The Role of Angiopoietins in Cardiovascular Outcomes of Kidney Transplant Recipients- An Ancillary Study From the FAVORIT.

INTRODUCTION: Kidney transplant recipients (KTRs) have increased risk of cardiovascular disease (CVD) mortality. We investigated vascular biomarkers, angiopoietin-1 and angiopoietin-2 (angpt-1, -2), in CVD development in KTRs. METHODS: This ancillary study from the FAVORIT, evaluates the associations of baseline plasma angpt-1,-2 levels in CVD development (primary outcome) and graft failure (GF) and death (secondary outcomes) in 2000 deceased donor KTRs. We used Cox regression to analyze the association of biomarker quartiles with outcomes. We adjusted for demographic, CVD and transplant-related variables; medications; urine albumin-to-creatinine ratio and randomization status. We calculated areas under the curves (AUC) to predict CVD or death, and GF or death by incorporating biomarkers alongside clinical variables. RESULTS: Participants' median age was 52 IQR [45, 59] years: with 37% women and 73% identifying as white. Median time from transplantation was 3.99 IQR [1.58, 7.93] years and to CVD development was 2.54 IQR [1.11-3.80] years. Quartiles of angpt-1 were not associated with outcomes. Whereas higher levels of angpt-2 (quartile 4) were associated with about 2 times the risk of CVD, GF and death [aHR 1.85 (1.25 - 2.73), P<.01; 2.24 (1.36 - 3.70), P<.01; 2.30 (1.48 - 3.58), P<.01, respectively] as compared to quartile 1. Adding angiopoietins to pre-existing clinical variables improved prediction of CVD or death (AUC improved from 0.70 to 0.72, P=0.005) and GF or death (AUC improved from 0.68 to 0.70, P =0.005). Angpt-2 may partially explain the increased risk of future CVD in KTRs. Further research is needed to assess the utility of using angiopoietins in the clinical care of KTRs. CONCLUSION: Angpt-2 may be a useful prognostic tool for future CVD in KTRs. Combining angiopoietins with clinical markers may tailor follow-up to mitigate CVD risk.

Kidney Transplant Outcomes From Deceased Donors Who Received Dialysis.

Importance: Recipient outcomes after kidney transplant from deceased donors who received dialysis prior to kidney donation are not well described. Objective: To compare outcomes of transplant recipients who received kidneys from deceased donors who underwent dialysis prior to kidney donation vs recipients of kidneys from deceased donors who did not undergo dialysis. Design, Setting, and Participants: A retrospective cohort study was conducted including data from 58 US organ procurement organizations on deceased kidney donors and kidney transplant recipients. From 2010 to 2018, 805 donors who underwent dialysis prior to kidney donation were identified. The donors who underwent dialysis prior to kidney donation were matched 1:1 with donors who did not undergo dialysis using a rank-based distance matrix algorithm; 1944 kidney transplant recipients were evaluated. Exposure: Kidney transplants from deceased donors who underwent dialysis prior to kidney donation compared with kidney transplants from deceased donors who did not undergo dialysis. Main Outcomes and Measures: The 4 study outcomes were delayed graft function (defined as receipt of dialysis by the kidney recipient ≤1 week after transplant), all-cause graft failure, death-censored graft failure, and death. Results: From 2010 to 2018, 1.4% of deceased kidney donors (805 of 58 155) underwent dialysis prior to kidney donation. Of these 805 individuals, 523 (65%) donated at least 1 kidney. A total of 969 kidneys (60%) were transplanted and 641 kidneys (40%) were discarded. Among the donors with kidneys transplanted, 514 (mean age, 33 years [SD, 10.8 years]; 98 had hypertension [19.1%] and 36 had diabetes [7%]) underwent dialysis prior to donation and were matched with 514 (mean age, 33 years [SD, 10.9 years]; 98 had hypertension [19.1%] and 36 had diabetes [7%]) who did not undergo dialysis. Kidney transplants from donors who received dialysis prior to donation (n = 954 kidney recipients) were associated with a higher risk of delayed graft function compared with kidney transplants from donors who did not receive dialysis (n = 990 kidney recipients) (59.2% vs 24.6%, respectively; adjusted odds ratio, 4.17 [95% CI, 3.28-5.29]). The incidence rates did not significantly differ at a median follow-up of 34.1 months for all-cause graft failure (43.1 kidney transplants per 1000 person-years from donors who received dialysis prior to donation vs 46.9 kidney transplants per 1000 person-years from donors who did not receive dialysis; adjusted hazard ratio [HR], 0.90 [95% CI, 0.70-1.15]), for death-censored graft failure (22.5 vs 20.6 per 1000 person-years, respectively; adjusted HR, 1.18 [95% CI, 0.83-1.69]), or for death (24.6 vs 30.8 per 1000 person-years; adjusted HR, 0.76 [95% CI, 0.55-1.04]). Conclusions and Relevance: Compared with receiving a kidney from a deceased donor who did not undergo dialysis, receiving a kidney from a deceased donor who underwent dialysis prior to kidney donation was associated with a significantly higher incidence of delayed graft function, but no significant difference in graft failure or death at follow-up.

Deceased-Donor Acute Kidney Injury and Acute Rejection in Kidney Transplant Recipients: A Multicenter Cohort.

RATIONALE & OBJECTIVE: Donor acute kidney injury (AKI) activates innate immunity, enhances HLA expression in the kidney allograft, and provokes recipient alloimmune responses. We hypothesized that injury and inflammation that manifested in deceased-donor urine biomarkers would be associated with higher rates of biopsy-proven acute rejection (BPAR) and allograft failure after transplantation. STUDY DESIGN: Prospective cohort. SETTING & PARTICIPANTS: 862 deceased donors for 1,137 kidney recipients at 13 centers. EXPOSURES: We measured concentrations of interleukin 18 (IL-18), kidney injury molecule 1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL) in deceased donor urine. We also used the Acute Kidney Injury Network (AKIN) criteria to assess donor clinical AKI. OUTCOMES: The primary outcome was a composite of BPAR and graft failure (not from death). A secondary outcome was the composite of BPAR, graft failure, and/or de novo donor-specific antibody (DSA). Outcomes were ascertained in the first posttransplant year. ANALYTICAL APPROACH: Multivariable Fine-Gray models with death as a competing risk. RESULTS: Mean recipient age was 54 ± 13 (SD) years, and 82% received antithymocyte globulin. We found no significant associations between donor urinary IL-18, KIM-1, and NGAL and the primary outcome (subdistribution hazard ratio [HR] for highest vs lowest tertile of 0.76 [95% CI, 0.45-1.28], 1.20 [95% CI, 0.69-2.07], and 1.14 [95% CI, 0.71-1.84], respectively). In secondary analyses, we detected no significant associations between clinically defined AKI and the primary outcome or between donor biomarkers and the composite outcome of BPAR, graft failure, and/or de novo DSA. LIMITATIONS: BPAR was ascertained through for-cause biopsies, not surveillance biopsies. CONCLUSIONS: In a large cohort of kidney recipients who almost all received induction with thymoglobulin, donor injury biomarkers were associated with neither graft failure and rejection nor a secondary outcome that included de novo DSA. These findings provide some reassurance that centers can successfully manage immunological complications using deceased-donor kidneys with AKI.

Plasma Soluble Tumor Necrosis Factor Receptor Concentrations and Clinical Events After Hospitalization: Findings From the ASSESS-AKI and ARID Studies.

RATIONALE & OBJECTIVE: The role of plasma soluble tumor necrosis factor receptor 1 (sTNFR1) and sTNFR2 in the prognosis of clinical events after hospitalization with or without acute kidney injury (AKI) is unknown. STUDY DESIGN: Prospective cohort. SETTING & PARTICIPANTS: Hospital survivors from the ASSESS-AKI (Assessment, Serial Evaluation, and Subsequent Sequelae of Acute Kidney Injury) and ARID (AKI Risk in Derby) studies with and without AKI during the index hospitalization who had baseline serum samples for biomarker measurements. PREDICTORS: We measured sTNFR1 and sTNFR2 from plasma samples obtained 3 months after discharge. OUTCOMES: The associations of biomarkers with longitudinal kidney disease incidence and progression, heart failure, and death were evaluated. ANALYTICAL APPROACH: Cox proportional hazard models. RESULTS: Among 1,474 participants with plasma biomarker measurements, 19% had kidney disease progression, 14% had later heart failure, and 21% died during a median follow-up of 4.4 years. For the kidney outcome, the adjusted HRs (AHRs) per doubling in concentration were 2.9 (95% CI, 2.2-3.9) for sTNFR1 and 1.9 (95% CI, 1.5-2.5) for sTNFR2. AKI during the index hospitalization did not modify the association between biomarkers and kidney events. For heart failure, the AHRs per doubling in concentration were 1.9 (95% CI, 1.4-2.5) for sTNFR1 and 1.5 (95% CI, 1.2-2.0) for sTNFR2. For mortality, the AHRs were 3.3 (95% CI, 2.5-4.3) for sTNFR1 and 2.5 (95% CI, 2.0-3.1) for sTNFR2. The findings in ARID were qualitatively similar in terms of the magnitude of association between biomarkers and outcomes. LIMITATIONS: Different biomarker platforms and AKI definitions; limited generalizability to other ethnic groups. CONCLUSIONS: Plasma sTNFR1 and sTNFR2 measured 3 months after hospital discharge were independently associated with clinical events regardless of AKI status during the index admission. sTNFR1 and sTNFR2 may assist with the risk stratification of patients during follow-up.

Angiopoietins as Prognostic Markers for Future Kidney Disease and Heart Failure Events after Acute Kidney Injury.

BACKGROUND: The mechanisms underlying long-term sequelae after AKI remain unclear. Vessel instability, an early response to endothelial injury, may reflect a shared mechanism and early trigger for CKD and heart failure. METHODS: To investigate whether plasma angiopoietins, markers of vessel homeostasis, are associated with CKD progression and heart failure admissions after hospitalization in patients with and without AKI, we conducted a prospective cohort study to analyze the balance between angiopoietin-1 (Angpt-1), which maintains vessel stability, and angiopoietin-2 (Angpt-2), which increases vessel destabilization. Three months after discharge, we evaluated the associations between angiopoietins and development of the primary outcomes of CKD progression and heart failure and the secondary outcome of all-cause mortality 3 months after discharge or later. RESULTS: Median age for the 1503 participants was 65.8 years; 746 (50%) had AKI. Compared with the lowest quartile, the highest quartile of the Angpt-1:Angpt-2 ratio was associated with 72% lower risk of CKD progression (adjusted hazard ratio [aHR], 0.28; 95% confidence interval [CI], 0.15 to 0.51), 94% lower risk of heart failure (aHR, 0.06; 95% CI, 0.02 to 0.15), and 82% lower risk of mortality (aHR, 0.18; 95% CI, 0.09 to 0.35) for those with AKI. Among those without AKI, the highest quartile of Angpt-1:Angpt-2 ratio was associated with 71% lower risk of heart failure (aHR, 0.29; 95% CI, 0.12 to 0.69) and 68% less mortality (aHR, 0.32; 95% CI, 0.15 to 0.68). There were no associations with CKD progression. CONCLUSIONS: A higher Angpt-1:Angpt-2 ratio was strongly associated with less CKD progression, heart failure, and mortality in the setting of AKI.

Results from the TRIBE-AKI Study found associations between post-operative blood biomarkers and risk of chronic kidney disease after cardiac surgery.

Patients undergoing cardiac surgery are placed under intense physiologic stress. Blood and urine biomarkers measured peri-operatively may help identify patients at higher risk for adverse long-term kidney outcomes.We sought to determine independent associations of various biomarkers with development or progression of chronic kidney disease (CKD) following cardiac surgery. In this sub-study of the prospective cohort -TRIBE-AKI Study, we evaluated 613 adult patients undergoing cardiac surgery in Canada in our primary analysis and tested the association of 40 blood and urinary biomarkers with the primary composite outcome of CKD incidence or progression. In those with baseline estimated glomerular filtration rate (eGFR) over 60 mL/min/1.73m2, we defined CKD incidence as a 25% reduction in eGFR and an eGFR under 60. In those with baseline eGFR under 60 mL/min/1.73m2, we defined CKD progression as a 50% reduction in eGFR or eGFR under 15. Results were evaluated in a replication cohort of 310 patients from one study site in the United States. Over a median follow-up of 5.6 years, 172 patients developed the primary outcome. Each log increase in basic fibroblast growth factor (adjusted hazard ratio 1.52 [95% confidence interval 1.19, 1.93]), Kidney Injury Molecule-1 (1.51 [0.98, 2.32]), N-terminal pro-B-type natriuretic peptide (1.19 [1.01, 1.41]), and tumor necrosis factor receptor 1 (1.75 [1.18, 2.59]) were associated with outcome after adjustment for demographic factors, serum creatinine, and albuminuria. Similar results were noted in the replication cohort. Although there was no interaction by acute kidney injury in continuous analysis, mortality was higher in the no acute kidney injury group by biomarker tertile. Thus, elevated post-operative levels of blood biomarkers following cardiac surgery were independently associated with the development of CKD. These biomarkers can provide additional value in evaluating CKD incidence and progression after cardiac surgery.

The Association of COVID-19 With Acute Kidney Injury Independent of Severity of Illness: A Multicenter Cohort Study.

RATIONALE & OBJECTIVE: Although coronavirus disease 2019 (COVID-19) has been associated with acute kidney injury (AKI), it is unclear whether this association is independent of traditional risk factors such as hypotension, nephrotoxin exposure, and inflammation. We tested the independent association of COVID-19 with AKI. STUDY DESIGN: Multicenter, observational, cohort study. SETTING & PARTICIPANTS: Patients admitted to 1 of 6 hospitals within the Yale New Haven Health System between March 10, 2020, and August 31, 2020, with results for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing via polymerase chain reaction of a nasopharyngeal sample. EXPOSURE: Positive test for SARS-CoV-2. OUTCOME: AKI by KDIGO (Kidney Disease: Improving Global Outcomes) criteria. ANALYTICAL APPROACH: Evaluated the association of COVID-19 with AKI after controlling for time-invariant factors at admission (eg, demographic characteristics, comorbidities) and time-varying factors updated continuously during hospitalization (eg, vital signs, medications, laboratory results, respiratory failure) using time-updated Cox proportional hazard models. RESULTS: Of the 22,122 patients hospitalized, 2,600 tested positive and 19,522 tested negative for SARS-CoV-2. Compared with patients who tested negative, patients with COVID-19 had more AKI (30.6% vs 18.2%; absolute risk difference, 12.5% [95% CI, 10.6%-14.3%]) and dialysis-requiring AKI (8.5% vs 3.6%) and lower rates of recovery from AKI (58% vs 69.8%). Compared with patients without COVID-19, patients with COVID-19 had higher inflammatory marker levels (C-reactive protein, ferritin) and greater use of vasopressors and diuretic agents. Compared with patients without COVID-19, patients with COVID-19 had a higher rate of AKI in univariable analysis (hazard ratio, 1.84 [95% CI, 1.73-1.95]). In a fully adjusted model controlling for demographic variables, comorbidities, vital signs, medications, and laboratory results, COVID-19 remained associated with a high rate of AKI (adjusted hazard ratio, 1.40 [95% CI, 1.29-1.53]). LIMITATIONS: Possibility of residual confounding. CONCLUSIONS: COVID-19 is associated with high rates of AKI not fully explained by adjustment for known risk factors. This suggests the presence of mechanisms of AKI not accounted for in this analysis, which may include a direct effect of COVID-19 on the kidney or other unmeasured mediators. Future studies should evaluate the possible unique pathways by which COVID-19 may cause AKI.

Contemporary incidence and risk factors of post transplant Erythrocytosis in deceased donor kidney transplantation.

BACKGROUND: Post-Transplant erythrocytosis (PTE) has not been studied in large recent cohorts. In this study, we evaluated the incidence, risk factors, and outcome of PTE with current transplant practices using the present World Health Organization criteria to define erythrocytosis. We also tested the hypothesis that the risk of PTE is greater with higher-quality kidneys. METHODS: We utilized the Deceased Donor Study which is an ongoing, multicenter, observational study of deceased donors and their kidney recipients that were transplanted between 2010 and 2013 across 13 centers. Eryrthocytosis is defined by hemoglobin> 16.5 g/dL in men and> 16 g/dL in women. Kidney quality is measured by Kidney Donor Profile Index (KDPI). RESULTS: Of the 1123 recipients qualified to be in this study, PTE was observed at a median of 18 months in 75 (6.6%) recipients. Compared to recipients without PTE, those with PTE were younger [mean 48±11 vs 54±13 years, p < 0.001], more likely to have polycystic kidney disease [17% vs 6%, p < 0.001], have received kidneys from younger donors [36 ±13 vs 41±15 years], and be on RAAS inhibitors [35% vs 22%, p < 0.001]. Recipients with PTE were less likely to have received kidneys from donors with hypertension [16% vs 32%, p = 0.004], diabetes [1% vs 11%, p = 0.008], and cerebrovascular event (24% vs 36%, p = 0.036). Higher KDPI was associated with decreased PTE risk [HR 0.98 (95% CI: 0.97-0.99)]. Over 60 months of follow-up, only 17 (36%) recipients had sustained PTE. There was no association between PTE and graft failure or mortality, CONCLUSIONS: The incidence of PTE was low in our study and PTE resolved in majority of patients. Lower KDPI increases risk of PTE. The underutilization of RAAS inhibitors in PTE patients raises the possibility of under-recognition of this phenomenon and should be explored in future studies.

Association of plasma-soluble ST2 and galectin-3 with cardiovascular events and mortality following cardiac surgery.

BACKGROUND: Cardiac surgery induces hemodynamic stress on the myocardium, and this process can be associated with significant post-operative morbidity and mortality. Soluble suppression of tumorigenicity 2 (sST2) and galectin-3 (gal-3) are biomarkers of myocardial remodeling and fibrosis; however, their potential association with post-operative changes is unknown. METHODS: We measured peri-operative plasma sST2 and gal-3 levels in two prospective cohorts (TRIBE-AKI and NNE) of over 1800 patients who underwent cardiac surgery. sST2 and gal-3 levels were evaluated for association with a composite primary outcome of cardiovascular event or mortality over median follow-up periods of 3.4 and 6.0 years, respectively, for the two cohorts. Meta-analysis of hazard ratio estimates from the cohorts was performed using random effects models. RESULTS: Cohorts demonstrated event rates of 70.2 and 66.8 per 1000 person-years for the primary composite outcome. After adjustment for clinical covariates, higher post-operative sST2 and gal-3 levels were significantly associated with cardiovascular event or mortality [pooled estimate HRs: sST2 1.29 (95% CI 1.16, 1.44); gal-3 1.26 (95% CI 1.09, 1.46)]. These associations were not significantly modified by pre-operative congestive heart failure or AKI. CONCLUSIONS: Higher post-operative sST2 and gal-3 values were associated with increased incidence of cardiovascular event or mortality. These two biomarkers should be further studied for potential clinical utility for patients undergoing cardiac surgery.

Real-Time Prediction of Acute Kidney Injury in Hospitalized Adults: Implementation and Proof of Concept.

RATIONALE & OBJECTIVE: Acute kidney injury (AKI) is diagnosed based on changes in serum creatinine concentration, a late marker of this syndrome. Algorithms that predict elevated risk for AKI are of great interest, but no studies have incorporated such an algorithm into the electronic health record to assist with clinical care. We describe the experience of implementing such an algorithm. STUDY DESIGN: Prospective observational cohort study. SETTING & PARTICIPANTS: 2,856 hospitalized adults in a single urban tertiary-care hospital with an algorithm-predicted risk for AKI in the next 24 hours>15%. Alerts were also used to target a convenience sample of 100 patients for measurement of 16 urine and 6 blood biomarkers. EXPOSURE: Clinical characteristics at the time of pre-AKI alert. OUTCOME: AKI within 24 hours of pre-AKI alert (AKI24). ANALYTICAL APPROACH: Descriptive statistics and univariable associations. RESULTS: At enrollment, mean predicted probability of AKI24 was 19.1%; 18.9% of patients went on to develop AKI24. Outcomes were generally poor among this population, with 29% inpatient mortality among those who developed AKI24 and 14% among those who did not (P<0.001). Systolic blood pressure<100mm Hg (28% of patients with AKI24 vs 18% without), heart rate>100 beats/min (32% of patients with AKI24 vs 24% without), and oxygen saturation<92% (15% of patients with AKI24 vs 6% without) were all more common among those who developed AKI24. Of all biomarkers measured, only hyaline casts on urine microscopy (72% of patients with AKI24 vs 25% without) and fractional excretion of urea nitrogen (20% [IQR, 12%-36%] among patients with AKI24 vs 34% [IQR, 25%-44%] without) differed between those who did and did not develop AKI24. LIMITATIONS: Single-center study, reliance on serum creatinine level for AKI diagnosis, small number of patients undergoing biomarker evaluation. CONCLUSIONS: A real-time AKI risk model was successfully integrated into the EHR.

Deceased-donor acute kidney injury is not associated with kidney allograft failure.

Deceased-donor acute kidney injury (AKI) is associated with organ discard and delayed graft function, but data on longer-term allograft survival are limited. We performed a multicenter study to determine associations between donor AKI (from none to severe based on AKI Network stages) and all-cause graft failure, adjusting for donor, transplant, and recipient factors. We examined whether any of the following factors modified the relationship between donor AKI and graft survival: kidney donor profile index, cold ischemia time, donation after cardiac death, expanded-criteria donation, kidney machine perfusion, donor-recipient gender combinations, or delayed graft function. We also evaluated the association between donor AKI and a 3-year composite outcome of all-cause graft failure or estimated glomerular filtration rate ≤ 20 mL/min/1.73 m2 in a subcohort of 30% of recipients. Among 2,430 kidneys transplanted from 1,298 deceased donors, 585 (24%) were from donors with AKI. Over a median follow-up of 4.0 years, there were no significant differences in graft survival by donor AKI stage. We found no evidence that pre-specified variables modified the effect of donor AKI on graft survival. In the subcohort, donor AKI was not associated with the 3-year composite outcome. Donor AKI was not associated with graft failure in this well-phenotyped cohort. Given the organ shortage, the transplant community should consider measures to increase utilization of kidneys from deceased donors with AKI.

The Association of Angiogenesis Markers With Acute Kidney Injury and Mortality After Cardiac Surgery.

RATIONALE & OBJECTIVE: The process of angiogenesis after kidney injury may determine recovery and long-term outcomes. We evaluated the association of angiogenesis markers with acute kidney injury (AKI) and mortality after cardiac surgery. STUDY DESIGN: Prospective cohort. SETTING & PARTICIPANTS: 1,444 adults undergoing cardiac surgery in the TRIBE-AKI (Translational Research Investigating Biomarker Endpoints for Acute Kidney Injury) cohort. EXPOSURES: Plasma concentrations of 2 proangiogenic markers (vascular endothelial growth factor A [VEGF] and placental growth factor [PGF]) and 1 antiangiogenic marker (soluble VEGF receptor 1 [VEGFR1]), measured pre- and postoperatively within 6 hours after surgery. OUTCOMES: AKI, long AKI duration (≥7 days), and 1-year all-cause mortality. ANALYTICAL APPROACH: Multivariable logistic regression. RESULTS: Following cardiac surgery, plasma VEGF concentrations decreased 2-fold, and PGF and VEGFR1 concentrations increased 1.5- and 8-fold, respectively. There were no meaningful associations of preoperative concentrations of angiogenic markers with outcomes of AKI and mortality. Higher postoperative VEGF and PGF concentrations were independently associated with lower odds of AKI (adjusted ORs of 0.89 [95% CI, 0.82-0.98] and 0.69 [95% CI, 0.55-0.87], respectively), long AKI duration (0.65 [95% CI, 0.49-0.87] and 0.48 [95% CI, 0.28-0.82], respectively), and mortality (0.74 [95% CI, 0.62-0.89] and 0.46 [95% CI, 0.31-0.68], respectively). In contrast, higher postoperative VEGFR1 concentrations were independently associated with higher odds of AKI (1.56; 95% CI, 1.31-1.87), long AKI duration (1.75; 95% CI, 1.09-2.82), and mortality (2.28; 95% CI, 1.61-3.22). LIMITATIONS: Angiogenesis markers were not measured after hospital discharge, so we were unable to determine long-term trajectories of angiogenesis marker levels during recovery and follow-up. CONCLUSIONS: Higher levels of postoperative proangiogenic markers, VEGF and PGF, were associated with lower AKI and mortality risk, whereas higher postoperative antiangiogenic VEGFR1 levels were associated with higher risk for AKI and mortality.

Reliability of deceased-donor procurement kidney biopsy images uploaded in United Network for Organ Sharing.

Prior studies demonstrate poor agreement among pathologists' interpretation of kidney biopsy slides. Reliability of representative images of these slides uploaded to the United Network of Organ Sharing (UNOS) web portal for clinician review has not been studied. We hypothesized high agreement among pathologists' image interpretation, since static images eliminate variation induced by viewing different areas of movable slides. To test our hypothesis, we compared the assessments of UNOS-uploaded images recorded in standardized forms by three pathologists. We selected 100 image sets, each having at least two images from kidneys of deceased donors. Weighted Cohen's kappa was used for inter-rater agreement. Mean (SD) donor age was 50 (13). Acute tubular injury had kappas of 0.12, 0.14, and 0.19; arteriolar hyalinosis 0.16, 0.27, and 0.38; interstitial inflammation 0.30, 0.33, and 0.49; interstitial fibrosis 0.28, 0.32, and 0.67; arterial intimal fibrosis 0.34, 0.42, and 0.59; tubular atrophy 0.35, 0.41, and 0.52; glomeruli thrombi 0.32, 0.53, and 0.85; and global glomerulosclerosis 0.68, 0.70, and 0.77. Pathologists' agreement demonstrated kappas of 0.12 to 0.77. The lower values raise concern about the reliability of using images. Although further research is needed to understand how uploaded images are used clinically, the field may consider higher-quality standards for biopsy photomicrographs.

Perspective on Clinical Application of Biomarkers in AKI.

Several biomarkers of renal injury have been identified but the utility of these biomarkers is largely confined to research studies, whereas widespread clinical applicability is limited. This is partly because the use of serum creatinine as the comparator has several limitations and restricts the full interpretation of biomarker performance. To highlight the potential for clinical application of biomarkers, the most pertinent biomarker data are summarized here, using clinically relevant scenarios in which biomarkers could assist with diagnostic and management dilemmas. The paradigms proposed in this review aim to enhance the clinical diagnosis, management, and prognosis of AKI through the combined use of available clinical markers and novel inflammatory, injury, and repair biomarkers.

Kidney Injury and Repair Biomarkers in Marathon Runners.

BACKGROUND: Investigation into strenuous activity and kidney function has gained interest given increasing marathon participation. STUDY DESIGN: Prospective observational study. SETTING & PARTICIPANTS: Runners participating in the 2015 Hartford Marathon. PREDICTOR: Completing a marathon. OUTCOMES: Acute kidney injury (AKI) as defined by AKI Network (AKIN) criteria. Stage 1 AKI was defined as 1.5- to 2-fold or 0.3-mg/dL increase in serum creatinine level within 48 hours of day 0 and stage 2 was defined as a more than 2- to 3-fold increase in creatinine level. Microscopy score was defined by the number of granular casts and renal tubular epithelial cells. MEASUREMENTS: Samples were collected 24 hours premarathon (day 0), immediately postmarathon (day 1), and 24 hours postmarathon (day 2). Measurements of serum creatinine, creatine kinase, and urine albumin were completed, as well as urine microscopy analysis. 6 injury urine biomarkers (IL-6, IL-8, IL-18, kidney injury molecule 1, neutrophil gelatinase-associated lipocalin, and tumor necrosis factor α) and 2 repair urine biomarkers (YKL-40 and monocyte chemoattractant protein 1) were measured. RESULTS: 22 marathon runners were included. Mean age was 44 years and 41% were men. 82% of runners developed an increase in creatinine level equivalent to AKIN-defined AKI stages 1 and 2. 73% had microscopy diagnoses of tubular injury. Serum creatinine, urine albumin, and injury and repair biomarker levels peaked on day 1 and were significantly elevated compared to day 0 and day 2. Serum creatine kinase levels continued to significantly increase from day 0 to day 2. LIMITATIONS: Small sample size and limited clinical data available at all time points. CONCLUSIONS: Marathon runners developed AKI and urine sediment diagnostic of tubular injury. An increase in injury and repair biomarker levels suggests structural damage to renal tubules occurring after marathon. The results of our study should be validated in larger cohorts with longer follow-up of kidney function.

Biomarkers for the detection of renal fibrosis and prediction of renal outcomes: a systematic review.

BACKGROUND: Fibrosis is the unifying pathway leading to chronic kidney disease. Identifying biomarkers of fibrosis may help predict disease progression. METHODS: We performed a systematic review to evaluate the reliability of blood and urine biomarkers in identifying fibrosis on biopsy as well as predicting renal outcomes. Using MEDLINE and EMBASE, a two-stage search strategy was implemented. Stage I identified a library of biomarkers correlating with fibrosis on biopsy. Stage II evaluated the association between biomarkers identified in stage I, and renal outcomes. Only biomarkers with moderate positive correlation with fibrosis (r > 0.40) or acceptable area under the curve (AUC >0.65) advanced to stage II. RESULTS: Stage I identified 17 studies and 14 biomarkers. Five biomarkers met criteria to advance to stage II, but only three were independently associated with renal outcomes. Transforming growth factor ß (TGF-ß) correlated with fibrosis (r = 0.60), and was associated with 1.7-3.9 times the risk of worsening renal function in 426 patients. Monocyte chemoattractant protein-1 (MCP-1) diagnosed fibrosis with AUC of 0.66 and was associated with 2.3-11.0 times the risk of worsening renal function in 596 patients. Matrix metalloproteinase-2 (MMP-2) correlated with fibrosis (r = 0.41), and was associated with 2.5 times the risk of worsening renal function. CONCLUSIONS: Given the heterogeneity of the data due to diverse patient populations along with differing renal outcomes, a meta-analysis could not be conducted. Nonetheless we can conclude from the published data that TGF-ß, MCP-1 and MMP-2 may identify patients at risk for renal fibrosis and hence worse renal outcomes.

The Role of Vascular Biomarkers in Outcomes of Patients with Kidney Disease.

BACKGROUND: Vascular biomarkers may explain the link between acute kidney injury (AKI) and poor long-term outcomes such as cardiovascular disease (CVD). Vessel injury is exceedingly common in AKI and contributes to the development of kidney fibrosis and CVD. As prominent determinants of vessel stability in the body, angiopoietins and other prominent vascular biomarkers may explain this biological link. SUMMARY: Angiopoietin-1 (Angpt-1) promotes vessel stability by decreasing inflammation, apoptosis, and vessel permeability. By contrast, angiopoietin-2 (Angpt-2) blocks the binding of Angpt-1 to its receptor and thus contributes to vessel instability and permeability. Based on our findings, higher levels of Angpt-1 relative to Angpt-2 were strongly associated with less risk of kidney disease progression, heart failure, and death in hospitalized patients with AKI. In chronic kidney disease patients, it has been shown that endothelial damage in glomerular vasculature triggers Angpt-2 secretion, leading to poor outcomes such as CVD and mortality. Furthermore, in kidney transplant recipients, Angpt-2 levels significantly decrease after transplantation suggesting that transplantation may reduce Angpt-2 levels and decrease rates of poor outcomes. Other vascular health pathways - such as vascular endothelial growth factor and placental growth factor - were associated with improved rates of survival after cardiac surgery in participants with and without AKI. KEY MESSAGES: Vascular health biomarkers provide actionable pathways for clinical intervention in reducing CVD and mortality for AKI patients. There is great need for future research that focuses on developing robust prognostic vascular biomarker panels in order to help identify high-risk AKI survivors who may benefit from targeted follow-up and therapy, with the intention to prevent kidney and cardiac complications.

Analysis of the human kidney transcriptome and plasma proteome identifies markers of proximal tubule maladaptation to injury.

Acute kidney injury (AKI) is a major risk factor for long-term adverse outcomes, including chronic kidney disease. In mouse models of AKI, maladaptive repair of the injured proximal tubule (PT) prevents complete tissue recovery. However, evidence for PT maladaptation and its etiological relationship with complications of AKI is lacking in humans. We performed single-nucleus RNA sequencing of 120,985 nuclei in kidneys from 17 participants with AKI and seven healthy controls from the Kidney Precision Medicine Project. Maladaptive PT cells, which exhibited transcriptomic features of dedifferentiation and enrichment in pro-inflammatory and profibrotic pathways, were present in participants with AKI of diverse etiologies. To develop plasma markers of PT maladaptation, we analyzed the plasma proteome in two independent cohorts of patients undergoing cardiac surgery and a cohort of marathon runners, linked it to the transcriptomic signatures associated with maladaptive PT, and identified nine proteins whose genes were specifically up- or down-regulated by maladaptive PT. After cardiac surgery, both cohorts of patients had increased transforming growth factor-ß2 (TGFB2), collagen type XXIII-α1 (COL23A1), and X-linked neuroligin 4 (NLGN4X) and had decreased plasminogen (PLG), ectonucleotide pyrophosphatase/phosphodiesterase 6 (ENPP6), and protein C (PROC). Similar changes were observed in marathon runners with exercise-associated kidney injury. Postoperative changes in these markers were associated with AKI progression in adults after cardiac surgery and post-AKI kidney atrophy in mouse models of ischemia-reperfusion injury and toxic injury. Our results demonstrate the feasibility of a multiomics approach to discovering noninvasive markers and associating PT maladaptation with adverse clinical outcomes.

A randomized clinical trial assessing the effect of automated medication-targeted alerts on acute kidney injury outcomes.

Acute kidney injury is common among hospitalized individuals, particularly those exposed to certain medications, and is associated with substantial morbidity and mortality. In a pragmatic, open-label, National Institutes of Health-funded, parallel group randomized controlled trial (clinicaltrials.gov NCT02771977), we investigate whether an automated clinical decision support system affects discontinuation rates of potentially nephrotoxic medications and improves outcomes in patients with AKI. Participants included 5060 hospitalized adults with AKI and an active order for any of three classes of medications of interest: non-steroidal anti-inflammatory drugs, renin-angiotensin-aldosterone system inhibitors, or proton pump inhibitors. Within 24 hours of randomization, a medication of interest was discontinued in 61.1% of the alert group versus 55.9% of the usual care group (relative risk 1.08, 1.04 - 1.14, p = 0.0003). The primary outcome - a composite of progression of acute kidney injury, dialysis, or death within 14 days - occurred in 585 (23.1%) of individuals in the alert group and 639 (25.3%) of patients in the usual care group (RR 0.92, 0.83 - 1.01, p = 0.09). Trial Registration Clinicaltrials.gov NCT02771977.