stored during the 1999-2000 examination among 908 HIV-infected participants in the Women's Interagency HIV study (WIHS). Mean follow-up was 10.2 years. Predictors of differential glomerular filtration rate (GFR) estimates were evaluated with multivariable linear regression. The associations of baseline categories (90 ml/min per 1.73 m) of creatinine estimated GFR (eGFRcr), cystatin C eGFR (eGFRcys), and combined creatinine-cystatin C eGFR (eGFRcr-cys) with all-cause mortality were evaluated using multivariable Cox regression. The net reclassification index (NRI) was calculated to evaluate the effect of cystatin C on reclassification of CKD staging.ResultsCKD risk factors were associated with lower eGFRcys and eGFRcr-cys values compared with eGFRcr. Relative to eGFR more than 90, the eGFR less than 60 category by eGFRcys (Adjusted hazard ratio: 2.56; 95% confidence interval: 1.63-4.02), eGFRcr-cys (3.11; 1.94-5.00), and eGFRcr (2.34; 1.44-3.79) was associated with increased mortality risk. However, the eGFR 60-90 category was associated with increased mortality risk for eGFRcys (1.80; 1.28-2.53) and eGFRcr-cys (1.91; 1.38-2.66) but not eGFRcr (1.20; 0.85-1.67). The overall NRI for mortality was 26% when reclassifying from eGFRcr to eGFRcys (P