Effects of race distance and probiotics intervention on kidney, muscle, and gut injury and inflammation biomarker responses during running.

Muscle and kidney injury in endurance athletes is worrying for health, and its relationship with physical external workload (eWL) needs to be explored. This study aimed to analyze which eWL indexes have more influence on muscle and kidney injury biomarkers. 20 well-trained trail runners (age = 38.95 ± 9.99 years) ran ~35.27 km (thermal-index = 23.2 ± 1.8 °C, cumulative-ascend = 1815 m) wearing inertial measurement units (IMU) in six different spots (malleolus peroneus [MPleft/MPright], vastus lateralis [VLleft/VLright], lumbar [L1–L3], thoracic [T2–T4]) for eWL measuring using a special suit. Muscle and kidney injury serum biomarkers (creatin-kinase [sCK], creatinine (sCr), ureic-nitrogen (sBUN), albumin [sALB]) were assessed pre-, -post0h and post24h. A principal component (PC) analysis was performed in each IMU spot to extract the main variables that could explain eWL variance. After extraction, PC factors were inputted in multiple regression analysis to explain biomarkers delta change percentage (Δ%). sCK, sCr, sBUN, sALB presented large differences (p < 0.05) between measurements (pre < post24h < post0h). PC’s explained 77.5–86.5% of total eWL variance. sCK Δ% was predicted in 40 to 47% by L1–L3 and MPleft; sCr Δ% in 27% to 45% by L1–L3 and MPleft; and sBUN Δ% in 38%-40% by MPright and MPleft. These findings could lead to a better comprehension of how eWL (impacts, player load and approximated entropy) could predict acute kidney and muscle injury. These findings support the new hypothesis of mechanical kidney injury during trail running based on L1–L3 external workload data.

APOL1 Genotype and Glomerular and Tubular Kidney Injury in Women With HIV

The use of kidney function and injury markers for early detection of drug-related glomerular or tubular kidney injury in infants, children and adolescents requires age-specific data on reference intervals in a pediatric healthy population. This study characterizes serum values for eight kidney function and injury markers in healthy infants, children and adolescents. A single center prospective observational study was conducted between December 2018 and June 2019. Serum samples from 142 healthy infants, children and adolescents aged between 0 and≤15 years were collected. Statistical analyses for eight markers (albumin (ALB), β2-microglobulin (B2M), β-trace protein (BTP), creatinine (SCR), cystatin C (CYSC), kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), uromodulin (URO)) were performed to obtain reference intervals and associations with age, sex and weight were investigated (Pearson correlation, linear and piecewise regression). ALB and SCR increased with age (p<0.01), whereas B2M, BTP and KIM-1 values decreased with advancing age (p<0.05) in this healthy pediatric study population. CYSC showed dependency on sex (lower concentration in females) and decreased with age until reaching approximately 1.8 years; thereafter an increase with age was seen. NGAL and URO did not show any age-dependency. This study provides age appropriate reference intervals for key serum kidney function and injury markers determined in healthy infants, children and adolescents. Such reference intervals facilitate the interpretation of changes in kidney function and injury markers in daily practice, and allow early detection of glomerular and tubular injury in infancy, childhood and adolescence.

Occupational heat stress among wildland firefighters (WFFs) performing arduous work or working in hot work environments may cause kidney dysfunction and injury. Kidney function and injury biomarkers (serum and urine) were measured among 39 WFFs pre- and post-fire season in 2018-2019. The same biomarkers were measured in 19 of these 39 WFFs over 3 days during a 2019 mid-season fire incident. Median differences in biomarker concentrations across the fire season and across the mid-season incident were evaluated using the Sign test. The primary outcome of interest was the cystatin C-based estimated glomerular filtration rate (eGFRcys). The eGFRcys decreased (median difference = -5 mL/min/1.73 m2; interquartile range [IQR] = -8, -2 mL/min/1.73 m2; p = 0.008), and 53% of participants lost ≥ 2% of their body weight across the first day of the mid-season fire incident. Median eGFRcys did not decrease across the fire season (median difference = 0 mL/min/1.73 m2; IQR = -5, 5 mL/min/1.73 m2; p = 0.52). The albumin-creatinine ratio and the ratios of urine kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin concentrations to urine osmolality increased across ≥ 1 day during the mid-season incident. A temporary decrease in kidney function and changes in biomarkers of kidney injury were observed during a wildland fire incident. Additional research is warranted to confirm these findings, assess associations with occupational heat stress, and determine whether persistent, clinically relevant kidney injury and dysfunction occur among WFFs over time. The findings also support the need for continued efforts to promote optimal hydration of WFFs.

Evaluation of acute kidney injury in dogs with complicated or uncomplicated Babesia rossi infection

ACUTE KIDNEY INJURY (AKI) is a common clinical condition that is associated with significantly high rates of morbidity and mortality particularly in critically ill patients (1, 2, 10, 18). Despite fundamental advances in understanding the etiology and pathophysiology of AKI the current therapeutic approaches remain limited to supportive measures (e.g., dialysis). Treatment for AKI is confounded by several variables including patient demographics, severity of AKI, and AKI associated with complex medical and surgical interventions. Therefore, there is a growing need to provide timely and accurate diagnosis to allow for the implementation of potentially novel therapeutic interventions to overcome AKI. Studies in animal models of AKI have highlighted the therapeutic potential for a number of interventions. However, translation of these potential therapies to humans has yielded inconclusive and equivocal results (2, 5, 12). One of the proposed reasons for such failure is the lack of early markers for AKI and hence an unacceptable delay in initiating therapy. In current clinical practice, identification and severity of AKI is generally based on elevations in serum creatinine levels. Unfortunately, creatinine is an unreliable indicator of early AKI for multiple reasons. For example, a significant decrease (50%) in glomerular filtration rate (GFR) may be necessary to raise the serum creatinine above the normal laboratory range (2, 9, 11). In sepsis, production of creatinine from the muscle is reduced, and relying on changes in serum creatinine to diagnose AKI in such settings could delay diagnosis of AKI (3). Recent studies have conclusively shown that the morbidity and mortality associated with AKI are correlated with the severity of kidney injury. The data from these studies and animal models indicate that prevention or decrease in the extent of injury could significantly lower negative outcomes

Do Children With Acute Kidney Injury Require Long-term Evaluation for CKD?

Diabetes is a leading cause of ESKD worldwide, resulting in substantial patient morbidity and healthcare costs. Fenofibrate and other fibrate therapies may improve lipid profiles and prevent cardiovascular events in people with CKD, and thus may be useful as adjunctive therapies to reduce the risk of cardiovascular disease (1). However, fibrates have been linked to an increase in the concentration of serum creatinine, the cause of which is uncertain and may be reversible upon discontinuation of the fibrate. Recent published data from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial confirms a higher risk of doubling the concentration of serum creatinine from baseline with fenofibrate versus placebo (2). These participants were a part of the overall ACCORD trial, which was a two-by-two factorial design trial with type 2 diabetes, who were being treated with open-label simvastatin to receive either masked fenofibrate or placebo. In this study we measured new urinary biomarkers in ACCORD participants to establish that the rise is serum creatinine with fibrate use is not associated with markers of inflammation or kidney injury (3,4). These biomarkers have been shown to help dissociate increases in serum creatinine due to hemodynamic or noninjury causes versus actual tubular injury in previous studies (3,4). We obtained urine samples (at baseline and at 2 years) from a subgroup of 571 ACCORD participants, not randomly selected (a mix of matched CKD 1:1 case-control and randomized patients) who were all receiving statins. These patients were randomized to either placebo (n=329) or fenofibrate (n=242) at the initiation of the ACCORD study. We measured four urine biomarkers: kidney injury molecule-1 (KIM-1) and IL-18, two biomarkers specific to injury or damage to kidney tubules; monocyte chemoattractant protein (MCP-1), a biomarker of inflammation; and a biomarker of repair (YKL40) of kidney tubules. We measured these biomarkers once per sample using the four-plex prototype assay on the Mesoscale Platform (Meso Scale Diagnostics). Intra- and interassay coefficients of variation were 2.2%–6.8% for urinary IL-18, 5.0%–9.3% for urinary KIM-1, 3.6%–15.3% for urinary MCP-1, and 1.6%–12.1% for urinary YKL-40. The average lower limit of detection obtained from multiple runs was 0.09 pg/ml for IL-18, 0.28 pg/ml for KIM-1, 0.05 pg/ml for MCP-1, and 0.16 pg/ml for YKL-40. Our primary outcome was the change in the concentration of these urinary biomarkers and the changes in eGFR and random urine albumin-to-creatinine ratio (UACR) over 2 years. Median (interquartile range) were calculated for baseline and follow-up period comparing both arms. We used quantile regression method to estimate the median change and 95% confidence interval from baseline to year 2 for eGFR, serum creatinine, and urinary biomarkers. We also calculated the ratio of the mean change at year 2 for fenofibrate arm versus placebo arm. The median (25th, 75th percentile) age was 62 (57, 66) years, eGFR was 89 (76–95) ml/min per 1.73 m2, and UACR was 13 (6–48) mg/g; 58% were men and 74% were white. Baseline clinical characteristics including BP, medications, comorbidities, eGFR, UACR, and all four biomarker levels were similar in the two randomization groups. At 24 months, eGFR was 22.8 ml/min per 1.73 m2 lower (P<0.001) and serum creatinine 0.30 mg/dl higher (P<0.001) with fenofibrate versus placebo. In contrast, UACR and all four urine biomarkers of kidney injury or repair were similar or decreased from baseline in ACCORD participants randomized to fenofibrate versus placebo (Table 1). In a stratified analysis, even participants with the highest quintile of 2-year decrements in eGFR with fenofibrate (−30.4 to −73.5 ml/min per 1.73 m2) still had lower or unchanged UACR and urine biomarkers over the same 2-year period (data not shown). Table 1. - Effects of fenofibrate versus placebo on longitudinal changes in eGFR, serum creatinine, UACR, and urine tubular damage markers in a subset of participants in ACCORD Kidney-Based Parameters Statin+Fenofibrate P Value Statin+Placebo P Value n=242 n=329 eGFR ml/min per 1.73 m2, median (IQR) Baseline 89.1 (76.2–96.2) <0.001 88.0 (74.4–94.8) 0.02 Year 2 66.3 (51.8–86.2) 84.4 (70.7–93.8) Change from baseline to year 2 (95% CI) −22.6 (−28.1 to −17.1) <0.001 −3.6 (−6.6 to −0.6) 0.02 Ratio of the mean change fibrates versus placebo a ↓18% (↓22%, ↓14%) UACR (mg/g), median (IQR) Baseline 13.0 (6.6–70.9) 0.1 12.3 (6.3–36.8) 0.7 Year 2 9.6 (5.4–29.1) 11.9 (6.4–41.5) Change from baseline to year 2 (95% CI) −3.2 (−8.6 to 2.1) 0.2 −0.4 (−3.8 to 3.0) 0.8 Ratio of the mean change fibrates versus placebo a ↓20% (↓38%, ↑3%) Serum creatinine (mg/dl), median (IQR) Baseline 0.8 (0.7–1.0) <0.001 0.9 (0.8–1.0) 0.4 Year 2 1.1 (0.9–1.3) 0.9 (0.7–1.0) Change from baseline to year 2 (95% CI) 0.3 (0.2 to 0.3) <0.001 −0.04 (−0.1 to −0.00) 0.1 Ratio of the mean change fibrates versus placebo a ↑22% (↑19%, ↑27%) uKIM-1, pg/ml, median (IQR) Baseline 931.0 (488.4–1668.6) 0.002 767.8 (381.4–1492.1) 0.3 Year 2 691.3 (394.4–1178.7) 717.7 (384.3–1323.8) Change from baseline to year 2 (95% CI) −239.7 (−403.3 to −76.1) 0.004 −50.2 (−191.6 to 91.3) 0.5 Ratio of the mean change fibrates versus placebo a ↓6% (↓17%, ↑6%) uIL-18, ng/ml, median (IQR) Baseline 26.7 (13.1–57.4) 0.2 28.0 (13.2–50.9) 0.3 Year 2 24.0 (10.6–41.7) 30.0 (14.4–51.2) Change from baseline to year 2 (95% CI) −2.7 (−8.2 to 2.8) 0.3 2.0 (−3.5 to 7.5) 0.5 Ratio of the mean change fibrates versus placebo a ↓25% (↓34%, ↓14%) uMCP-1, pg/ml, median (IQR) Baseline 164.0 (79.3–293.9) 0.1 158.9 (70.1–286.6) 0.6 Year 2 138.8 (73.1–241.8) 150.2 (71.6–271.3) Change from baseline to year 2 (95% CI) −25.2 (−58.0 to 7.6) 0.1 −8.7 (−37.8 to 20.4) 0.6 Ratio of the mean change fibrates versus placebo a ↓2% (↓14%, ↑11%) uYKL-40, ng/ml, median (IQR) Baseline 319.0 (104.2–675.5) 0.2 273.5 (68.2–734.0) 0.2 Year 2 404.1 (132.4–864.4) 341.2 (107.0–823.2) Change from baseline to year 2 (95% CI) 85.2 (−26.3 to 196.6) 0.1 64.9 (−32.3 to 162.2) 0.2 Ratio of the mean change fibrates versus placebo a ↑8% (↓17%, ↑39%) UACR, urine albumin-to-creatinine ratio; ACCORD, Action to Control Cardiovascular Risk in Diabetes trial; IQR, interquartile range; 95% CI, 95% confidence interval; uKIM-1, urinary kidney injury molecule-1; uIL-18, urinary IL-18; uMCP-1; urinary monocyte chemoattractant protein 1; uYKL-40, urinary human cartilage glycoprotein-39; (↑), increased biomarker levels; (↓) decreased biomarker levels.aRatio of the mean change at year 2 for fenofibrate arm versus placebo arm. In conclusion, initiating fenofibrate increased the concentration of serum creatinine with no concomitant increase in the concentration of a panel of urinary biomarkers representing tubular injury, inflammation, or fibrosis. These findings are consistent with previous findings from ACCORD that fenofibrate discontinuation led the reduction in the concentration of serum creatinine (5). We acknowledge there are some limitations to our methods. These include the following: (1) lack of availability of multiple measurements of serum creatinine; (2) inability to rule out any episodes of AKI; (3) the lack of potential generalizability of the findings to nontrial populations; (4) the coefficient of variation of the biomarker assays may have diminished the ability to detect the true effect (or lack thereof) of fibrates versus placebo over time, with confidence intervals that crossed unity; and (5) because our study population is not entirely randomly selected, there could be an element of potential selection bias. However, despite this, only the upper bound of the ratio of the mean in urine YKL-40 (39%) exceeded the median magnitude of rise in serum creatinine (22%). Moreover, other data demonstrated that the withdrawal of fenofibrate led to a reduction of serum creatinine in the ACCORD trial population also supports the notion the change in serum creatinine on fibrates are likely due to physiologic changes rather than actual kidney tubular injury (5). Given results from this report and other kidney injury biomarker analyses from ACCORD-BP and Systolic BP Intervention Trial (SPRINT) (3,4), more efforts should be made in future clinical trials to measure markers of kidney injury in a portion of trial participants to distinguish benign changes in serum creatinine from true kidney injury. This distinction is clinically important and may allay some prescribers avoiding the use of beneficial medications simply because they cause a nonpathologic rise in the concentration of serum creatinine. Disclosures Dr. Coca, Dr, Nadkarni, and Dr. Parikh are members of the advisory board of RenalytixAI and own equity in the company. Outside of the submitted work, Dr. Coca reports personal fees from CHF Solutions, Goldfinch Bio, Janssen, Takeda, and Quark. Also outside of the submitted work, Dr. Coca reports personal and other fees and stock options from pulseData and personal and other fees from RenalytixAI. Dr. Nadkarni reports personal and other fees from BioVie Inc. and pulseData. Dr. Nadkarni also reports a position as cofounder of and personal and other fees from RenalytixAI. Dr. Parikh reports consulting fees from Akebia Therapeutics, Inc. and Genfit Biopharmaceutical Company and other fees from RenalytixAI. Dr. Chan, Dr. Chauhan, Dr. Debnath, Dr. Garg, and Dr. Saha have nothing to disclose. Funding Dr. Chan is supported by grants from National Institutes of Health and Renal Research Institute. Dr. Coca is supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), grant R01DK096549. Dr. Garg received partnership funding from Astellas for a research grant funded by the Canadian Institutes of Health Research. Dr. Nadkarni reports a grant from Goldfinch Bio. Dr. Parikh reports grants from NIDDK and the National Heart, Lung, and Blood Institute. Dr. Coca, Dr. Nadkarni, and Dr. Parikh are members and are supported in part by the CKD Biomarker Consortium (1U01DK106962-01).

Pathophysiology and Pathology of Acute Kidney Injury in Patients With COVID-19.

To investigate kidney injury in preeclampsia, we analyzed 14 biomarkers in urine specimen from 4 groups of pregnant women (normotensive pregnant women and those with pregnancy complicated with chronic hypertension or mild or severe preeclampsia). These biomarkers included 1) podocyte glycoproteins nephrin and podocalyxin, 2) matrix metallopeptidase (MMP)-2 and MMP-9 and their inhibitor tissue inhibitor of metalloproteinase-2, 3) inflammatory molecules and cytokines soluble VCAM-1, TNF-α, soluble TNF receptor receptor-1, IL-6, IL-8, IL-10, and IL-18, and 4) kidney injury biomarkers neutrophil gelatinase-associated lipocalin and kidney injury molecule-1. Postpartum urine specimens (6-8 wk) from normotensive women and those with severe preeclampsia were also evaluated. We found that, first, urine levels of nephrin, MMP-2, MMP-9, and kidney injury molecule-1 were significantly higher before delivery in severe preeclampsia than normotensive groups. The increased levels were all reduced to levels similar to those of the normotensive control group in postpartum specimens from the severe preeclampsia group. Second, soluble VCAM-1, soluble TNF receptor-1, and neutrophil gelatinase-associated lipocalin levels were significantly increased in the severe preeclampsia group compared with the normotensive control group before delivery, but levels of these molecules were significantly reduced in postpartum specimens in both groups. Third, IL-6 and IL-8 levels were not different between preeclampsia and normotensive groups but significantly increased in pregnancy complicated with chronic hypertension. Finally, tissue inhibitor of metalloproteinase-2 and IL-18 levels were not different among the study groups before delivery but were significantly reduced in postpartum specimens from normotensive controls. Our results indicate that the kidney experiences an increased inflammatory response during pregnancy. Most interestingly, tubular epithelial cell injury may also occur in severe preeclampsia. These biomarkers could be used to assess podocyte or tubular injury and kidney inflammatory responses during pregnancy and to evaluate postpartum kidney injury recovery in pregnancy-complicated disorders.

Remote Ischemic Preconditioning: Is the Groove in the Heart?

Save the Beans

Sepsis is a risk factor for acute kidney injury (AKI) in neonates, for which no effective treatment exists. The phosphodiesterase inhibitor pentoxifylline (PTX) has demonstrated renal protection from ischemia and inflammation in adult rodents. We hypothesized that addition of PTX to antibiotics may attenuate immune and histological AKI in a murine neonatal sepsis model. Postnatal (PN) day 1 C57BL/6J mice were injected with E. coli K1 strain at 105 colony forming units per gram weight or saline control. After 1.5 hours, septic pups randomly received saline, gentamicin or cefotaxime, with/without PTX. 5.5h after sepsis initiation, kidneys and blood were harvested for measurements of biomarkers of inflammation and kidney injury. Renal sections from PN7 mice were used for histology and immunofluorescence. Linear mixed effect models were employed to fit the outcomes including interaction between treatment group and sex. Septic mice demonstrated robust expression of pro-inflammatory cytokines, chemokines and biomarkers of tubular injury in renal tissue, which were attenuated in response to combined PTX and antibiotics (gentamicin or cefotaxime): chemokines (p<0.001), plasma (p<0.01) and tissue IL-6 (p<0.05), plasma TNF (p<0.001), NGAL (p<0.01), CXCL10 (p<0.01), osteopontin (p<0.05), and VEGF (p<0.05), with a trend for KIM-1 (tissue concentration: p=0.21, fluorescence area: p=0.12). Interactions between treatment and sex were present for several cytokines and kidney injury biomarkers. Immunofluorescence findings for the tubular injury markers (NGAL and KIM-1) were consistent with biomarker expression in tissue lysates. Neonatal E. coli sepsis leads to increased expression of renal tissue inflammation and injury biomarkers consistent with AKI, which may be attenuated with PTX combined with antibiotic treatment.

Novel urine biomarkers may improve identification of children at greater risk of rapid kidney function decline, and elucidate the pathophysiology of CKD progression. 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. 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. 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.

582 Background: Kidney injury molecule-1 (KIM-1) is overexpressed in clear cell and papillary renal cell carcinoma (RCC) and in proximal tubular kidney injury. While circulating KIM-1 is a minimally invasive biomarker for RCC, it is unknown whether kidney disease, a common comorbidity among RCC patients, impacts the association of KIM-1 with RCC outcomes. We evaluated the association between KIM-1 and outcomes in metastatic RCC after adjustment for multiple kidney injury biomarkers using plasma proteomics. Methods: Plasma samples from patients with metastatic clear cell and papillary RCC were obtained prior to 1 st line systemic therapy. Samples were analyzed using a high-throughput aptamer-based proteomics assay (SomaLogic), and results were log-transformed for analysis. Clinical and laboratory data, as well as cancer outcomes, were retrospectively curated. Spearman’s ρ was used to evaluate correlations between circulating KIM-1 and kidney injury biomarkers (cystatin C, TNFR1, TNFR2, eGFR). Cox regression analyses were used to evaluate the association between KIM-1 as a continuous variable and overall survival (OS) and progression-free survival (PFS), after adjusting for kidney injury biomarkers. Performance of KIM-1 tertiles versus IMDC risk groups for prognosticating OS was evaluated using the C-index. Results: Among 210 patients, higher baseline KIM-1 was associated with worse PFS (p = 0.004) and OS (p &lt; 0.001) in univariate Cox regression analysis (Table). The prognostic value of KIM-1 was consistent across clear cell and papillary RCC (p-value for interaction = 0.98). KIM-1 remained prognostic for PFS (p = 0.01) and OS (p &lt; 0.001) after multivariable adjustment for kidney injury biomarkers and eGFR (Table). Median follow-up was 22.1 months. Kidney injury biomarkers (cystatin C, TNFR1, TNFR2, eGFR) were correlated with each other but not with plasma KIM-1. KIM-1 tertiles (high/medium/low) were more prognostic for OS than the IMDC risk groups (C-index, KIM-1 0.63 vs. IMDC groups 0.58) and the addition of KIM-1 to the IMDC model improved its performance (C-index, KIM-1 + IMDC groups 0.64). Conclusions: Plasma KIM-1 was associated with PFS and OS in metastatic clear cell and papillary RCC. Plasma KIM-1 was not correlated with kidney injury biomarkers, suggesting that at least in metastatic RCC, circulating KIM-1 derives predominantly from tumor rather than benign kidney. The addition of KIM-1 improves IMDC model performance and may be useful for risk prognostication in RCC. Association of KIM-1 with PFS and OS in metastatic RCC. Multivariable models are adjusted for kidney injury markers (cystatin C, TNFR1, TNFR2) and eGFR. log KIM-1 HR (95% CI) p-value OS (univariate) 1.4 (1.2 – 1.7) &lt;0.001*** PFS (univariate) 1.2 (1.1 – 1.4) 0.004** OS (multivariate) 1.4 (1.2 – 1.6) &lt;0.001*** PFS (multivariate) 1.2 (1.1 – 1.3) 0.01**