Plasma Kidney Injury Molecule-1 for Preoperative Prediction of Renal Cell Carcinoma Versus Benign Renal Masses, and Association With Clinical Outcomes.

PURPOSE: Both clear cell and papillary renal cell carcinomas (RCCs) overexpress kidney injury molecule-1 (KIM-1). We investigated whether plasma KIM-1 (pKIM-1) may be a useful risk stratification tool among patients with suspicious renal masses. METHODS: Prenephrectomy pKIM-1 was measured in two independent cohorts of patients with renal masses. Cohort 1, from the prospective K2 trial, included 162 patients found to have clear cell RCC (cases) and 162 patients with benign renal masses (controls). Cohort 2 included 247 patients with small (cT1a) renal masses from an academic biorepository, of whom 184 had RCC. We assessed the relationship between pKIM-1, surgical pathology, and clinical outcomes. RESULTS: In Cohort 1, pKIM-1 distinguished RCC versus benign masses with area under the receiver operating curve (AUC-ROC, 0.81 [95% CI, 0.76 to 0.86]). In Cohort 2 (cT1a only), pKIM-1 distinguished RCC versus benign masses (AUC-ROC, 0.74 [95% CI, 0.67 to 0.80]) and the addition of pKIM-1 to an established nomogram for predicting malignancy improved the model AUC-ROC (0.65 [95% CI, 0.57 to 0.74] v 0.78 [95% CI, 0.72 to 0.85]). A pKIM-1 cutpoint identified using Cohort 2 demonstrated sensitivity of 92.5% and specificity of 60% for identifying RCC in Cohort 1. In long-term follow-up of RCC cases (Cohort 1), higher prenephrectomy pKIM-1 was associated with worse metastasis-free survival (multivariable MFS hazard ratio [HR] 1.29 per unit increase in log pKIM-1, 95% CI, 1.10 to 1.53) and overall survival (multivariable OS HR 1.31 per unit increase in log pKIM-1, 95% CI, 1.10 to 1.54). In long-term follow-up of Cohort 2, no metastatic events occurred, consistent with the favorable prognosis of resected cT1a RCC. CONCLUSION: Among patients with renal masses, pKIM-1 is associated with malignant pathology, worse MFS, and risk of death. pKIM-1 may be useful for selecting patients with renal masses for intervention versus surveillance.

Plasma Biomarkers and Incident CKD Among Individuals Without Diabetes.

Rationale & Objective: Biomarkers of kidney disease progression have been identified in individuals with diabetes and underlying chronic kidney disease (CKD). Whether or not these markers are associated with the development of CKD in a general population without diabetes or CKD is not well established. Study Design: Prospective observational cohort. Setting & Participants: In the Atherosclerosis Risk in Communities) study, 948 participants were studied. Exposures: The baseline plasma biomarkers of kidney injury molecule-1 (KIM-1), monocyte chemoattractant protein-1 (MCP-1), soluble urokinase plasminogen activator receptor (suPAR), tumor necrosis factor receptor 1 (TNFR-1), tumor necrosis factor receptor 2 (TNFR-2), and human cartilage glycoprotein-39 (YKL-40) measured in 1996-1998. Outcome: Incident CKD after 15 years of follow-up defined as ≥40% estimated glomerular filtration rate decline to <60 mL/min/1.73 m2 or dialysis dependence through United States Renal Data System linkage. Analytical Approach: Logistic regression and C statistics. Results: There were 523 cases of incident CKD. Compared with a random sample of 425 controls, there were greater odds of incident CKD per 2-fold higher concentration of KIM-1 (OR, 1.49; 95% CI, 1.25-1.78), suPAR (OR, 2.57; 95% CI, 1.74-3.84), TNFR-1 (OR, 2.20; 95% CI, 1.58-3.09), TNFR-2 (OR, 2.03; 95% CI, 1.37-3.04). After adjustment for all biomarkers, KIM-1 (OR, 1.42; 95% CI, 1.19-1.71), and suPAR (OR, 1.86; 95% CI, 1.18-2.92) remained associated with incident CKD. Compared with traditional risk factors, the addition of all 6 biomarkers improved the C statistic from 0.695-0.731 (P < 0.01) and using the observed risk of 12% for incident CKD, the predicted risk gradient changed from 5%-40% (for the 1st-5th quintile) to 4%-44%. Limitations: Biomarkers and creatinine were measured at one time point. Conclusions: Higher levels of KIM-1, suPAR, TNFR-1, and TNFR-2 were associated with higher odds of incident CKD among individuals without diabetes. Plain-Language Summary: For people with diabetes or kidney disease, several biomarkers have been shown to be associated with worsening kidney disease. Whether these biomarkers have prognostic significance in people without diabetes or kidney disease is less studied. Using the Atherosclerosis Risk in Communities study, we followed individuals without diabetes or kidney disease for an average of 15 years after biomarker measurement to see if these biomarkers were associated with the development of kidney disease. We found that elevated levels of KIM-1, suPAR, TNFR-1, and TNFR-2 were associated with the development of kidney disease. These biomarkers may help identify individuals who would benefit from interventions to prevent the development of kidney disease.

Autophagy as a Therapeutic Target for Chronic Kidney Disease and the Roles of TGF-ß1 in Autophagy and Kidney Fibrosis.

Autophagy is a lysosomal protein degradation system that eliminates cytoplasmic components such as protein aggregates, damaged organelles, and even invading pathogens. Autophagy is an evolutionarily conserved homoeostatic strategy for cell survival in stressful conditions and has been linked to a variety of biological processes and disorders. It is vital for the homeostasis and survival of renal cells such as podocytes and tubular epithelial cells, as well as immune cells in the healthy kidney. Autophagy activation protects renal cells under stressed conditions, whereas autophagy deficiency increases the vulnerability of the kidney to injury, resulting in several aberrant processes that ultimately lead to renal failure. Renal fibrosis is a condition that, if chronic, will progress to end-stage kidney disease, which at this point is incurable. Chronic Kidney Disease (CKD) is linked to significant alterations in cell signaling such as the activation of the pleiotropic cytokine transforming growth factor-ß1 (TGF-ß1). While the expression of TGF-ß1 can promote fibrogenesis, it can also activate autophagy, which suppresses renal tubulointerstitial fibrosis. Autophagy has a complex variety of impacts depending on the context, cell types, and pathological circumstances, and can be profibrotic or antifibrotic. Induction of autophagy in tubular cells, particularly in the proximal tubular epithelial cells (PTECs) protects cells against stresses such as proteinuria-induced apoptosis and ischemia-induced acute kidney injury (AKI), whereas the loss of autophagy in renal cells scores a significant increase in sensitivity to several renal diseases. In this review, we discuss new findings that emphasize the various functions of TGF-ß1 in producing not just renal fibrosis but also the beneficial TGF-ß1 signaling mechanisms in autophagy.

Plasma Biomarkers as Risk Factors for Incident CKD.

Introduction: Earlier identification of individuals at high risk of chronic kidney disease (CKD) may facilitate improved risk factor mitigation. Methods: We evaluated the association of novel plasma biomarkers with incident CKD using a case-cohort design in participants without diabetes and with baseline estimated glomerular filtration rate (eGFR) ≥ 60 ml/min per 1.73 m2 in the Multi-Ethnic Study of Atherosclerosis (MESA) and Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohorts. Incident CKD was defined as development of eGFR < 60 ml/min per 1.73 m2 and ≥40% decline in eGFR from baseline. We measured plasma markers of inflammation/fibrosis-soluble tumor necrosis factor receptors (TNFRs) 1 and 2 (TNFR-1 and TNFR-2), monocyte chemotactic protein-1 (MCP-1), chitinase 3-like protein 1 (YKL-40), and soluble urokinase-type plasminogen activator receptor (suPAR)-and tubular injury (kidney injury molecule 1 [KIM-1]). Cox regression models weighted for the case-cohort design were used to estimate hazard ratios (HRs) of incident CKD after adjustment for CKD risk factors, eGFR, and albuminuria. Results: In MESA (median follow-up of 9.2 years), there were 497 individuals in the random subcohort and 163 incident CKD cases. In REGARDS (median follow-up of 9.4 years), there were 497 individuals in the random subcohort and 497 incident CKD cases. Each 2-fold higher plasma KIM-1 (adjusted HR 1.38 [95% CI 1.05-1.81]), suPAR (1.96 [1.10-3.49]), TNFR-1 (1.65 [1.04-2.62]), TNFR-2 (2.02 [1.21-3.38]), and YKL-40 (1.38 [1.09-1.75]) concentrations were associated with incident CKD in MESA. In REGARDS, TNFR-1 (1.99 [1.43-2.76]) and TNFR-2 (1.76 [1.22-2.54]) were associated with incident CKD. Conclusion: Plasma concentrations of soluble TNFR-1 and TNFR-2 are consistently associated with incident CKD in nondiabetic community-living individuals in MESA and REGARDS.

Deletion of STAT3 from Foxd1 cell population protects mice from kidney fibrosis by inhibiting pericytes trans-differentiation and migration.

Signal transduction and activator of transcription 3 (STAT3) is a key transcription factor implicated in the pathogenesis of kidney fibrosis. Although Stat3 deletion in tubular epithelial cells is known to protect mice from fibrosis, vFoxd1 cells remains unclear. Using Foxd1-mediated Stat3 knockout mice, CRISPR, and inhibitors of STAT3, we investigate its function. STAT3 is phosphorylated in tubular epithelial cells in acute kidney injury, whereas it is expanded to interstitial cells in fibrosis in mice and humans. Foxd1-mediated deletion of Stat3 protects mice from folic-acid- and aristolochic-acid-induced kidney fibrosis. Mechanistically, STAT3 upregulates the inflammation and differentiates pericytes into myofibroblasts. STAT3 activation increases migration and profibrotic signaling in genome-edited, pericyte-like cells. Conversely, blocking Stat3 inhibits detachment, migration, and profibrotic signaling. Furthermore, STAT3 binds to the Collagen1a1 promoter in mouse kidneys and cells. Together, our study identifies a previously unknown function of STAT3 that promotes kidney fibrosis and has therapeutic value in fibrosis.

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.

Corrigendum: Immunological Impact of a Gluten-Free Dairy-Free Diet in Children With Kidney Disease: A Feasibility Study.

[This corrects the article DOI: 10.3389/fimmu.2021.624821.].

Variability in CKD Biomarker Studies: Soluble Urokinase Plasminogen Activator Receptor (suPAR) and Kidney Disease Progression in the Chronic Kidney Disease in Children (CKiD) Study.

RATIONALE & OBJECTIVE: Biomarker studies are important for generating mechanistic insight and providing clinically useful predictors of chronic kidney disease (CKD) progression. However, variability across studies can often muddy the evidence waters. Here we evaluated real-world variability in biomarker studies using two published studies, independently conducted, of the novel plasma marker soluble urokinase-type plasminogen activator receptor (suPAR) for predicting CKD progression in children with CKD. STUDY DESIGN: A comparison of 2 prospective cohort studies. SETTING & PARTICIPANTS: 541 children from the Chronic Kidney Disease in Children (CKiD) study, median age 12 years, median glomerular filtration rate (GFR) of 54 mL/min/1.73m2. OUTCOME: The first occurrence of either a 50% decline in GFR from baseline or incident end-stage kidney disease. ANALYTICAL APPROACH: The suPAR plasma marker was measured using the Quantikine ELISA immunoassay in the first study and Meso Scale Discovery (MSD) platform in the second. The analytical approaches varied. We used suPAR data from the 2 assays and mimicked each analytical approach in an overlapping subset. RESULTS: We found that switching assays had the greatest impact on inferences, resulting in a 38% to 66% change in the magnitude of the effect estimates. Covariate and modeling choices resulted in an additional 8% to 40% variability in the effect estimate. The cumulative variability led to different inferences despite using a similar sample of CKiD participants and addressing the same question. LIMITATIONS: The estimated variability does not represent optimal repeatability but instead illustrates real-world variability that may be present in the CKD biomarker literature. CONCLUSIONS: Our results highlight the importance of validation, avoiding conclusions based on P value thresholds, and providing comparable metrics. Further transparency of data and equal weighting of negative and positive findings in explorations of novel biomarkers will allow investigators to more quickly weed out less promising biomarkers.

Therapeutic silencing of SMOC2 prevents kidney function loss in mouse model of chronic kidney disease.

Chronic kidney disease (CKD) is associated with substantial morbidity and mortality. We developed a mouse model that mimics human CKD with inflammation, extracellular matrix deposition, tubulointerstitial fibrosis, increased proteinuria, and associated reduction in glomerular filtration rate over time. Using this model, we show that genetic deficiency of SMOC2 or therapeutic silencing of SMOC2 with small interfering RNAs (siRNAs) after disease onset significantly ameliorates inflammation, fibrosis, and kidney function loss. Mechanistically, we found that SMOC2 promotes fibroblast to myofibroblast differentiation by activation of diverse cellular signaling pathways including MAPKs, Smad, and Akt. Thus, targeting SMOC2 therapeutically offers an approach to prevent fibrosis progression and CKD after injury.

Urine Biomarkers of Kidney Tubule Health, Injury, and Inflammation are Associated with Progression of CKD in Children.

BACKGROUND: Novel urine biomarkers may improve identification of children at greater risk of rapid kidney function decline, and elucidate the pathophysiology of CKD progression. METHODS: We investigated the relationship between urine biomarkers of kidney tubular health (EGF and α-1 microglobulin), tubular injury (kidney injury molecule-1; KIM-1), and inflammation (monocyte chemoattractant protein-1 [MCP-1] and YKL-40) and CKD progression. The prospective CKD in Children Study enrolled children aged 6 months to 16 years with an eGFR of 30-90ml/min per 1.73m2. Urine biomarkers were assayed a median of 5 months [IQR: 4-7] after study enrollment. We indexed the biomarker to urine creatinine by dividing the urine biomarker concentration by the urine creatinine concentration to account for the concentration of the urine. The primary outcome was CKD progression (a composite of a 50% decline in eGFR or kidney failure) during the follow-up period. RESULTS: Overall, 252 of 665 children (38%) reached the composite outcome over a median follow-up of 6.5 years. After adjustment for covariates, children with urine EGF concentrations in the lowest quartile were at a seven-fold higher risk of CKD progression versus those with concentrations in the highest quartile (fully adjusted hazard ratio [aHR], 7.1; 95% confidence interval [95% CI], 3.9 to 20.0). Children with urine KIM-1, MCP-1, and α-1 microglobulin concentrations in the highest quartile were also at significantly higher risk of CKD progression versus those with biomarker concentrations in the lowest quartile. Addition of the five biomarkers to a clinical model increased the discrimination and reclassification for CKD progression. CONCLUSIONS: After multivariable adjustment, a lower urine EGF concentration and higher urine KIM-1, MCP-1, and α-1 microglobulin concentrations were each associated with CKD progression in children.

Immunological Impact of a Gluten-Free Dairy-Free Diet in Children With Kidney Disease: A Feasibility Study.

Kidney disease affects 10% of the world population and is associated with increased mortality. Steroid-resistant nephrotic syndrome (SRNS) is a leading cause of end-stage kidney disease in children, often failing standard immunosuppression. Here, we report the results of a prospective study to investigate the immunological impact and safety of a gluten-free and dairy-free (GF/DF) diet in children with SRNS. The study was organized as a four-week summer camp implementing a strict GF/DF diet with prospective collection of blood, urine and stool in addition to whole exome sequencing WES of DNA of participants. Using flow cytometry, proteomic assays and microbiome metagenomics, we show that GF/DF diet had a major anti-inflammatory effect in all participants both at the protein and cellular level with 4-fold increase in T regulatory/T helper 17 cells ratio and the promotion of a favorable regulatory gut microbiota. Overall, GF/DF can have a significant anti-inflammatory effect in children with SRNS and further trials are warranted to investigate this potential dietary intervention in children with SRNS.

Endothelin-1 and Parameters of Systolic Blood Pressure in Hemodialysis.

BACKGROUND: Hypertension is common in hemodialysis (HD) patients. Increased blood pressure (BP) variability, particularly higher and lower extremes, is associated with adverse outcomes. We explored the association of endothelin-1 (ET-1), a potent vasoconstrictor, with different BP parameters (pre-HD, intra-HD, and post-HD) during HD in a contemporary patient cohort. METHODS: This study uses the DaVita Biorepository, a longitudinal prospective cohort study with quarterly collection of clinical data and biospecimens. Unadjusted and adjusted linear mixed effects regression models were fit to determine association of pre-HD ET-1 (log-transformed and quartiles) with HD-related systolic BP (SBP) parameters (pre-HD, nadir intra-HD, and post-HD). As ET-1 was measured at baseline, analyses were restricted to 1 year of follow-up. RESULTS: Among 769 participants, mean age was 52 years, 42% were females, and 41% were Black. Mean pre-HD SBP was 152 (±28) mm Hg and mean ET-1 concentration was 2.3 (±1.2) ng/ml. In fully adjusted models, each unit increase in SD of log-transformed ET-1 was associated with a 2.7 (95% confidence interval [CI] 1.5, 4.0) mm Hg higher pre-SBP; 1.6 (95% CI 0.9, 2.3) mm Hg higher nadir SBP; and 2.0 (95% CI 1.1, 2.9) mm Hg higher post-SBP. Each SD increase in log-transformed ET-1 was associated with 21% higher odds of experiencing intradialytic hypertension (odds ratio 1.21; 95% CI 1.10-1.34). CONCLUSIONS: Higher baseline ET-1 levels are independently associated with higher SBP and higher odds of intradialytic hypertension. These results highlight a potential role for ET-1 in BP control in HD patients and raise the possibility of ET-1 antagonism as a therapeutic target.

KIM-1 mediates fatty acid uptake by renal tubular cells to promote progressive diabetic kidney disease.

Tubulointerstitial abnormalities are predictive of the progression of diabetic kidney disease (DKD), and their targeting may be an effective means for prevention. Proximal tubular (PT) expression of kidney injury molecule (KIM)-1, as well as blood and urinary levels, are increased early in human diabetes and can predict the rate of disease progression. Here, we report that KIM-1 mediates PT uptake of palmitic acid (PA)-bound albumin, leading to enhanced tubule injury with DNA damage, PT cell-cycle arrest, interstitial inflammation and fibrosis, and secondary glomerulosclerosis. Such injury can be ameliorated by genetic ablation of the KIM-1 mucin domain in a high-fat-fed streptozotocin mouse model of DKD. We also identified TW-37 as a small molecule inhibitor of KIM-1-mediated PA-albumin uptake and showed in vivo in a kidney injury model in mice that it ameliorates renal inflammation and fibrosis. Together, our findings support KIM-1 as a new therapeutic target for DKD.

Plasma KIM-1 Is Associated with Recurrence Risk after Nephrectomy for Localized Renal Cell Carcinoma: A Trial of the ECOG-ACRIN Research Group (E2805).

PURPOSE: No circulating biomarkers are currently available to identify patients at highest risk of recurrence after nephrectomy for renal cell carcinoma (RCC). Kidney injury molecule-1 (KIM-1) is overexpressed in RCC and its ectodomain circulates in plasma. We investigated whether plasma KIM-1 is a prognostic biomarker in patients with localized RCC after nephrectomy. EXPERIMENTAL DESIGN: The ECOG-ACRIN E2805 (ASSURE) trial evaluated adjuvant sunitinib, sorafenib, or placebo in resected high-risk RCC. KIM-1 levels were measured from banked plasma at trial enrollment 4-12 weeks after nephrectomy. Lognormal accelerated failure time models were used to test for association between KIM-1 and disease-free survival (DFS) as well as overall survival (OS). RESULTS: Plasma from 418 patients was analyzed. Higher post-nephrectomy KIM-1 was associated with worse DFS across all study arms after adjustment for Fuhrman grade, T stage, N stage, and tumor histology [survival time ratio 0.56 for 75th vs. 25th percentile of KIM-1; 95% confidence interval (CI), 0.42-0.73; P < 0.001]. The association between KIM-1 and DFS was stronger among patients with pathologic nodal involvement (P interaction = 0.0086). The addition of post-nephrectomy KIM-1 improved the concordance of clinical prognostic models [Stage, Size, Grade, and Necrosis (SSIGN) concordance 0.57 vs. 0.43, P = 0.05; UCLA International Staging System (UISS) concordance 0.60 vs. 0.40, P = 0.0005]. Higher post-nephrectomy KIM-1 was also associated with worse OS after multivariable adjustment (survival time ratio 0.71 for 75th vs. 25th percentile of KIM-1; 95% CI, 0.56-0.91; P < 0.001). CONCLUSIONS: Post-nephrectomy plasma KIM-1 is associated with DFS and OS in RCC, and may be a biomarker for microscopic residual disease.

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.

Serum Concentrations of Per- and Polyfluoroalkyl Substances and Risk of Renal Cell Carcinoma.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are highly persistent chemicals that have been detected in the serum of over 98% of the US population. Studies among highly exposed individuals suggest an association with perfluorooctanoic acid (PFOA) exposure and kidney cancer. It remains unclear whether PFOA or other PFAS are renal carcinogens or if they influence risk of renal cell carcinoma (RCC) at concentrations observed in the general population. METHODS: We measured prediagnostic serum concentrations of PFOA and 7 additional PFAS in 324 RCC cases and 324 individually matched controls within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Multivariable conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CIs) relating serum PFAS concentrations and RCC risk. Individual PFAS were modeled continuously (log2-transformed) and categorically, with adjustment for kidney function and additional potential confounders. All statistical tests were 2-sided. RESULTS: We observed a positive association with RCC risk for PFOA (doubling in serum concentration, ORcontinuous = 1.71, 95% CI = 1.23 to 2.37, P = .002) and a greater than twofold increased risk among those in the highest quartile vs the lowest (OR = 2.63, 95% CI = 1.33 to 5.20, Ptrend = .007). The association with PFOA was similar after adjustment for other PFAS (ORcontinuous = 1.68, 95% CI = 1.07 to 2.63, P = .02) and remained apparent in analyses restricted to individuals without evidence of diminished kidney function and in cases diagnosed 8 or more years after phlebotomy. CONCLUSIONS: Our findings add substantially to the weight of evidence that PFOA is a renal carcinogen and may have important public health implications for the many individuals exposed to this ubiquitous and highly persistent chemical.

Association of Multiple Plasma Biomarker Concentrations with Progression of Prevalent Diabetic Kidney Disease: Findings from the Chronic Renal Insufficiency Cohort (CRIC) Study.

BACKGROUND: Although diabetic kidney disease is the leading cause of ESKD in the United States, identifying those patients who progress to ESKD is difficult. Efforts are under way to determine if plasma biomarkers can help identify these high-risk individuals. METHODS: In our case-cohort study of 894 Chronic Renal Insufficiency Cohort Study participants with diabetes and an eGFR of <60 ml/min per 1.73 m2 at baseline, participants were randomly selected for the subcohort; cases were those patients who developed progressive diabetic kidney disease (ESKD or 40% eGFR decline). Using a multiplex system, we assayed plasma biomarkers related to tubular injury, inflammation, and fibrosis (KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40). Weighted Cox regression models related biomarkers to progression of diabetic kidney disease, and mixed-effects models estimated biomarker relationships with rate of eGFR change. RESULTS: Median follow-up was 8.7 years. Higher concentrations of KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40 were each associated with a greater risk of progression of diabetic kidney disease, even after adjustment for established clinical risk factors. After accounting for competing biomarkers, KIM-1, TNFR-2, and YKL-40 remained associated with progression of diabetic kidney disease; TNFR-2 had the highest risk (adjusted hazard ratio, 1.61; 95% CI, 1.15 to 2.26). KIM-1, TNFR-1, TNFR-2, and YKL-40 were associated with rate of eGFR decline. CONCLUSIONS: Higher plasma levels of KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40 were associated with increased risk of progression of diabetic kidney disease; TNFR-2 had the highest risk after accounting for the other biomarkers. These findings validate previous literature on TNFR-1, TNFR-2, and KIM-1 in patients with prevalent CKD and provide new insights into the influence of suPAR and YKL-40 as plasma biomarkers that require validation.

Low Complement C4 Predicts Improvement of Kidney Function After Direct-Acting Antiviral Therapy for Hepatitis C Virus.

Direct-acting antiviral therapies (DAAs) may improve kidney function and proteinuria in certain patients with hepatitis C infection (HCV) and chronic kidney disease (CKD). To improve our understanding of HCV-mediated kidney dysfunction, we aimed to evaluate the baseline predictors of improvement in proteinuria after DAAs in a single-arm, pilot, clinical trial of ledipasvir 90 mg/sofosbuvir 400 mg once daily for patients with HCV genotype 1 or 4 infection and proteinuric CKD (≥300 mg proteinuria per gram creatinine). Plasma biomarkers of complement system (C3 and C4) and urinary kidney injury biomarkers were measured at baseline, 8 weeks on treatment, 12 weeks following treatment, and 1 year following treatment. We then conducted a retrospective cohort study of patients at Partners Healthcare who had baseline complement component 4 (C4) measured before DAAs for HCV and evaluated the change in estimated glomerular filtration rate (eGFR) before and after therapy. Ten patients with HCV and proteinuric CKD were enrolled in the trial. The mean age was 64 years, 70% male, 70% white, and 30% black. Baseline creatinine was 1.25 mg/dL (SD 0.44), eGFR was 65 mL/min/1.73 m2 (SD 29), and proteinuria was 0.98 g/g creatinine (SD 0.7). Sustained virologic response at 12 weeks was achieved by 80% of patients. Patients with low baseline C4 had improved proteinuria, urinary neutrophil gelatinase-associated lipocalin, and interleukin-18 after ledipasvir and sofosbuvir treatment. The retrospective study included 50 patients with CKD and HCV. Twenty patients (40%) had low baseline C4; these patients significantly improved their eGFR (+3.4 ± 11.2 mL/min/1.73 m2) compared to those with normal baseline C4 (-4.4 ± 12.2 mL/min/1.73 m2; P = 0.028). Conclusion: Low C4 may be a marker of kidney dysfunction that improves with DAA therapy.

Plasma Endothelin-1 and Risk of Death and Hospitalization in Patients Undergoing Maintenance Hemodialysis.

BACKGROUND AND OBJECTIVES: 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.