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.

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.

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.

Association of the Urine-to-Plasma Urea Ratio With CKD Progression.

RATIONALE & OBJECTIVES: The urine-to-plasma (U/P) ratio of urea is correlated with urine-concentrating capacity and associated with progression of autosomal dominant polycystic kidney disease. As a proposed biomarker of tubular function, we hypothesized that the U/P urea ratio would also be associated with progression of more common forms of chronic kidney disease (CKD). STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: 3,723 adults in the United States with estimated glomerular filtration rate (eGFR) of 20-70 mL/min/1.73 m2, enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study. EXPOSURE: U/P urea ratio, calculated from 24-hour urine collections and plasma samples at baseline. OUTCOME: Associations of U/P urea ratio with eGFR slope, initiation of kidney replacement therapy (KRT), and CKD progression, defined as 50% decline in eGFR or incident KRT. ANALYTICAL APPROACH: Multivariable linear mixed-effects models tested associations with eGFR slope. Cox proportional hazards models tested associations with dichotomous CKD outcomes. RESULTS: The median U/P urea ratio was 14.8 (IQR, 9.5-22.2). Compared with participants in the highest U/P urea ratio quintile, those in the lowest quintile had a greater eGFR decline by 1.06 mL/min/1.73 m2 per year (P < 0.001) over 7.0 (IQR, 3.0-11.0) years of follow-up observation. Each 1-SD lower natural log-transformed U/P urea ratio was independently associated with CKD progression (HR, 1.22 [95% CI, 1.12-1.33]) and incident KRT (HR, 1.22 [95% CI, 1.10-1.33]). Associations differed by baseline eGFR (P interaction = 0.009). Among those with an eGFR ≥30 mL/min/1.73 m2, each 1-SD lower in ln(U/P urea ratio) was independently associated with CKD progression (HR, 1.30 [95% CI, 1.18-1.45]), but this was not significant among those with eGFR <30 mL/min/1.73 m2 (HR, 1.00 [95% CI, 0.84-1.20]). LIMITATIONS: Possibility of residual confounding. Single baseline 24-hour urine collection for U/P urea ratio. CONCLUSIONS: In a large and diverse cohort of patients with common forms of CKD, U/P urea was independently associated with disease progression and incident kidney failure. Associations were not significant among those with advanced CKD at baseline.

Kidney Tubulointerstitial Fibrosis and Tubular Secretion.

RATIONALE & OBJECTIVE: Tubular secretion plays an important role in the efficient elimination of endogenous solutes and medications, and lower secretory clearance is associated with risk of kidney function decline. We evaluated whether histopathologic quantification of interstitial fibrosis and tubular atrophy (IFTA) is associated with lower tubular secretory clearance in persons undergoing kidney biopsy. STUDY DESIGN: Cross-sectional. SETTINGS & PARTICIPANTS: The Boston Kidney Biopsy Cohort is a study of persons undergoing native kidney biopsies for clinical indications. EXPOSURES: Semiquantitative score of IFTA reported by 2 trained pathologists. OUTCOMES: We measured plasma and urine concentrations of 9 endogenous secretory solutes using a targeted liquid chromatography/mass spectrometry assay. We used linear regression to test associations of urine-to-plasma ratios (UPRs) of these solutes with IFTA score after controlling for estimated glomerular filtration rate (eGFR) and albuminuria. RESULTS: Among 418 participants, mean age was 53 years, 51% were women, 64% were White, and 18% were Black. Mean eGFR was 50mL/min/1.73m2, and median urinary albumin-creatinine ratio was 819mg/g. Compared with individuals with≤25% IFTA, those with>50% IFTA had 12%-37% lower UPRs for all 9 secretory solutes. Adjusting for age, sex, race, eGFR, and urine albumin and creatinine levels attenuated the associations, yet a trend of lower secretion across groups remained statistically significant (P<0.05 for trend) for 7 of 9 solutes. A standardized composite secretory score incorporating UPR for all 9 secretory solutes using the min-max method showed similar results (P<0.05 for trend). LIMITATIONS: Single time point and spot measures of secretory solutes. CONCLUSIONS: Greater IFTA severity is associated with lower clearance of endogenous secretory solutes even after adjusting for eGFR and albuminuria.

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.

Replacement of traditional prothrombin time monitoring with the new Fiix prothrombin time increases the efficacy of warfarin without increasing bleeding. A review article.

The antithrombotic effect of vitamin K antagonists (VKA) depends on controlled lowering of the activity of factors (F) II and X whereas reductions in FVII and FIX play little role. PT-INR based monitoring, however, is highly influenced by FVII, which has the shortest half-life of vitamin K-dependent coagulation factors. Hence, variability in the anticoagulant effect of VKA may be partly secondary to an inherent flaw of the traditional monitoring test itself. The Fiix prothrombin time (Fiix-PT) is a novel test that is only sensitive to reductions in FII and FX and is intended to stabilize the VKA effect. Two clinical studies have now demonstrated that when warfarin is monitored with the Fiix-PT based normalized ratio (Fiix-NR) instead of PT-INR, anticoagulation is stabilized and less testing and fewer dose adjustments are needed. Furthermore, the relative risk of thromboembolism was reduced by 50-56% in these studies without an increase in major bleeding.

Cadherin-11, Sparc-related modular calcium binding protein-2, and Pigment epithelium-derived factor are promising non-invasive biomarkers of kidney fibrosis.

Kidney fibrosis constitutes the shared final pathway of nearly all chronic nephropathies, but biomarkers for the non-invasive assessment of kidney fibrosis are currently not available. To address this, we characterize five candidate biomarkers of kidney fibrosis: Cadherin-11 (CDH11), Sparc-related modular calcium binding protein-2 (SMOC2), Pigment epithelium-derived factor (PEDF), Matrix-Gla protein, and Thrombospondin-2. Gene expression profiles in single-cell and single-nucleus RNA-sequencing (sc/snRNA-seq) datasets from rodent models of fibrosis and human chronic kidney disease (CKD) were explored, and Luminex-based assays for each biomarker were developed. Plasma and urine biomarker levels were measured using independent prospective cohorts of CKD: the Boston Kidney Biopsy Cohort, a cohort of individuals with biopsy-confirmed semiquantitative assessment of kidney fibrosis, and the Seattle Kidney Study, a cohort of patients with common forms of CKD. Ordinal logistic regression and Cox proportional hazards regression models were used to test associations of biomarkers with interstitial fibrosis and tubular atrophy and progression to end-stage kidney disease and death, respectively. Sc/snRNA-seq data confirmed cell-specific expression of biomarker genes in fibroblasts. After multivariable adjustment, higher levels of plasma CDH11, SMOC2, and PEDF and urinary CDH11 and PEDF were significantly associated with increasing severity of interstitial fibrosis and tubular atrophy in the Boston Kidney Biopsy Cohort. In both cohorts, higher levels of plasma and urinary SMOC2 and urinary CDH11 were independently associated with progression to end-stage kidney disease. Higher levels of urinary PEDF associated with end-stage kidney disease in the Seattle Kidney Study, with a similar signal in the Boston Kidney Biopsy Cohort, although the latter narrowly missed statistical significance. Thus, we identified CDH11, SMOC2, and PEDF as promising non-invasive biomarkers of kidney fibrosis.

The Associations of Plasma Biomarkers of Inflammation With Histopathologic Lesions, Kidney Disease Progression, and Mortality-The Boston Kidney Biopsy Cohort Study.

BACKGROUND: Soluble tumor necrosis factor receptor (sTNFR)-1, sTNFR-2, YKL-40, monocyte chemoattractant protein (MCP)-1, and soluble urokinase plasminogen activator receptor (suPAR) have emerged as promising biomarkers of inflammation but have not been evaluated across diverse types of kidney diseases. METHODS: We measured these plasma biomarkers in 523 individuals enrolled into a prospective, observational cohort study of patients undergoing clinically indicated native kidney biopsy at 3 tertiary care hospitals. Two kidney pathologists adjudicated biopsy specimens for semiquantitative scores of histopathology. Proportional hazard models tested associations between biomarkers and risks of kidney disease progression (composite of ≥40% estimated glomerular filtration rate [eGFR] decline or end-stage kidney disease [ESKD]) and death. RESULTS: Mean eGFR was 56.4±36 ml/min per 1.73 m2 and the median proteinuria (interquartile range) was 1.6 (0.4, 3.9) g/g creatinine. The most common primary clinicopathologic diagnoses were proliferative glomerulonephritis (29.2%), nonproliferative glomerulopathy (18.1%), advanced glomerulosclerosis (11.3%), and diabetic kidney disease (11.1%). sTNFR-1, sTNFR-2, MCP-1, and suPAR were associated with tubulointerstitial and glomerular lesions. YKL-40 was not associated with any histopathologic lesions after multivariable adjustment. During a median follow-up of 65 months, 182 participants suffered kidney disease progression and 85 participants died. After multivariable adjustment, each doubling of sTNFR-1, sTNFR-2, YKL-40, and MCP-1 was associated with increased risks of kidney disease progression, with hazard ratios ranging from 1.21 to 1.47. Each doubling of sTNFR-2, YKL-40, and MCP-1 was associated with increased risks of death, with hazard ratios ranging from 1.33 to 1.45. suPAR was not significantly associated with kidney disease progression or death. CONCLUSIONS: sTNFR-1, sTNFR-2, YKL-40, MCP-1, and suPAR are associated with underlying histopathologic lesions and adverse clinical outcomes across a diverse set of kidney diseases.

Ignoring instead of chasing after coagulation factor VII during warfarin management: an interrupted time series study.

During warfarin management, variability in prothrombin time-based international normalized ratio (PT-INR) is caused, in part, by clinically inconsequential fluctuations in factor VII (FVII). The new factor II and X (Fiix)-prothrombin time (Fiix-PT) and Fiix-normalized ratio (Fiix-NR), unlike PT-INR, are only affected by reduced FII and FX. We assessed the incidence of thromboembolism (TE) and major bleeding (MB) in all 2667 patients on maintenance-phase warfarin managed at our anticoagulation management service during 30 months; 12 months prior to and 18 months after replacing PT-INR monitoring with Fiix-NR monitoring. Months 13 to 18 were predefined as transitional months. Using 2-segmented regression, a breakpoint in the monthly incidence of TE became evident 6 months after test replacement, that was followed by a 56% reduction in incidence (from 2.82% to 1.23% per patient-year; P = .019). Three-segmented regression did not find any significant trend in TE incidence (slope, +0.03) prior to test replacement; however, during months 13 to 18 and 19 to 30, the incidence of TE decreased gradually (slope, -0.12; R2 = 0.20; P = .007). The incidence of MB (2.79% per patient-year) did not differ. Incidence comparison during the 12-month Fiix and PT periods confirmed a statistically significant reduction (55-62%) in TE. Fiix monitoring reduced testing, dose adjustments, and normalized ratio variability and prolonged testing intervals and time in range. We conclude that ignoring FVII during Fiix-NR monitoring in real-world practice stabilizes the anticoagulant effect of warfarin and associates with a major reduction in TEs without increasing bleeding.