Association of Albuminuria With Chronic Kidney Disease Progression in Persons With Chronic Kidney Disease and Normoalbuminuria : A Cohort Study.

BACKGROUND: Albuminuria is a major risk factor for chronic kidney disease (CKD) progression, especially when categorized as moderate (30 to 300 mg/g) or severe (>300 mg/g). However, there are limited data on the prognostic value of albuminuria within the normoalbuminuric range (<30 mg/g) in persons with CKD. OBJECTIVE: To estimate the increase in the cumulative incidence of CKD progression with greater baseline levels of albuminuria among persons with CKD who had normoalbuminuria (<30 mg/g). DESIGN: Multicenter prospective cohort study. SETTING: 7 U.S. clinical centers. PARTICIPANTS: 1629 participants meeting criteria from the CRIC (Chronic Renal Insufficiency Cohort) study with CKD (estimated glomerular filtration rate [eGFR], 20 to 70 mL/min/1.73 m2) and urine albumin-creatinine ratio (UACR) less than 30 mg/g. MEASUREMENTS: Baseline spot urine albumin divided by spot urine creatinine to calculate UACR as the exposure variable. The 10-year adjusted cumulative incidences of CKD progression (composite of 50% eGFR decline or kidney failure [dialysis or kidney transplantation]) from confounder adjusted survival curves using the G-formula. RESULTS: Over a median follow-up of 9.8 years, 182 of 1629 participants experienced CKD progression. The 10-year adjusted cumulative incidences of CKD progression were 8.7% (95% CI, 5.9% to 11.6%), 11.5% (CI, 8.8% to 14.3%), and 19.5% (CI, 15.4% to 23.5%) for UACR levels of 0 to less than 5 mg/g, 5 to less than 15 mg/g, and 15 mg/g or more, respectively. Comparing persons with UACR 15 mg/g or more to those with UACR 5 to less than 15 mg/g and 0 to less than 5 mg/g, the absolute risk differences were 7.9% (CI, 3.0% to 12.7%) and 10.7% (CI, 5.8% to 15.6%), respectively. The 10-year adjusted cumulative incidence increased linearly based on baseline UACR levels. LIMITATION: UACR was measured once. CONCLUSION: Persons with CKD and normoalbuminuria (<30 mg/g) had excess risk for CKD progression, which increased in a linear fashion with higher levels of albuminuria. PRIMARY FUNDING SOURCE: None.

Integrated Proteomic and Metabolomic Modules associated with Risk of Kidney Disease Progression.

BACKGROUND: Proteins and metabolites play crucial roles in various biological functions and are frequently interconnected through enzymatic or transport processes. METHODS: We present an integrated analysis of 4,091 proteins and 630 metabolites in the Chronic Renal Insufficiency Cohort Study (N=1,708; average follow-up for kidney failure [KF], 9.5 years, with 537 events). Proteins and metabolites were integrated using an unsupervised clustering method and we assessed associations between clusters and CKD progression and kidney failure using Cox proportional hazards models. Analyses were adjusted for demographics and risk factors including the estimated glomerular filtration rate (eGFR) and urine protein-creatinine ratio. Associations were identified in a discovery sample (random two-thirds, N=1139) and then evaluated in a replication sample (one-third, N=569). RESULTS: We identified 139 modules of correlated proteins and metabolites, which were represented by their principal components (PC). Modules and PC loadings were projected onto the replication sample which demonstrated a consistent network structure. Two modules, representing a total of 236 proteins and 82 metabolites, were robustly associated with both CKD progression and kidney failure in both discovery and validation samples. Using gene set enrichment, several transmembrane related terms were identified as over-represented in these modules. Transmembrane-ephrin receptor activity displayed the largest odds (OR = 13.2, P-value = 5.5×10 -5 ). A module containing CRIM1 and NPNT expressed in podocytes demonstrated particularly strong associations with kidney failure (P-value = 2.6×10 -5 ). CONCLUSIONS: This study demonstrates that integration of the proteome and metabolome can identify functions of pathophysiologic importance in kidney disease.

Plasma Proteins associated with Chronic Histopathologic Lesions on Kidney Biopsy.

BACKGROUND: The severity of chronic histopathologic lesions on kidney biopsy is independently associated with higher risk of progressive chronic kidney disease (CKD). Because kidney biopsies are invasive, identification of blood markers that report on underlying kidney histopathology has the potential to enhance CKD care. METHODS: We examined the association between 6592 plasma protein levels measured by aptamers and the severity of interstitial fibrosis and tubular atrophy (IFTA), glomerulosclerosis, arteriolar sclerosis, and arterial sclerosis among 434 participants of the Boston Kidney Biopsy Cohort. For proteins significantly associated with at least one histologic lesion, we assessed renal arteriovenous protein gradients among 21 individuals who had undergone invasive catheterization and assessed the expression of the cognate gene among 47 individuals with single cell RNA sequencing data in the Kidney Precision Medicine Project. RESULTS: In models adjusted for estimated glomerular filtration rate (eGFR), proteinuria, and demographic factors, we identified 35 proteins associated with one or more chronic histologic lesions, including 20 specific for IFTA, 8 specific for glomerulosclerosis, and 1 specific for arteriolar sclerosis. In general, higher levels of these proteins were associated with more severe histologic score and lower eGFR. Exceptions included testican-2 and NELL1, which were associated with less glomerulosclerosis and IFTA, respectively, and higher eGFR; notably, both of these proteins demonstrated significantly higher levels from artery to renal vein, demonstrating net kidney release. In the Kidney Precision Medicine Project, 13 of the 35 protein hits had cognate gene expression enriched in one or more cell types in the kidney, including podocyte expression of select glomerulosclerosis markers (including testican-2) and tubular expression of several IFTA markers (including NELL1). CONCLUSIONS: Proteomic analysis identified circulating proteins associated with chronic histopathologic lesions, some of which have concordant site-specific expression within the kidney.

Elevated Cardiac Biomarkers in Relatively Healthy U.S. Adults.

Background: Despite the importance of early cardiovascular disease (CVD) intervention, little data exists for evaluating cardiovascular risk in adults without traditional CVD risk factors (e.g., diabetes, hypertension). Methods: We included 4,544 adults from the 1999-2004 National Health and Nutrition Examination Survey without prevalent diabetes, hypertension, chronic kidney disease, or CVD. We used multi-variable adjusted Cox proportional hazards regression modeling to assess the relationship between logarithmically transformed cardiac biomarkers (high sensitivity cardiac troponin T (hs-cTnT), hs-cTnI (Abbott, Ortho, and Siemens assays), and NT-proBNP) and CVD mortality among a nationally representative cohort of relatively healthy adults. Results: The mean age was 38.2 years (SD 12.8) and 53.9% were women. 8.7% had elevated levels of hs-cTnT or NT-proBNP above previously established thresholds for subclinical CVD. In multivariable adjusted models, each doubling of hs-cTnT was associated with a 49% increased risk of CVD mortality (Hazard Ratio (HR) 1.49, 95%CI 1.02-2.17, p=0.04). Only two of the hs-cTnI assays (Abbott and Ortho) were significantly associated with CVD mortality (Abbott HR 1.48, 95%CI 1.06-2.07, p=0.02; Ortho HR 1.47, 95%CI 1.23-1.77, p=0.0001). Each doubling of NT-proBNP was associated with a 41% increased risk of CVD mortality (HR 1.38, 95%CI 1.09-1.74, p=0.008). Conclusion: Younger patients who maintain relatively good health may still carry occult CVD risk. Efforts to reduce population-wide CVD should consider novel methods for risk stratification, as standard CVD risk factors may overlook subpopulations at risk.

Structural and Psychosocial Challenges Among Underserved Patients Receiving Hemodialysis During and Beyond the COVID-19 Pandemic: A Qualitative Study.

Rationale & Objective: Racial and ethnic minority groups in the United States are disproportionately affected by chronic kidney disease and progressive kidney failure and face significantly more socioeconomic and psychosocial challenges. However, how such patients' social environment and stigmatization shape their illness experiences and abilities to cope before and during the coronavirus disease 2019 (COVID-19) pandemic has not been well documented, even as social scientific research predicts these groups' exponential vulnerability. Study Design: Qualitative study using semistructured interviews to elicit individual patient narratives about their personal illness experiences before and during the COVID-19 pandemic, any challenges they faced, and their sources of support. Setting & Participants: Using purposive sampling, we recruited 20 adult patients receiving maintenance hemodialysis from centers affiliated with a safety-net hospital in Boston, Massachusetts. Analytical Approach: Interviews were audiotaped, transcribed, and analyzed using thematic content analysis to identify patients' challenges and supports before and during the pandemic. Results: Of the 20 patients in the study, 9 were women, and 18 self-identified as Black or African American. Three main themes emerged, whereby most patients described: (1) stigma and stigmatization as a central element of their life experience; (2) the pandemic as a difficult experience but not a complete rupture from their prepandemic life; and (3) social networks, particularly family, friends, and religious communities, as sources of support crucial to coping with their debilitating illness. Limitations: Whether the findings apply to other settings is unknown, as participants were recruited from centers in a single safety-net urban hospital setting. Conclusions: Psychosocial and environmental factors, including institutional racism and stigmatization, play significant roles in amplifying the burdens shouldered by racial and ethnic minority individuals with kidney disease who now also face the COVID-19 pandemic that has since turned endemic. The results of this study can inform the development of policy interventions aimed at alleviating tensions and structural conditions that impinge on kidney disease patients' wellbeing and health outcomes. Plain-Language Summary: Members of racial and ethnic minority groups in the United States experience the highest rates of progressive kidney failure and face significantly more socioeconomic and psychosocial challenges. We interviewed 20 patients who receive maintenance hemodialysis treatment from centers affiliated with a safety-net hospital. Patients described stigmatization as a central element of their life experience and the pandemic as a difficult challenge (but not a complete rupture) that added to their struggles with illness-related, race-related, and class-related stigmas. Social networks, particularly family, friends, and religious communities, are key sources of support crucial to coping with illness. Findings from this study can inform health care providers and community workers and guide the development of policy interventions to provide better support for these patients.

Circulating Proteins and Mortality in CKD: A Proteomics Study of the AASK and ARIC Cohorts.

Rationale & Objective: Proteomics could provide pathophysiologic insight into the increased risk of mortality in patients with chronic kidney disease (CKD). This study aimed to investigate associations between the circulating proteome and all-cause mortality among patients with CKD. Study Design: Observational cohort study. Setting & Participants: Primary analysis in 703 participants in the African American Study of Kidney Disease and Hypertension (AASK) and validation in 1,628 participants with CKD in the Atherosclerosis Risk in Communities (ARIC) study who attended visit 5. Exposure: Circulating proteins. Outcome: All-cause mortality. Analytical Approach: Among AASK participants, we evaluated the associations of 6,790 circulating proteins with all-cause mortality using multivariable Cox proportional hazards models. Proteins with significant associations were further studied in ARIC Visit 5 participants with CKD. Results: In the AASK cohort, the mean age was 54.5 years, 271 (38.5%) were women, and the mean measured glomerular filtration rate (GFR) was 46 mL/min/1.73 m2. The median follow-up was 9.6 years, and 7 distinct proteins were associated with all-cause mortality at the Bonferroni-level threshold (P < 0.05 of the 6,790) after adjustment for demographics and clinical factors, including baseline measured estimated GFR and proteinuria. In the ARIC visit 5 cohort, the mean age was 77.2 years, 903 (55.5%) were women, the mean estimated GFR was 54 mL/min/1.73 m2 and median follow-up was 6.9 years. Of the 7 proteins found in AASK, 3 (ß2-microglobulin, spondin-1, and N-terminal pro-brain natriuretic peptide) were available in the ARIC data, with all 3 significantly associated with death in ARIC. Limitations: Possibility of unmeasured confounding. Cause of death was not known. Conclusions: Using large-scale proteomic analysis, proteins were reproducibly associated with mortality in 2 cohorts of participants with CKD. Plain-Language Summary: Patients with chronic kidney disease (CKD) have a high risk of premature death, with various pathophysiological processes contributing to this increased risk of mortality. This observational cohort study aimed to investigate the associations between circulating proteins and all-cause mortality in patients with CKD using large-scale proteomic analysis. The study analyzed data from the African American Study of Kidney Disease and Hypertension (AASK) study and validated the findings in the Atherosclerosis Risk in Communities (ARIC) Study. A total of 6,790 circulating proteins were evaluated in AASK, and 7 proteins were significantly associated with all-cause mortality. Three of these proteins (ß2-microglobulin, spondin-1, and N-terminal pro-brain natriuretic peptide (BNP)) were also measured in ARIC and were significantly associated with death. Additional studies assessing biomarkers associated with mortality among patients with CKD are needed to evaluate their use in clinical practice.

Associations Between Kidney Histopathologic Lesions and Incident Cardiovascular Disease in Adults With Chronic Kidney Disease.

Importance: Histologic lesions in the kidney may reflect or contribute to systemic processes that may lead to adverse cardiovascular events. Objective: To assess the association between kidney histopathologic lesion severity and the risk of incident major adverse cardiovascular events (MACE). Design, Setting, and Participants: This prospective observational cohort study included participants without a history of myocardial infarction, stroke, or heart failure from the Boston Kidney Biopsy Cohort recruited from 2 academic medical centers in Boston, Massachusetts. Data were collected from September 2006 and November 2018, and data were analyzed from March to November 2021. Exposures: Semiquantitative severity scores for kidney histopathologic lesions adjudicated by 2 kidney pathologists, a modified kidney pathology chronicity score, and primary clinicopathologic diagnostic categories. Main Outcomes and Measures: The main outcome was the composite of death or incident MACE, which included myocardial infarction, stroke, and heart failure hospitalization. All cardiovascular events were independently adjudicated by 2 investigators. Cox proportional hazards models estimated associations of histopathologic lesions and scores with cardiovascular events adjusted for demographic characteristics, clinical risk factors, estimated glomerular filtration rate (eGFR), and proteinuria. Results: Of 597 included participants, 308 (51.6%) were women, and the mean (SD) age was 51 (17) years. The mean (SD) eGFR was 59 (37) mL/min per 1.73 m2, and the median (IQR) urine protein to creatinine ratio was 1.54 (0.39-3.95). The most common primary clinicopathologic diagnoses were lupus nephritis, IgA nephropathy, and diabetic nephropathy. Over a median (IQR) of 5.5 (3.3-8.7) years of follow-up, the composite of death or incident MACE occurred in 126 participants (37 per 1000 person-years). Compared with the reference group of individuals with proliferative glomerulonephritis, the risk of death or incident MACE was highest in individuals with nonproliferative glomerulopathy (hazard ratio [HR], 2.61; 95% CI, 1.30-5.22; P = .002), diabetic nephropathy (HR, 3.56; 95% CI, 1.62-7.83; P = .002), and kidney vascular diseases (HR, 2.86; 95% CI, 1.51-5.41; P = .001) in fully adjusted models. The presence of mesangial expansion (HR, 2.98; 95% CI, 1.08-8.30; P = .04) and arteriolar sclerosis (HR, 1.68; 95% CI, 1.03-2.72; P = .04) were associated with an increased risk of death or MACE. Compared with minimal chronicity, greater chronicity was significantly associated with an increased risk of death or MACE (severe: HR, 2.50; 95% CI, 1.06-5.87; P = .04; moderate: HR, 1.66; 95% CI, 0.74-3.75; P = .22; mild: HR, 2.22; 95% CI, 1.01-4.89; P = .047) in fully adjusted models. Conclusions and Relevance: In this study, specific kidney histopathological findings were associated with increased risks of CVD events. These results provide potential insight into mechanisms of the heart-kidney relationship beyond those provided by eGFR and proteinuria.

The use of plasma biomarker-derived clusters for clinicopathologic phenotyping: results from the Boston Kidney Biopsy Cohort.

Background: Protein biomarkers may provide insight into kidney disease pathology but their use for the identification of phenotypically distinct kidney diseases has not been evaluated. Methods: We used unsupervised hierarchical clustering on 225 plasma biomarkers in 541 individuals enrolled into the Boston Kidney Biopsy Cohort, a prospective cohort study of individuals undergoing kidney biopsy with adjudicated histopathology. Using principal component analysis, we studied biomarker levels by cluster and examined differences in clinicopathologic diagnoses and histopathologic lesions across clusters. Cox proportional hazards models tested associations of clusters with kidney failure and death. Results: We identified three biomarker-derived clusters. The mean estimated glomerular filtration rate was 72.9 ± 28.7, 72.9 ± 33.4 and 39.9 ± 30.4 mL/min/1.73 m2 in Clusters 1, 2 and 3, respectively. The top-contributing biomarker in Cluster 1 was AXIN, a negative regulator of the Wnt signaling pathway. The top-contributing biomarker in Clusters 2 and 3 was Placental Growth Factor, a member of the vascular endothelial growth factor family. Compared with Cluster 1, individuals in Cluster 3 were more likely to have tubulointerstitial disease (P < .001) and diabetic kidney disease (P < .001) and had more severe mesangial expansion [odds ratio (OR) 2.44, 95% confidence interval (CI) 1.29, 4.64] and inflammation in the fibrosed interstitium (OR 2.49 95% CI 1.02, 6.10). After multivariable adjustment, Cluster 3 was associated with higher risks of kidney failure (hazard ratio 3.29, 95% CI 1.37, 7.90) compared with Cluster 1. Conclusion: Plasma biomarkers may identify clusters of individuals with kidney disease that associate with different clinicopathologic diagnoses, histopathologic lesions and adverse outcomes, and may uncover biomarker candidates and relevant pathways for further study.

Patients' Perspectives on Race and the Use of Race-Based Algorithms in Clinical Decision-Making: a Qualitative Study.

BACKGROUND: Clinical algorithms that incorporate race as a modifying factor to guide clinical decision-making have recently been criticized for propagating racial bias in medicine. Equations used to calculate lung or kidney function are examples of clinical algorithms that have different diagnostic parameters depending on an individual's race. While these clinical measures have multiple implications for clinical care, patients' awareness of and their perspectives on the application of such algorithms are unknown. OBJECTIVE: To examine patients' perspectives on race and the use of race-based algorithms in clinical decision-making. DESIGN: Qualitative study using semi-structured interviews. PARTICIPANTS: Twenty-three adult patients recruited at a safety-net hospital in Boston, MA. APPROACH: Interviews were analyzed using thematic content analysis and modified grounded theory. KEY RESULTS: Among the 23 study participants, 11 were women and 15 self-identified as Black or African American. Three categories of themes emerged: The first theme described definitions and the individual meanings participants ascribed to the term race. The second theme described perspectives on the role and consideration of race in clinical decision-making. Most study participants were unaware that race has been used as a modifying factor in clinical equations and rejected the incorporation of race in these equations. The third theme related to exposure to and experience of racism in healthcare settings. Experiences described by non-White participants ranged from microaggressions to overt acts of racism, including perceived racist encounters with healthcare providers. In addition, patients alluded to a deep mistrust in the healthcare system as a major barrier to equitable care. CONCLUSIONS: Our findings suggest that most patients are unaware of how race has been used to make risk assessments and guide clinical care. Further research on patients' perspectives is needed to inform the development of anti-racist policies and regulatory agendas as we move forward to combat systemic racism in medicine.

The relationship between low levels of albuminuria and cardiovascular mortality among apparently healthy adults.

Background: Albuminuria is associated with cardiovascular events among adults with underlying cardiovascular disease and diabetes, even at low levels of urinary albumin excretion. We hypothesized that low levels of albuminuria in the 'normal' range (urinary albumin-to-creatine ratio (UACR) <30 mg/g) are associated with cardiovascular death among apparently healthy adults. Methods: We studied adults who participated in the 1999-2014 National Health and Nutrition Examination Survey. We excluded participants with baseline cardiovascular disease, hypertension, diabetes, estimated glomerular filtration rate (eGFR) <60ml/min/1.73m2, those who were currently pregnant, and those who had received dialysis in the last year. After excluding these conditions, only 5.0% of the remaining population had UACR ≥30 mg/g (N=873) and were excluded. The final sample size was 16,247. We assessed the relationship between UACR and cardiovascular and all-cause mortality using multivariable-adjusted Cox proportional hazards models. Models were adjusted for age, sex, race or ethnicity, smoking status, systolic blood pressure, hemoglobin A1c, total cholesterol, health insurance, food insecurity, serum albumin, body mass index, use of statins, and eGFR. Results: Mean age was 38.9 years (SD 13.6) and 53.7% were women. The median length of follow-up was 12.2 years. In multivariable-adjusted models, each doubling of UACR (within the <30 mg/g range) was associated with a 36% higher risk of cardiovascular death [HR 1.36 (95% confidence interval (CI) 1.11-1.65)] and a 28% higher risk of all-cause mortality [HR 1.28 (95%CI 1.17-1.41)]. The highest tertile of UACR (7.1-29.9 mg/g) was associated with an 87% higher risk of cardiovascular death [HR 1.87 (95%CI 1.20-2.92)] and 59% higher risk of all-cause mortality [HR 1.59 (95%CI 1.28-1.96)], compared with the lowest tertile (< 4.3 mg/g). Conclusions: In a nationally representative sample of relatively healthy community-dwelling adults, higher levels of albuminuria in the conventionally "normal" range <30 mg/g in healthy individuals are associated with greater mortality. Overall, our findings contribute to the growing body of evidence on the existence of a risk gradient across all levels of albuminuria, even in the so-called normal range.

Urinary Proteomics Identifies Cathepsin D as a Biomarker of Rapid eGFR Decline in Type 1 Diabetes.

OBJECTIVE: Understanding mechanisms underlying rapid estimated glomerular filtration rate (eGFR) decline is important to predict and treat kidney disease in type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: We performed a case-control study nested within four T1D cohorts to identify urinary proteins associated with rapid eGFR decline. Case and control subjects were categorized based on eGFR decline ≥3 and <1 mL/min/1.73 m2/year, respectively. We used targeted liquid chromatography-tandem mass spectrometry to measure 38 peptides from 20 proteins implicated in diabetic kidney disease. Significant proteins were investigated in complementary human cohorts and in mouse proximal tubular epithelial cell cultures. RESULTS: The cohort study included 1,270 participants followed a median 8 years. In the discovery set, only cathepsin D peptide and protein were significant on full adjustment for clinical and laboratory variables. In the validation set, associations of cathepsin D with eGFR decline were replicated in minimally adjusted models but lost significance with adjustment for albuminuria. In a meta-analysis with combination of discovery and validation sets, the odds ratio for the association of cathepsin D with rapid eGFR decline was 1.29 per SD (95% CI 1.07-1.55). In complementary human cohorts, urine cathepsin D was associated with tubulointerstitial injury and tubulointerstitial cathepsin D expression was associated with increased cortical interstitial fractional volume. In mouse proximal tubular epithelial cell cultures, advanced glycation end product-BSA increased cathepsin D activity and inflammatory and tubular injury markers, which were further increased with cathepsin D siRNA. CONCLUSIONS: Urine cathepsin D is associated with rapid eGFR decline in T1D and reflects kidney tubulointerstitial injury.

Determinants and Outcomes Associated With Urinary Calcium Excretion in Chronic Kidney Disease.

CONTEXT: Abnormalities in calcium metabolism are common in chronic kidney disease (CKD). Diminished urinary calcium excretion may promote vascular calcification and increased urinary calcium excretion may lead to nephrolithiasis and nephrocalcinosis, conditions associated with CKD. OBJECTIVE: To study predictors of urinary calcium excretion and its association with adverse clinical outcomes in CKD. DESIGN, SETTING AND PATIENTS: This study assessed 3768 nondialysis participants in the Chronic Renal Insufficiency Cohort study from April 2003 to September 2008. Participants were followed up to October 2018. EXPOSURE: Clinically plausible predictors of urinary calcium excretion and 24-h urinary calcium excretion at baseline. MAIN OUTCOME MEASURES: Urinary calcium excretion; incident end stage kidney disease (ESKD), CKD progression [50% estimated glomerular filtration rate (eGFR) decline or incident ESKD], all-cause mortality, and atherosclerotic cardiovascular disease events. RESULTS: eGFR was positive correlated with 24-h urinary calcium excretion. The variables most strongly associated with 24-h urinary calcium excretion in males and females were 24-h urinary sodium (ß = 0.19 and 0.28, respectively), serum parathyroid hormone (ß = -0.22 and -0.20, respectively), loop diuretics (ß = 0.36 and 0.26, respectively), thiazide diuretics (ß = -0.49 and -0.53, respectively), and self-identified black race (ß = -0.23 and -0.27, respectively). Lower urinary calcium excretion was associated with greater risks of adverse outcomes, but these associations were greatly attenuated or nullified after adjustment for baseline eGFR. CONCLUSION: Urinary calcium excretion is markedly lower in individuals with CKD compared to the general population. Determinants of urinary calcium excretion differed between sexes and levels of CKD. Associations between urinary calcium excretion and adverse clinical events were substantially confounded by eGFR.

Plasma Kidney Injury Molecule 1 in CKD: Findings From the Boston Kidney Biopsy Cohort and CRIC Studies.

RATIONALE & OBJECTIVE: Plasma kidney injury molecule 1 (KIM-1) is a sensitive marker of proximal tubule injury, but its association with risks of adverse clinical outcomes across a spectrum of kidney diseases is unknown. STUDY DESIGN: Prospective, observational cohort study. SETTING & PARTICIPANTS: 524 individuals enrolled into the Boston Kidney Biopsy Cohort (BKBC) Study undergoing clinically indicated native kidney biopsy with biopsy specimens adjudicated for semiquantitative scores of histopathology by 2 kidney pathologists and 3,800 individuals with common forms of chronic kidney disease (CKD) enrolled into the Chronic Renal Insufficiency Cohort (CRIC) Study. EXPOSURE: Histopathologic lesions and clinicopathologic diagnosis in cross-sectional analyses, baseline plasma KIM-1 levels in prospective analyses. OUTCOMES: Baseline plasma KIM-1 levels in cross-sectional analyses, kidney failure (defined as initiation of kidney replacement therapy) and death in prospective analyses. ANALYTICAL APPROACH: Multivariable-adjusted linear regression models tested associations of plasma KIM-1 levels with histopathologic lesions and clinicopathologic diagnoses. Cox proportional hazards models tested associations of plasma KIM-1 levels with future kidney failure and death. RESULTS: In the BKBC Study, higher plasma KIM-1 levels were associated with more severe acute tubular injury, tubulointerstitial inflammation, and more severe mesangial expansion after multivariable adjustment. Participants with diabetic nephropathy, glomerulopathies, and tubulointerstitial disease had significantly higher plasma KIM-1 levels after multivariable adjustment. In the BKBC Study, CKD in 124 participants progressed to kidney failure and 85 participants died during a median follow-up time of 5 years. In the CRIC Study, CKD in 1,153 participants progressed to kidney failure and 1,356 participants died during a median follow-up time of 11.5 years. In both cohorts, each doubling of plasma KIM-1 level was associated with an increased risk of kidney failure after multivariable adjustment (hazard ratios of 1.19 [95% CI, 1.03-1.38] and 1.10 [95% CI, 1.06-1.15] for BKBC and CRIC, respectively). There was no statistically significant association of plasma KIM-1 levels with death in either cohort. LIMITATIONS: Generalizability and unmeasured confounding. CONCLUSIONS: Plasma KIM-1 is associated with underlying tubulointerstitial and mesangial lesions and progression to kidney failure in 2 cohort studies of individuals with kidney diseases.

Circulating Plasma Biomarkers in Biopsy-Confirmed Kidney Disease.

BACKGROUND AND OBJECTIVES: Biomarkers for noninvasive assessment of histopathology and prognosis are needed in patients with kidney disease. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Using a proteomics assay, we measured a multimarker panel of 225 circulating plasma proteins in a prospective cohort study of 549 individuals with biopsy-confirmed kidney diseases and semiquantitative assessment of histopathology. We tested the associations of each biomarker with histopathologic lesions and the risks of kidney disease progression (defined as ≥40% decline in eGFR or initiation of KRT) and death. RESULTS: After multivariable adjustment and correction for multiple testing, 46 different proteins were associated with histopathologic lesions. The top-performing markers positively associated with acute tubular injury and interstitial fibrosis/tubular atrophy were kidney injury molecule-1 (KIM-1) and V-set and Ig domain-containing protein 2 (VSIG2), respectively. Thirty proteins were significantly associated with kidney disease progression, and 35 were significantly associated with death. The top-performing markers for kidney disease progression were placental growth factor (hazard ratio per doubling, 5.4; 95% confidence interval, 3.4 to 8.7) and BMP and activin membrane-bound inhibitor (hazard ratio, 3.0; 95% confidence interval, 2.1 to 4.2); the top-performing markers for death were TNF-related apoptosis-inducing ligand receptor-2 (hazard ratio, 2.9; 95% confidence interval, 2.0 to 4.0) and CUB domain-containing protein-1 (hazard ratio, 2.4; 95% confidence interval, 1.8 to 3.3). CONCLUSION: We identified several plasma protein biomarkers associated with kidney disease histopathology and adverse clinical outcomes in individuals with a diverse set of kidney diseases. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_12_28_CJN09380721.mp3.