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Earlier identification of individuals at high risk of chronic kidney disease (CKD) may facilitate improved risk factor mitigation.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 mIn 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.Plasma concentrations of soluble TNFR-1 and TNFR-2 are consistently associated with incident CKD in nondiabetic community-living individuals in MESA and REGARDS.

Distribution of baseline KIM-1 values

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 (Pinteraction = 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.

Sensitivity analysis AFT model for DFS with imputation of KIM-1 levels below lower limit of detection (9.1 pg/mL)

Cardiovascular disease (CVD) is a major cause of mortality among people with diabetic kidney disease (DKD). The pathophysiology is inadequately explained by traditional CVD risk factors. The uremic solutes trimethylamine-N-oxide (TMAO) and asymmetric and symmetric dimethylarginine (ADMA, SDMA) have been linked to CVD in kidney failure with replacement therapy (KFRT), but data are limited in populations with diabetes and less severe kidney disease.Observational cohort.Random subcohort of 555 REGARDS (Reasons for Geographic and Racial Differences in Stroke) study participants with diabetes and estimated glomerular filtration rate (eGFR) 60 mL/min/1.73 mADMA, SDMA, and TMAO assayed by liquid chromatography-mass spectrometry in plasma and urine.Cardiovascular mortality (primary outcome); all-cause mortality and incident KFRT (secondary outcomes).Plasma concentrations and ratios of urine to plasma concentrations of ADMA, SDMA, and TMAO were tested for association with outcomes. Adjusted Cox regression models were fitted and hazard ratios of outcomes calculated per standard deviation and per doubling, and as interquartile comparisons.The mean baseline eGFR was 44 mL/min/1.73 mSingle cohort, restricted to patients with diabetes and eGFR 60 mL/min/1.73 mHigher plasma concentrations and lower ratios of urine to plasma concentrations of uremic solutes were independently associated with cardiovascular and all-cause mortality in DKD. Associations of ratios of urine to plasma concentrations with mortality suggest a connection between renal uremic solute clearance and CVD pathogenesis.

RATIONALE & OBJECTIVE: Determining whether a change in estimated glomerular filtration rate (eGFR) or albuminuria is clinically significant requires knowledge of short-term within-person variability of the measurements, which few studies have addressed in the setting of chronic kidney disease. STUDY DESIGN: Cross-sectional study with multiple collections over less than 4 weeks. SETTING & PARTICIPANTS: Clinically stable outpatients with chronic kidney disease (N = 50; mean age, 56.8 years; median eGFR, 40 mL/min/1.73 m(2); median urinary albumin-creatinine ratio (UACR), 173 mg/g). EXPOSURE: Repeat measurements from serially collected samples across 3 study visits. OUTCOMES: Measurements of urine albumin concentration (UAC), UACR, and plasma creatinine, cystatin C, β(2)-microglobulin (B2M), and beta trace protein (BTP). ANALYTICAL APPROACH: We calculated within-person coefficients of variation (CV(w)) values and corresponding reference change positive and negative (RCV(pos) and RCV(neg)) values using log-transformed measurements. RESULTS: Median CV(w) (RCV(pos); RCV(neg)) values of filtration markers were 5.4% (+16%; –14%) for serum creatinine, 4.1% (+12%; –11%) for cystatin C, 7.4% (+23%; –18%) for BTP, and 5.6% (+17%; –14%) for B2M. Results for albuminuria were 33.2% (+145%; –59%) for first-morning UAC, 50.6% (+276%; –73%) for random spot UAC, 32.5% (+141%; –58%) for first-morning UACR, and 29.7% (124%; –55%) for random spot UACR. CV(w) values for filtration markers were comparable across the range of baseline eGFRs. CV(w) values for UAC and UACR were comparable across the range of baseline albuminuria values. LIMITATIONS: Small sample size limits the ability to detect differences in variability across markers. Participants were recruited and followed up in a clinical and not research setting, so some preanalytical factors could not be controlled. CONCLUSIONS: eGFR markers appear to have relatively low short-term within-person variability, whereas variability in albuminuria appears to be high, making it difficult to distinguish random variability from meaningful biologic changes.

Few investigations have evaluated the incremental usefulness of tubular injury biomarkers for improved prediction of chronic kidney disease (CKD) progression. As such, we measured urinary kidney injury molecule-1, neutrophil gelatinase–associated lipocalin, N -acetyl-s-D-glucosaminidase and liver fatty acid binding protein under highly standardized conditions among 2466 enrollees of the prospective Chronic Renal Insufficiency Cohort Study. During 9433 person-years of follow-up, there were 581 cases of CKD progression defined as incident end-stage renal disease or halving of the estimated glomerular filtration rate. Levels of the urine injury biomarkers, normalized for urine creatinine, were strongly associated with CKD progression in unadjusted Cox proportional hazard models with hazard ratios in the range of 7 to 15 comparing the highest with the lowest quintiles. However, after controlling for the serum creatinine–based estimated glomerular filtration rate and urinary albumin/creatinine ratio, none of the normalized biomarkers was independently associated with CKD progression. None of the biomarkers improved on the high (0.89) C-statistic for the base clinical model. Thus, among patients with CKD, risk prediction with a clinical model that includes the serum creatinine–based estimated glomerular filtration rate and the urinary albumin/creatinine ratio is not improved on with the addition of renal tubular injury biomarkers.

Background: The urinary biomarkers of tubular injury ((urine neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1)) can indicate acute kidney injury before reductions in estimated glomerular filtration rate (eGFR) are clinically detectable. Whether elevations of these markers are associated with future risk of kidney disease has not been investigated. Methods: We studied the association of urinary NGAL and KIM-1 with kidney function decline in a 1:1 ratio case-control study among 686 MESA participants. NGAL and KIM-1 were measured at baseline (standardized for urinary creatinine) and expressed both as continuous and in deciles. eGFR was estimated by cystatin C. Cases were defined as persons with eGFR>60 ml/min/1.73m 2 who subsequently developed incident CKD (defined as eGFR 1ml/min/year) and/or had rapid kidney function decline (RKFD, ≥3ml/min/1.73m 2 /year) by the MESA year 5 visit. Of the 343 cases, 145 had incident CKD, 141 had RKFD and 57 had both. Controls were matched for age, gender, race, diabetes, and baseline eGFR. We adjusted for age, hypertension and presence of albuminuria (ACR ≥30 mg/g). Results: Higher levels of KIM-1 were significantly associated with kidney function decline, and these associations were strongest for the top decile compared to lowest decile. Presence of albuminuria only minimally attenuated the findings. NGAL levels were not associated with kidney function decline. (Table) Model OR (95%CI) for Incident CKD and/or Rapid Kidney Function Decline KIM-1 (pg/ml) * KIM-1-Cr Ratio * (pg/mg) KIM-1 ≥ 927 pg/ml (Top Decile) NGAL (ng/ml) * NGAL-Cr Ratio * (ng/mg) NGAL ≥ 36 ng/ml (Top Decile) Age Adjusted 1.15 (1.02, 1.29) 1.17 (1.02, 1.34) 2.09 (1.21, 3.62) 1.04 (0.99, 1.10) 1.03 (0.98, 1.09) 1.63 (0.96, 2.78) Age + HTN Adjusted 1.15 (1.03, 1.29) 1.16 (1.01, 1.33) 2.13 (1.22, 3.70) 1.04 (0.99, 1.10) 1.03 (0.98, 1.09) 1.58 (0.93, 2.71) + ACR ≥ 30mg/g 1.15 (1.02, 1.29) 1.13 (0.98, 1.30) 2.02 (1.15, 3.56) 1.04 (0.99, 1.10) 1.03 (0.97, 1.08) 1.55 (0.89, 2.70) * Per doubling. Top decile is compared to lowest decile Conclusions: KIM-1, a marker of tubular injury, is associated with future risk of kidney disease independent of albuminuria. Our findings suggest that urinary biomarkers of tubular injury are a promising tool for identifying persons at risk for CKD.