Disruption in glutathione metabolism and altered energy production in the liver and kidney after ischemic acute kidney injury in mice.

Acute kidney injury (AKI) is a systemic disease that affects energy metabolism in various remote organs in murine models of ischemic AKI. However, AKI-mediated effects in the liver have not been comprehensively assessed. After inducing ischemic AKI in 8-10-week-old, male C57BL/6 mice, mass spectrometry metabolomics revealed that the liver had the most distinct phenotype 24 h after AKI versus 4 h and 7 days. Follow up studies with in vivo [13C6]-glucose tracing on liver and kidney 24 h after AKI revealed 4 major findings: (1) increased flux through glycolysis and the tricarboxylic (TCA) cycle in both kidney and liver; (2) depleted hepatic glutathione levels and its intermediates despite unchanged level of reactive oxygen species, suggesting glutathione consumption exceeds production due to systemic oxidative stress after AKI; (3) hepatic ATP depletion despite unchanged rate of mitochondrial respiration, suggesting increased ATP consumption relative to production; (4) increased hepatic and renal urea cycle intermediates suggesting hypercatabolism and upregulation of the urea cycle independent of impaired renal clearance of nitrogenous waste. Taken together, this is the first study to describe the hepatic metabolome after ischemic AKI in a murine model and demonstrates that there is significant liver-kidney crosstalk after AKI.

Blood Pressure, Readmission, and Mortality Among Patients Hospitalized With Acute Kidney Injury.

Importance: Acute kidney injury (AKI) complicates 20% to 25% of hospital admissions and is associated with long-term mortality, especially from cardiovascular disease. Lower systolic blood pressure (SBP) following AKI may be associated with lower mortality, but potentially at the cost of higher short-term complications. Objective: To determine associations of SBP with mortality and hospital readmissions following AKI, and to determine whether time from discharge affects these associations. Design, Setting, and Participants: This retrospective cohort study of adults with AKI during a hospitalization in Veteran Healthcare Association (VHA) hospitals was conducted between January 2013 and December 2018. Patients with 1 year or less of data within the VA system prior to admission, severe or end-stage liver disease, stage 4 or 5 chronic kidney disease, end-stage kidney disease, metastatic cancer, and no blood pressure values within 30 days of discharge were excluded. Data analysis was conducted from May 2022 to February 2024. Exposure: SBP was treated as time-dependent (categorized as <120 mm Hg, 120-129 mm Hg, 130-139 mm Hg, 140-149 mm Hg, 150-159 mm Hg, and ≥160 mm Hg [comparator]). Time spent in each SBP category was accumulated over time and represented in 30-day increments. Main Outcomes and Measures: Primary outcomes were time to mortality and time to all-cause hospital readmission. Cox proportional hazards regression was adjusted for demographics, comorbidities, and laboratory values. To evaluate associations over time, hazard ratios (HRs) were calculated at 60 days, 90 days, 120 days, 180 days, 270 days, and 365 days from discharge. Results: Of 237 409 admissions with AKI, 80 960 (57 242 aged 65 years or older [70.7%]; 77 965 male [96.3%] and 2995 female [3.7%]) were included. The cohort had high rates of diabetes (16 060 patients [20.0%]), congestive heart failure (22 516 patients [28.1%]), and chronic lung disease (27 682 patients [34.2%]), and 1-year mortality was 15.9% (12 876 patients). Overall, patients with SBP between 130 and 139 mm Hg had the most favorable risk level for mortality and readmission. There were clear, time-dependent mediations on associations in all groups. Compared with patients with SBP of 160 mm Hg or greater, the risk of mortality for patients with SBP between 130 and 139 mm Hg decreased between 60 days (adjusted HR, 1.20; 99% CI, 1.00-1.44) and 365 days (adjusted HR, 0.58; 99% CI, 0.45-0.76). SBP less than 120 mm Hg was associated with increased risk of mortality at all time points. Conclusions and Relevance: In this retrospective cohort study of post-AKI patients, there were important time-dependent mediations of the association of blood pressure with mortality and readmission. These findings may inform timing of post-AKI blood pressure treatment.

Redox Regulation of Nrf2 in Cisplatin-Induced Kidney Injury.

Cisplatin, a potent chemotherapeutic agent, is marred by severe nephrotoxicity that is governed by mechanisms involving oxidative stress, inflammation, and apoptosis pathways. The transcription factor Nrf2, pivotal in cellular defense against oxidative stress and inflammation, is the master regulator of the antioxidant response, upregulating antioxidants and cytoprotective genes under oxidative stress. This review discusses the mechanisms underlying chemotherapy-induced kidney injury, focusing on the role of Nrf2 in cancer therapy and its redox regulation in cisplatin-induced kidney injury. We also explore Nrf2's signaling pathways, post-translational modifications, and its involvement in autophagy, as well as examine redox-based strategies for modulating Nrf2 in cisplatin-induced kidney injury while considering the limitations and potential off-target effects of Nrf2 modulation. Understanding the redox regulation of Nrf2 in cisplatin-induced kidney injury holds significant promise for developing novel therapeutic interventions. This knowledge could provide valuable insights into potential strategies for mitigating the nephrotoxicity associated with cisplatin, ultimately enhancing the safety and efficacy of cancer treatment.

Risk Factors for Death Among Veterans Following Acute Kidney Injury.

BACKGROUND: Acute kidney injury is prevalent among hospitalized veterans, and associated with increased risk of death following discharge. However, risk factors for death following acute kidney injury have not been well defined. We developed a mortality prediction model using Veterans Health Administration data. METHODS: This retrospective cohort study included inpatients from 2013 through 2018 with a creatinine increase of ≥0.3 mg/dL. We evaluated 45 variables for inclusion in our final model, with a primary outcome of 1-year mortality. Bootstrap sampling with replacement was used to identify variables selected in >60% of models using stepwise selection. Best sub-sets regression using Akaike information criteria was used to identify the best-fitting parsimonious model. RESULTS: A total of 182,683 patients were included, and 38,940 (21.3%) died within 1 year of discharge. The 10-variable model to predict mortality included age, chronic lung disease, cancer within 5 years, unexplained weight loss, dementia, congestive heart failure, hematocrit, blood urea nitrogen, bilirubin, and albumin. Notably, acute kidney injury stage, chronic kidney disease, discharge creatinine, and proteinuria were not selected for inclusion. C-statistics in the primary validation cohorts were 0.77 for the final parsimonious model, compared with 0.52 for acute kidney injury stage alone. CONCLUSION: We identified risk factors for long-term mortality following acute kidney injury. Our 10-variable model did not include traditional renal variables, suggesting that non-kidney factors contribute to the risk of death more than measures of kidney disease in this population, a finding that may have implications for post-acute kidney injury care.

Creatinine elevations from baseline at the time of cardiac surgery are associated with postoperative complications.

OBJECTIVES: Baseline kidney function is a key predictor of postoperative morbidity and mortality. Whether an increased creatinine at the time of surgery, compared with the lowest creatinine in the 3 months before surgery, is associated with poor outcomes has not been evaluated. We examined whether creatinine elevations from "baseline" were associated with adverse postoperative outcomes. METHODS: A total of 1486 patients who underwent cardiac surgery at the University of Colorado Hospital between January 2011 and May 2016 met inclusion criteria. "Change in creatinine from baseline" was defined as the difference between the immediate presurgical creatinine value and the lowest creatinine value within 3 months preceding surgery. Outcomes evaluated were in-hospital mortality, postoperative infection, postoperative stroke, development of stage 3 acute kidney injury, intensive care unit length of stay, and hospital length of stay. Outcomes were adjusted using a balancing score to account for differences in patient characteristics. RESULTS: There were significant increases in the odds of postoperative infection (odds ratio, 1.17; confidence interval, 1.02-1.34; per 0.1 mg/dL increase in creatinine), stage 3 acute kidney injury (odds ratio, 1.44; confidence interval; 1.18-1.75), intensive care unit length of stay (odds ratio, 1.13; confidence interval, 1.01-1.26), and hospital length of stay (odds ratio, 1.09; confidence interval, 1.05-1.13). There was a significant increase in mortality in the unadjusted analysis, although not after adjustment using a balancing score. There was no association with postoperative stroke. CONCLUSIONS: Elevations in creatinine at the time of surgery above the "baseline" level are associated with increased postoperative morbidity. Baseline creatinine should be established before surgery, and small changes in creatinine should trigger heightened vigilance in the postoperative period.

Stage 1 acute kidney injury is independently associated with infection following cardiac surgery.

OBJECTIVES: Severe acute kidney injury (AKI) is a known risk factor for infection and mortality. However, whether stage 1 AKI is a risk factor for infection has not been evaluated in adults. We hypothesized that stage 1 AKI following cardiac surgery would independently associate with infection and mortality. METHODS: In this retrospective propensity score-matched study, we evaluated 1620 adult patients who underwent nonemergent cardiac surgery at the University of Colorado Hospital from 2011 to 2017. Patients who developed stage 1 AKI by Kidney Disease Improving Global Outcomes creatinine criteria within 72 hours of surgery were matched to patients who did not develop AKI. The primary outcome was an infection, defined as a new surgical-site infection, positive blood or urine culture, or development of pneumonia. Secondary outcomes included in-hospital mortality, stroke, and intensive care unit (ICU) and hospital length of stay (LOS). RESULTS: Stage 1 AKI occurred in 293 patients (18.3%). Infection occurred in 20.9% of patients with stage 1 AKI compared with 8.1% in the no-AKI group (P < .001). In propensity-score matched analysis, stage 1 AKI independently associated with increased infection (odds ratio [OR]; 2.24, 95% confidence interval [CI], 1.37-3.17), ICU LOS (OR, 2.38; 95% CI, 1.71-3.31), and hospital LOS (OR, 1.30; 95% CI, 1.17-1.45). CONCLUSIONS: Stage 1 AKI is independently associated with postoperative infection, ICU LOS, and hospital LOS. Treatment strategies focused on prevention, early recognition, and optimal medical management of AKI may decrease significant postoperative morbidity.

KIM-1 and Kidney Disease Progression in Autosomal Dominant Polycystic Kidney Disease: HALT-PKD Results.

BACKGROUND: Cyst compression of renal tubules plays a role in the progression of autosomal dominant polycystic kidney disease (ADPKD) and may induce expression of kidney injury molecule-1 (KIM-1). Whether urinary KIM-1 indexed for creatinine (uKIM-1/Cr) is a prognostic marker of disease progression in ADPKD is unknown.In this secondary analysis of a prospective cohort study, we sought to determine whether patients with high as opposed to low uKIM-1/CR at baseline had greater rates of eGFR loss and height-adjusted total kidney volume (HtTKV) increase. METHODS: Baseline uKIM-1/Cr values were obtained from 754 participants in Halt Progression of Polycystic Kidney Disease (HALT-PKD) studies A (early ADPKD) and B (late ADPKD). The predictor was uKIM-1/Cr, which was dichotomized by a median value of 0.2417 pg/g, and the primary outcomes were measured longitudinally over time. Mixed-effects linear models were used in the analysis to calculate the annual slope of change in eGFR and HtTKV. RESULTS: Patients with high uKIM-1/Cr (above the median) had an annual decline in eGFR that was 0.47 mL/min greater than that in those with low uKIM-1/Cr (p = 0.0015) after adjustment for all considered covariates. This association was seen in study B patients alone (0.45 mL/min; p = 0.009), but not in study A patients alone (0.42 mL/min; p = 0.06). High baseline uKIM-1/Cr was associated with higher HtTKV in the baseline cross-sectional analysis compared to low uKIM-1/Cr (p = 0.02), but there was no difference between the groups in the mixed-effects model annual slopes. CONCLUSION: Elevated baseline uKIM-1/Cr is associated with a greater decline in eGFR over time. Further research is needed to determine whether uKIM-1/Cr improves risk stratification in patients with ADPKD.

IL-6-mediated hepatocyte production is the primary source of plasma and urine neutrophil gelatinase-associated lipocalin during acute kidney injury.

Neutrophil gelatinase associated lipocalin (NGAL, Lcn2) is the most widely studied biomarker of acute kidney injury (AKI). Previous studies have demonstrated that NGAL is produced by the kidney and released into the urine and plasma. Consequently, NGAL is currently considered a tubule specific injury marker of AKI. However, the utility of NGAL to predict AKI has been variable suggesting that other mechanisms of production are present. IL-6 is a proinflammatory cytokine increased in plasma by two hours of AKI and mediates distant organ effects. Herein, we investigated the role of IL-6 in renal and extra-renal NGAL production. Wild type mice with ischemic AKI had increased plasma IL-6, increased hepatic NGAL mRNA, increased plasma NGAL, and increased urine NGAL; all reduced in IL-6 knockout mice. Intravenous IL-6 in normal mice increased hepatic NGAL mRNA, plasma NGAL and urine NGAL. In mice with hepatocyte specific NGAL deletion (Lcn2hep-/-) and ischemic AKI, hepatic NGAL mRNA was absent, and plasma and urine NGAL were reduced. Since urine NGAL levels appear to be dependent on plasma levels, the renal handling of circulating NGAL was examined using recombinant human NGAL. After intravenous recombinant human NGAL administration to mice, human NGAL in mouse urine was detected by ELISA during proximal tubular dysfunction, but not in pre-renal azotemia. Thus, during AKI, IL-6 mediates hepatic NGAL production, hepatocytes are the primary source of plasma and urine NGAL, and plasma NGAL appears in the urine during proximal tubule dysfunction. Hence, our data change the paradigm by which NGAL should be interpreted as a biomarker of AKI.

Critical Care Nephrology: Core Curriculum 2020.

The intensive care unit (ICU) is a common source of high-acuity nephrology consultations. Although advanced chronic kidney disease is associated with increased ICU mortality, the prognosis of acute kidney injury (AKI) requiring renal replacement therapy is far worse, with short-term mortality rates that often exceed 50%. As such, it is essential that practicing nephrologists be comfortable caring for critically ill patients. This Core Curriculum article emphasizes the developments of the last decade since the last Core Curriculum installment on this topic in 2009. We focus on some of the most common causes of AKI in the critical care setting and use these AKI causes to delve into specific topics most relevant to critical care nephrology, including acute respiratory distress syndrome, extracorporeal membrane oxygenation, evolving concepts in fluid management, and shock. We conclude by reviewing the basics of palliative care nephrology and dialysis decision making in the ICU.

Thrombocytopenia After Cardiopulmonary Bypass Is Associated With Increased Morbidity and Mortality.

BACKGROUND: Thrombocytopenia is a risk factor for morbidity and mortality in critically ill patients, and is common after cardiopulmonary bypass (CPB). In this study, we evaluate whether thrombocytopenia after CPB is an independent risk factor for postoperative morbidity and mortality. METHODS: We retrospectively evaluated 1364 patients requiring CPB at the University of Colorado Hospital between January 2011 and May 2016. Platelet nadir, absolute change in platelets, and percent change in platelets were modeled as continuous variables. Patients with postoperative thrombocytopenia (defined a nadir <75 × 103/µL within 72 hours) were also compared with patients without thrombocytopenia in a propensity-matched model. The primary outcome was in-hospital mortality, and secondary outcomes included postoperative infection, postoperative acute kidney injury (AKI), postoperative stroke, and prolonged intensive care unit (ICU) and hospital lengths of stay (LOS). RESULTS: Postoperative thrombocytopenia occurred in 356 (26.0%) patients. In multivariable analysis, platelet nadir was significantly inversely associated with mortality (odds ratio [OR], 0.955; 95% confidence interval [CI], 0.934-0.975; P < .001), postoperative infection (OR, 0.992; 95% CI, 0.986-0.999; P = .03), AKI (all stage) (OR, 0.993; 95% CI, 0.988-0.998; P = .01), AKI (stage 3) (OR, 0.966; 95% CI, 0.951-0.982; P < .001), postoperative stroke (OR, 0.974; 95% CI, 0.956-0.992; P = .006), prolonged ICU stay (OR, 0.986; 95% CI, 0.981-0.991; P < .001), and hospital LOS (OR, 0.998; 95% CI, 0.997-0.999; P = .001). Percent change in platelets from baseline was also significantly associated with all primary and secondary outcomes. CONCLUSIONS: Postoperative thrombocytopenia is independently associated with postoperative mortality, AKI, infection, stroke, and prolonged ICU and hospital LOS. Serial platelet monitoring may help identify patients at higher risk of postoperative complications. Further studies investigating strategies to reduce postoperative thrombocytopenia, including reducing CPB time, are needed.

Postoperative Complications Are Not Elevated in Well-Compensated ESRD Patients Undergoing Cardiac Surgery: End-Stage Renal Disease Cardiac Surgery Outcomes.

BACKGROUND: Patients with end-stage renal disease (ESRD) are at high risk for cardiac disease requiring surgery, and have been shown to have increased surgical risks. There have been significant improvements in ESRD management, surgical techniques, and patient selection over the past 10 y. We evaluated rates of serious postoperative outcomes in stable, well-dialyzed patients with ESRD undergoing nonemergent cardiac surgery compared to the general cardiac surgery population. METHODS: In this propensity-score matched study, we evaluated 1451 adult patients who underwent nonemergent cardiac surgery at the University of Colorado Hospital (UCH) between 2011 and 2016. Patients with ESRD were compared to nonESRD patients. The primary outcome was a composite endpoint, including 30-d mortality, stroke, postoperative infection, and prolonged intensive care unit (ICU) length of stay (LOS). RESULTS: A total of 35 patients with ESRD met inclusion criteria. These select patients were younger with few comorbidities than the nonESRD population. There were no statistically significant differences in the composite outcome between ESRD and nonESRD patients in the propensity-matched analysis (OR 0.70, CI 0.29-1.72, P = 0.44). There were no significant differences or trends for in-hospital mortality, postoperative stroke, infection, ICU LOS, or hospital LOS between the patients with and without ESRD. CONCLUSIONS: Stable ESRD patients undergoing nonemergent surgery are not at increased risk of major postoperative complications when compared to those without ESRD. Well-compensated ESRD patients should not be excluded from surgical consideration.

Biomarkers of Drug-Induced Kidney Toxicity.

Blood urea nitrogen and serum creatinine are imperfect markers of kidney function because they are influenced by many renal and nonrenal factors independent of kidney function. A biomarker that is released directly into the blood or urine by the kidney in response to injury may be a better early marker of drug-induced kidney toxicity than blood urea nitrogen and serum creatinine. Urine albumin and urine protein, as well as urinary markers kidney injury molecule-1 (KIM-1), ß2-microglobulin (B2M), cystatin C, clusterin, and trefoil factor-3 (TFF-3) have been accepted by the Food and Drug Administration and European Medicines Agency as highly sensitive and specific urinary biomarkers to monitor drug-induced kidney injury in preclinical studies and on a case-by-case basis in clinical trials. Other biomarkers of drug-induced kidney toxicity that have been detected in the urine of rodents or patients include IL-18, neutrophil gelatinase-associated lipocalin, netrin-1, liver-type fatty acid-binding protein (L-FABP), urinary exosomes, and TIMP2 (insulin-like growth factor-binding protein 7)/IGFBP7 (insulin-like growth factor-binding protein 7), also known as NephroCheck, the first Food and Drug Administration-approved biomarker testing platform to detect acute kidney injury in patients. In the future, a combined use of functional and damage markers may advance the field of biomarkers of drug-induced kidney toxicity. Earlier detection of drug-induced kidney toxicity with a kidney-specific biomarker may result in the avoidance of nephrotoxic agents in clinical studies and may allow for earlier intervention to repair damaged kidneys.

Continuous Renal Replacement Therapy Dosing in the Severely Underweight: A Case Report.

Guidelines recommend that patients treated with continuous renal replacement therapy be delivered an effluent dose of 20 to 25 mL/kg/h. There is debate, especially at the extremes of body mass index, as to whether actual or ideal body weight (IBW) should be used in these dose calculations. A middle-aged woman with severe anorexia presented with 48 hours of altered mental status. Laboratory tests showed severe metabolic acidosis necessitating intubation, which was ultimately found to be due to nonprescribed use of metformin for weight loss. The patient became anuric and was initiated on continuous venovenous hemodialysis. Due to refractory acidosis, the modality was converted to continuous venovenous hemodiafiltration by adding postfilter hypertonic bicarbonate solution. Based on changes in sodium and bicarbonate levels over 4 hours with hypertonic bicarbonate solution, we were able to calculate an "effective" volume of distribution for this severely underweight patient. Our calculations suggest that IBW gives a better approximation of effective volume of distribution than actual body weight in a severely underweight woman. Inadequate effluent flow rate calculated based on actual rather than IBW may lead to insufficient correction of metabolic derangements in extremely underweight patients.

The role of type I hypersensitivity reaction and IgE-mediated mast cell activation in acute interstitial nephritis.

BACKGROUND: Acute interstitial nephritis (AIN) presents with acute kidney injury, with evidence of interstitial inflammation and tubulitis on histology, and the presence of fever, rash, and eosinophiluria. Although the pathogenesis of this disease is not well understood, cell-mediated immunity is thought to play a major role. We hypothesized that IgE mediated mast cell activation is also involved in the pathogenesis of renal injury in AIN. METHODS: 28 patients, with biopsy proven AIN over a 5-year period, were included in this study. Clinical data, including renal outcomes and the etiologies of AIN, were evaluated in all patients. Available tissues (renal biopsy) from 26 of the patients were stained for ß-tryptase (marker for mast cell degranulation), IgE, IL-16, and CD3. A negative control for immunostaining was included. RESULTS: Samples from all 26 individuals stained positive for ß-tryptase (mean of 11.16 cells/high power field), IgE (mean average of 0.68 cells/HPF), IL-16 (28% of the interstitium), and CD3 (33% of the interstitium). Acute interstitial nephritis was due to medication in 73%, systemic disease in 15%, and unknown (idiopathic) in 12% of the cases. 86% of patients were treated with corticosteroids. 18% required acute inpatient dialysis, with 7% remaining on dialysis longterm. CONCLUSIONS: Our study suggests that IgE and mast cell activation may play a role in the pathogenesis of AIN.

Are 5-7 Days of Folic Acid Supplementation Necessary prior to Pemetrexed? Observations from a Case Series.

OBJECTIVE: Current regulatory guidelines advise 5-7 days of folic acid supplementation prior to pemetrexed. Although taking folic acid during and after pemetrexed therapy is important, it remains unclear whether premedication is truly necessary, particularly as it can be inconvenient for patients, can contribute to their anxiety by delaying chemotherapy, and can create challenges in scheduling chemotherapy. METHODS AND RESULTS: We retrospectively sought to identify and evaluate outcomes among non-small cell lung cancer patients who received less than the advised folic acid premedication. Only 8 patients were identified. However, upon critical examination of first-cycle chemotherapy outcomes, we observed no major adverse events with a shortened course of folic acid premedication. CONCLUSION: In the very rare circumstance where urgent therapy is warranted, a healthcare provider can lookto this small case series and find modest precedent for the safe administration of pemetrexed in the absence of a full week of folic acid premedication.