Rakesh Malhotra

Oliguria is an early predictor of higher mortality in critically ill patients

Oliguria is a valuable marker of kidney function and a criterion for diagnosing and staging acute kidney injury (AKI). However, the utility of urine output as a specific metric for renal dysfunction is somewhat controversial. To study this issue further we tested whether urine output is a sensitive, specific, and early measure for diagnosing and staging AKI in 317 critically ill patients in a prospective observational study. Urine output was assessed every hour and serum creatinine every 12 to 24  h. The sensitivity and specificity of different definitions of oliguria for the diagnosis of AKI were compared with the Acute Kidney Injury Network serum creatinine criterion. The incidence of AKI increased from 24%, based solely on serum creatinine, to 52% by adding the urine output as a diagnostic criterion. Oliguric patients without a change in serum creatinine had an intensive care unit mortality rate (8.8%) significantly higher than patients without AKI (1.3%), and similar to oliguric patients with an increase in serum creatinine (10.4%). The diagnosis of AKI occurred earlier in oliguric than in non-oliguric patients. Oliguria of more than 12  h and oliguria of 3 or more episodes were associated with an increased mortality rate. Thus, urine output is a sensitive and early marker for AKI and is associated with adverse outcomes in intensive care unit patients.

Biomarkers for the Early Detection and Prognosis of Acute Kidney Injury

AKI is an increasingly common disorder that is strongly linked to short- and long-term morbidity and mortality. Despite a growing heterogeneity in its causes, providing a timely and certain diagnosis of AKI remains challenging. In this review, we summarize the evolution of AKI biomarker studies over the past few years, focusing on two major areas of investigation: the early detection and prognosis of AKI. We highlight some of the lessons learned in conducting AKI biomarker studies, including ongoing attempts to address the limitations of creatinine as a reference standard and the recent shift toward evaluating the prognostic potential of these markers. Lastly, we suggest current gaps in knowledge and barriers that may be hindering their incorporation into care and a full ascertainment of their value.

Association Between More Intensive vs Less Intensive Blood Pressure Lowering and Risk of Mortality in Chronic Kidney Disease Stages 3 to 5: A Systematic Review and Meta-analysis

Importance Trials in patients with hypertension have demonstrated that intensive blood pressure (BP) lowering reduces the risk of cardiovascular disease and all-cause mortality but may increase the risk of chronic kidney disease (CKD) incidence and progression. Whether intensive BP lowering is associated with a mortality benefit in patients with prevalent CKD remains unknown. Objectives To conduct a systematic review and meta-analysis of randomized clinical trials (RCTs) to investigate if more intensive compared with less intensive BP control is associated with reduced mortality risk in persons with CKD stages 3 to 5. Data Sources Ovid MEDLINE, Cochrane Library, EMBASE, PubMed, Science Citation Index, Google Scholar, and clinicaltrials.gov electronic databases. Study Selection All RCTs were included that compared 2 defined BP targets (either active BP treatment vs placebo or no treatment, or intensive vs less intensive BP control) and enrolled adults (≥18 years) with CKD stages 3 to 5 (estimated glomerular filtration rate <60 mL/min/1.73 m2) exclusively or that included a CKD subgroup between January 1, 1950, and June 1, 2016. Data Extraction and Synthesis Two of us independently evaluated study quality and extracted characteristics and mortality events among persons with CKD within the intervention phase for each trial. When outcomes within the CKD group had not previously been published, trial investigators were contacted to request data within the CKD subset of their original trials. Main Outcome and Measure All-cause mortality during the active treatment phase of each trial. Results This study identified 30 RCTs that potentially met the inclusion criteria. The CKD subset mortality data were extracted in 18 trials, among which there were 1293 deaths in 15 924 participants with CKD. The mean (SD) baseline systolic BP (SBP) was 148 (16) mm Hg in both the more intensive and less intensive arms. The mean SBP dropped by 16 mm Hg to 132 mm Hg in the more intensive arm and by 8 mm Hg to 140 mm Hg in the less intensive arm. More intensive vs less intensive BP control resulted in 14.0% lower risk of all-cause mortality (odds ratio, 0.86; 95% CI, 0.76-0.97; P = .01), a finding that was without significant heterogeneity and appeared consistent across multiple subgroups. Conclusions and Relevance Randomization to more intensive BP control is associated with lower mortality risk among trial participants with hypertension and CKD. Further studies are required to define absolute BP targets for maximal benefit and minimal harm.

Renal kallikrein excretion and epigenetics in human acute kidney injury: Expression, mechanisms and consequences

BackgroundRenal kallikrein (KLK1) synthesis and urinary excretion are reportedly diminished during AKI (acute kidney injury) in animal models, and provision of kallikrein abrogates renal injury in this setting, but data in human AKI is limited. Therefore we first examined KLK1 renal excretion in human AKI, and then probed potential endocrine and epigenetic mechanisms for its alterations.MethodsKLK1 enzymatic activity excretion was evaluated in urine from patients with established or incipient AKI, versus healthy/non-hospital as well as ICU controls. Endocrine control of KLK1 excretion was then probed by catecholamine and aldosterone measurements in established AKI versus healthy controls. To examine epigenetic control of KLK1 synthesis, we tested blood and urine DNA for changes in promoter CpG methylation of the KLK1 gene, as well as LINE-1 elements, by bisulfite sequencing.ResultsPatients with early/incipient AKI displayed a modest reduction of KLK1 excretion, but unexpectedly, established AKI displayed substantially elevated urine KLK1 excretion, ~11-fold higher than healthy controls, and ~3-fold greater than ICU controls. We then probed potential mechanisms of the change. Established AKI patients had lower SBP, higher heart rate, and higher epinephrine excretion than healthy controls, though aldosterone excretion was not different. Promoter KLK1 CpG methylation was higher in blood than urine DNA, while KLK1 methylation in blood DNA was significantly higher in established AKI than healthy controls, though KLK1 methylation in urine tended to be higher in AKI, directionally consistent with earlier/incipient but not later/established changes in KLK1 excretion in AKI. On multivariate ANOVA, AKI displayed coordinate changes in KLK1 excretion and promoter methylation, though directionally opposite to expectation. Control (LINE-1 repetitive element) methylation in blood and urine DNA was similar between AKI and controls.ConclusionsUnexpectedly, increased KLK1 excretion in AKI patients was found; this increase is likely to be due in part to increments in adrenergic tone during BP depression. Epigenetic changes at KLK1 may also play a role in early changes of KLK1 expression and thus AKI susceptibility or recovery.

A risk prediction score for acute kidney injury in the intensive care unit

Background Acute kidney injury (AKI) is common in critically ill patients and is associated with high morbidity and mortality. Early identification of high-risk patients provides an opportunity to develop strategies for prevention, early diagnosis and treatment of AKI. Methods We undertook this multicenter prospective cohort study to develop and validate a risk score for predicting AKI in patients admitted to an intensive care unit (ICU). Patients were screened for predictor variables within 48 h of ICU admission. Baseline and acute risk factors were recorded at the time of screening and serum creatinine was measured daily for up to 7 days. A risk score model for AKI was developed with multivariate regression analysis combining baseline and acute risk factors in the development cohort (573 patients) and the model was further evaluated on a test cohort (144 patients). Validation was performed on an independent prospective cohort of 1300 patients. The discriminative ability of the risk model was assessed by the area under the receiver operating characteristic curve (AUROC) and model calibration was evaluated by Hosmer-Lemeshow statistic. AKI was defined by the Kidney Disease: Improving Global Outcomes criteria (absolute change of 0.3 mg/dL or relative change of 50% from baseline serum creatinine in 48 h to 7 days, respectively). Results AKI developed in 754 (37.2%) patients. In the multivariate model, chronic kidney disease, chronic liver disease, congestive heart failure, hypertension, atherosclerotic coronary vascular disease, pH ≤ 7.30, nephrotoxin exposure, sepsis, mechanical ventilation and anemia were identified as independent predictors of AKI and the AUROC for the model in the test cohort was 0.79 [95% confidence interval (CI) 0.70-0.89]. On the external validation cohort, the AUROC value was 0.81 (95% CI 0.78-0.83). The risk model demonstrated good calibration in both cohorts. Positive and negative predictive values for the optimal cutoff value of ≥ 5 points in test and validation cohorts were 22.7 and 96.1% and 31.8 and 95.4%, respectively. Conclusions A risk score model integrating chronic comorbidities and acute events at ICU admission can identify patients at high risk to develop AKI. This risk assessment tool could help clinicians to stratify patients for primary prevention, surveillance and early therapeutic intervention to improve care and outcomes of ICU patients.

Relationship of Neutrophil-to-Lymphocyte Ratio and Serum Albumin Levels with C-Reactive Protein in Hemodialysis Patients: Results from 2 International Cohort Studies

Background/Aim: The neutrophil-to-lymphocyte ratio (NLR), defined as the neutrophil count divided by lymphocyte count, is an inexpensive and readily available parameter, which may serve as a surrogate for inflammation markers, such as C-reactive protein (CRP). The aim of this study was to determine the utility of NLR in the prediction of elevated CRP levels in hemodialysis (HD) patients. Methods: We analyzed 43,272 HD patients from 2 distinct cohorts within the Monitoring Dialysis Outcomes research collaboration in whom contemporaneous measurements of neutrophil and lymphocyte counts, serum albumin and CRP levels were available. Logistic regression was used to determine the relationship of trichotomized NLR (<2.5, 2.5-5 and >5.0) and albumin levels (<3.1, 3.1-4.0 and >4.0 g/dl) with elevated CRP levels (>10.0, >20.0 and >30.0 mg/l). Congruence of the prediction models was examined by comparing the regression parameters and by cross-validating each regression equation within the other cohort. Results: We found that NLR >5.0 vs. <2.5 (cohort 1: OR 2.3; p < 0.0001 and cohort 2: OR 2.0; p < 0.0001) was associated with CRP levels >10.0 mg/l. Stepwise increase in odds ratio for CRP >10.0 mg/l was observed with the combination of high NLR and low albumin levels (NLR >5.0 and albumin <3.1) (cohort 1: OR 7.6; p < 0.0001 and cohort 2: OR 11.9; p < 0.0001). Cross-validation of the 2 regression models revealed a predictive accuracy of 0.68 and 0.69 in the respective cohorts. Conclusion: This study suggests that NLR could serve as a potential surrogate marker for CRP. Our results may add to diagnostic abilities in settings where CRP is not measured routinely in HD patients. NLR is easy to integrate into daily practice and may be used as a marker of systemic inflammation.

Levels of Protein C and Soluble Thrombomodulin in Critically Ill Patients with Acute Kidney Injury: A Multicenter Prospective Observational Study

Endothelial dysfunction contributes to the development of acute kidney injury (AKI) in animal models of ischemia reperfusion injury and sepsis. There are limited data on markers of endothelial dysfunction in human AKI. We hypothesized that Protein C (PC) and soluble thrombomodulin (sTM) levels could predict AKI. We conducted a multicenter prospective study in 80 patients to assess the relationship of PC and sTM levels to AKI, defined by the AKIN creatinine (AKI Scr) and urine output criteria (AKI UO). We measured marker levels for up to 10 days from intensive care unit admission. We used area under the curve (AUC) and time-dependent multivariable Cox proportional hazard model to predict AKI and logistic regression to predict mortality/non-renal recovery. Protein C and sTM were not different in patients with AKI UO only versus no AKI. On intensive care unit admission, as PC levels are usually lower with AKI Scr, the AUC to predict the absence of AKI was 0.63 (95%CI 0.44-0.78). The AUC using log10 sTM levels to predict AKI was 0.77 (95%CI 0.62-0.89), which predicted AKI Scr better than serum and urine neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C, urine kidney injury molecule-1 and liver-fatty acid-binding protein. In multivariable models, PC and urine NGAL levels independently predicted AKI (p=0.04 and 0.02) and PC levels independently predicted mortality/non-renal recovery (p=0.04). In our study, PC and sTM levels can predict AKI Scr but are not modified during AKI UO alone. PC levels could independently predict mortality/non-renal recovery. Additional larger studies are needed to define the relationship between markers of endothelial dysfunction and AKI.

The Effect of Extended Release Niacin on Markers of Mineral Metabolism in CKD

BACKGROUND AND OBJECTIVES Niacin downregulates intestinal sodium-dependent phosphate transporter 2b expression and reduces intestinal phosphate transport. Short-term studies have suggested that niacin lowers serum phosphate concentrations in patients with CKD and ESRD. However, the long-term effects of niacin on serum phosphate and other mineral markers are unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Trial was a randomized, double-blind, placebo-controlled trial testing extended release niacin in persons with prevalent cardiovascular disease. We examined the effect of randomized treatment with niacin (1500 or 2000 mg) or placebo on temporal changes in markers of mineral metabolism in 352 participants with eGFR<60 ml/min per 1.73 m2 over 3 years. Changes in each marker were compared over time between the niacin and placebo arms using linear mixed effects models. RESULTS Randomization to niacin led to 0.08 mg/dl lower plasma phosphate concentrations per year of treatment compared with placebo (P<0.01) and 0.25 mg/dl lower mean phosphate 3 years after baseline (3.32 versus 3.57 mg/dl; P=0.03). In contrast, randomization to niacin was not associated with statistically significant changes in plasma intact fibroblast growth factor 23, parathyroid hormone, calcium, or vitamin D metabolites over 3 years. CONCLUSIONS The use of niacin over 3 years lowered serum phosphorous concentrations but did not affect other markers of mineral metabolism in participants with CKD.

Performance of the Surprise Question Compared to Prediction Models in Hemodialysis Patients: A Prospective Study

Background: The surprise question (SQ) (“Would you be surprised if this patient were still alive in 6 or 12 months?”) is used as a mortality prognostication tool in hemodialysis (HD) patients. We compared the performance of the SQ with that of prediction models (PMs) for 6- and 12-month mortality prediction. Methods: Demographic, clinical, laboratory, and dialysis treatment indicators were used to model 6- and 12-month mortality probability in a HD patients training cohort (n = 6,633) using generalized linear models (GLMs). A total of 10 nephrologists from 5 HD clinics responded to the SQ in 215 patients followed prospectively for 12 months. The performance of PM was evaluated in the validation (n = 6,634) and SQ cohorts (n = 215) using the areas under receiver operating characteristics curves. We compared sensitivities and specificities of PM and SQ. Results: The PM and SQ cohorts comprised 13,267 (mean age 61 years, 55% men, 54% whites) and 215 (mean age 62 years, 59% men, 50% whites) patients, respectively. During the 12-month follow-up, 1,313 patients died in the prediction model cohort and 22 in the SQ cohort. For 6-month mortality prediction, the GLM had areas under the curve of 0.77 in the validation cohort and 0.77 in the SQ cohort. As for 12-month mortality, areas under the curve were 0.77 and 0.80 in the validation and SQ cohorts, respectively. The 6- and 12-month PMs had sensitivities of 0.62 (95% CI 0.35–0.88) and 0.75 (95% CI 0.56–0.94), respectively. The 6- and 12-month SQ sensitivities were 0.23 (95% CI 0.002–0.46) and 0.35 (95% CI 0.14–0.56), respectively. Conclusion: PMs exhibit superior sensitivity compared to the SQ for mortality prognostication in HD patients.

Starting and Stopping Renal Replacement Therapy in the Critically Ill

Abstract Most cases of acute kidney injury (AKI) in critical care settings are caused by effective volume depletion, sepsis syndrome, and nephrotoxicity. Although these are generally reversible processes, a significant number of patients require renal replacement therapy (RRT) to replace renal function and support other organs during the disease process. When renal replacement or renal support is required, there is a far worse prognosis than with lesser degrees of renal injury. 1 , 2 , 3 Several dialysis techniques are now available for RRT to manage AKI. Acute intermittent hemodialysis, peritoneal dialysis, and continuous techniques are the main treatment modalities. Considerable debate has ensued over the choice of modality, the amount and frequency of dialysis, and the duration of therapy in the acute setting, especially for the critically ill patients. There is a paucity of information on the criteria for initiating and stopping RRT. Timing of the intervention or the criteria used to start therapy is based on individual preferences and experience, and no set guidelines are followed. This chapter addresses the pertinent issues that should be considered for initiating and stopping RRT in the critically ill patient.