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  • 1
    In: Kidney International, Elsevier BV, Vol. 100, No. 3 ( 2021-09), p. 672-683
    Type of Medium: Online Resource
    ISSN: 0085-2538
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2021
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  • 2
    In: Diabetes Care, American Diabetes Association, Vol. 45, No. 6 ( 2022-06-02), p. 1416-1427
    Abstract: 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 & lt;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.
    Type of Medium: Online Resource
    ISSN: 0149-5992
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2022
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  • 3
    In: American Journal of Kidney Diseases, Elsevier BV, Vol. 79, No. 2 ( 2022-02), p. 231-243.e1
    Type of Medium: Online Resource
    ISSN: 0272-6386
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
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  • 4
    In: JAMA Cardiology, American Medical Association (AMA), Vol. 8, No. 4 ( 2023-04-01), p. 357-
    Abstract: 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 m 2 , 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.
    Type of Medium: Online Resource
    ISSN: 2380-6583
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2023
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  • 5
    In: Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 32, No. 3 ( 2021-3), p. 639-653
    Abstract: Staging CKD by eGFR and urine albumin-creatinine ratio does not fully capture underlying patient heterogeneity. Applying machine learning consensus clustering to multidimensional patient data, including demographics, biomarkers from blood and urine, health status and behaviors, and medication use, enables subtyping of patients with CKD into three distinct subgroups defined by 72 baseline characteristics. These subgroups are strongly associated with future risks of kidney disease, cardiovascular events, and death, independent of established CKD risk factors. Identification of clinically meaningful subgroups among patients with CKD provides an important step toward patient classification and precision medicine in nephrology. Background CKD is a heterogeneous condition with multiple underlying causes, risk factors, and outcomes. Subtyping CKD with multidimensional patient data holds the key to precision medicine. Consensus clustering may reveal CKD subgroups with different risk profiles of adverse outcomes. Methods We used unsupervised consensus clustering on 72 baseline characteristics among 2696 participants in the prospective Chronic Renal Insufficiency Cohort (CRIC) study to identify novel CKD subgroups that best represent the data pattern. Calculation of the standardized difference of each parameter used the cutoff of ±0.3 to show subgroup features. CKD subgroup associations were examined with the clinical end points of kidney failure, the composite outcome of cardiovascular diseases, and death. Results The algorithm revealed three unique CKD subgroups that best represented patients’ baseline characteristics. Patients with relatively favorable levels of bone density and cardiac and kidney function markers, with lower prevalence of diabetes and obesity, and who used fewer medications formed cluster 1 ( n =1203). Patients with higher prevalence of diabetes and obesity and who used more medications formed cluster 2 ( n =1098). Patients with less favorable levels of bone mineral density, poor cardiac and kidney function markers, and inflammation delineated cluster 3 ( n =395). These three subgroups, when linked with future clinical end points, were associated with different risks of CKD progression, cardiovascular disease, and death. Furthermore, patient heterogeneity among predefined subgroups with similar baseline kidney function emerged. Conclusions Consensus clustering synthesized the patterns of baseline clinical and laboratory measures and revealed distinct CKD subgroups, which were associated with markedly different risks of important clinical outcomes. Further examination of patient subgroups and associated biomarkers may provide next steps toward precision medicine.
    Type of Medium: Online Resource
    ISSN: 1046-6673 , 1533-3450
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
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  • 6
    In: Kidney Medicine, Elsevier BV, Vol. 4, No. 8 ( 2022-08), p. 100496-
    Type of Medium: Online Resource
    ISSN: 2590-0595
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
    detail.hit.zdb_id: 3009701-0
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  • 7
    In: Kidney Medicine, Elsevier BV, Vol. 5, No. 11 ( 2023-11), p. 100717-
    Type of Medium: Online Resource
    ISSN: 2590-0595
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
    detail.hit.zdb_id: 3009701-0
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  • 8
    Online Resource
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    Ovid Technologies (Wolters Kluwer Health) ; 2020
    In:  Clinical Journal of the American Society of Nephrology Vol. 15, No. 6 ( 2020-6), p. 784-793
    In: Clinical Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 15, No. 6 ( 2020-6), p. 784-793
    Abstract: Endothelin-1 is a potent endothelium-derived vasoconstrictor peptide implicated in the pathogenesis of hypertension, congestive heart failure, and inflammation, all of which are critical pathophysiologic features of CKD. Design, setting, participants, & measurements To test the hypothesis that plasma endothelin-1 levels are associated with increased risks of mortality and hospitalization in patients with chronic kidney failure, we measured plasma endothelin-1 levels in a prospective cohort of 794 individuals receiving maintenance hemodialysis. The primary outcomes were time to death and time to hospitalization. Results The median plasma endothelin-1 level was 2.02 (interquartile range, 1.57–2.71) pg/ml. During a median follow-up period of 28 (interquartile range, 21–29) months, 253 individuals (32%) died and 643 individuals (81%) were hospitalized at least once. In multivariable models adjusted for demographic, clinical, and laboratory variables, individuals in the highest quartile of plasma endothelin-1 had a 2.44-fold higher risk of death (hazard ratio, 2.44; 95% confidence interval, 1.61 to 3.70) and a 1.54-fold higher risk of hospitalization (hazard ratio, 1.54; 95% confidence interval, 1.19 to 1.99) compared with individuals in the lowest quartile. The Harrell C -statistic of the fully adjusted model increased from 0.73 to 0.74 after addition of natural log-transformed plasma endothelin-1 ( P 〈 0.001) for all-cause mortality, and increased from 0.608 to 0.614 after addition of natural log-transformed plasma endothelin-1 ( P =0.002) for hospitalization. Conclusions Higher plasma endothelin-1 is associated with adverse clinical events in patients receiving hemodialysis independent of previously described risk factors. Podcast This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_05_15_CJN11130919.mp3
    Type of Medium: Online Resource
    ISSN: 1555-9041 , 1555-905X
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
    detail.hit.zdb_id: 2216582-4
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  • 9
    In: Clinical Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 17, No. 1 ( 2022-01), p. 27-37
    Abstract: 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
    Type of Medium: Online Resource
    ISSN: 1555-9041 , 1555-905X
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 2216582-4
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  • 10
    In: Clinical Kidney Journal, Oxford University Press (OUP), Vol. 16, No. 1 ( 2023-01-24), p. 90-99
    Abstract: 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  & lt; .001) and diabetic kidney disease (P  & lt; .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.
    Type of Medium: Online Resource
    ISSN: 2048-8505 , 2048-8513
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 2656786-6
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