Zoltan H. Endre

Acute kidney injury: an increasing global concern

Despite an increasing incidence of acute kidney injury in both high-income and low-income countries and growing insight into the causes and mechanisms of disease, few preventive and therapeutic options exist. Even small acute changes in kidney function can result in short-term and long-term complications, including chronic kidney disease, end-stage renal disease, and death. Presence of more than one comorbidity results in high severity of illness scores in all medical settings. Development or progression of chronic kidney disease after one or more episode of acute kidney injury could have striking socioeconomic and public health outcomes for all countries. Concerted international action encompassing many medical disciplines is needed to aid early recognition and management of acute kidney injury.

Improved performance of urinary biomarkers of acute kidney injury in the critically ill by stratification for injury duration and baseline renal function

To better understand the diagnostic and predictive performance of urinary biomarkers of kidney injury, we evaluated γ-glutamyltranspeptidase (GGT), alkaline phosphatase (AP), neutrophil-gelatinase-associated lipocalin (NGAL), cystatin C (CysC), kidney injury molecule-1 (KIM-1), and interleukin-18 (IL-18) in a prospective observational study of 529 patients in 2 general intensive care units (ICUs). Comparisons were made using the area under the receiver operator characteristic curve (AUC) for diagnosis or prediction of acute kidney injury (AKI), dialysis, or death, and reassessed after patient stratification by baseline renal function (estimated glomerular filtration rate, eGFR) and time after renal insult. On ICU entry, no biomarker had an AUC above 0.7 in the diagnosis or prediction of AKI. Several biomarkers (NGAL, CysC, and IL-18) predicted dialysis (AUC over 0.7), and all except KIM-1 predicted death at 7 days (AUC between 0.61 and 0.69). Performance was improved by stratification for eGFR or time or both. With eGFR <60 ml/min, CysC and KIM-1 had AUCs of 0.69 and 0.73, respectively, within 6 h of injury, and between 12 and 36 h, CysC (0.88), NGAL (0.85), and IL-18 (0.94) had utility. With eGFR >60 ml/min, GGT (0.73), CysC (0.68), and NGAL (0.68) had the highest AUCs within 6 h of injury, and between 6 and 12 h, all AUCs except AP were between 0.68 and 0.78. Beyond 12 h, NGAL (0.71) and KIM-1 (0.66) performed best. Thus, the duration of injury and baseline renal function should be considered in evaluating biomarker performance to diagnose AKI.

Early intervention with erythropoietin does not affect the outcome of acute kidney injury (the EARLYARF trial).

We performed a double-blind placebo-controlled trial to study whether early treatment with erythropoietin could prevent the development of acute kidney injury in patients in two general intensive care units. As a guide for choosing the patients for treatment we measured urinary levels of two biomarkers, the proximal tubular brush border enzymes gamma-glutamyl transpeptidase and alkaline phosphatase. Randomization to either placebo or two doses of erythropoietin was triggered by an increase in the biomarker concentration product to levels above 46.3, with a primary outcome of relative average plasma creatinine increase from baseline over 4 to 7 days. Of 529 patients, 162 were randomized within an average of 3.5 h of a positive sample. There was no difference in the incidence of erythropoietin-specific adverse events or in the primary outcome between the placebo and treatment groups. The triggering biomarker concentration product selected patients with more severe illness and at greater risk of acute kidney injury, dialysis, or death; however, the marker elevations were transient. Early intervention with high-dose erythropoietin was safe but did not alter the outcome. Although these two urine biomarkers facilitated our early intervention, their transient increase compromised effective triaging. Further, our study showed that a composite of these two biomarkers was insufficient for risk stratification in a patient population with a heterogeneous onset of injury.

Potential use of biomarkers in acute kidney injury: report and summary of recommendations from the 10th Acute Dialysis Quality Initiative consensus conference

Over the last decade there has been considerable progress in the discovery and development of biomarkers of kidney disease, and several have now been evaluated in different clinical settings. While there is a growing literature on the performance of various biomarkers in clinical studies, there is limited information on how these biomarkers would be utilized by clinicians to manage patients with acute kidney injury (AKI). Recognizing this gap in knowledge, we convened the 10th Acute Dialysis Quality Initiative (ADQI) meeting to review the literature on biomarkers in AKI and their application in clinical practice. We asked an international group of experts to assess four broad areas for biomarker utilization for AKI: risk assessment, diagnosis and staging; differential diagnosis; prognosis and management and novel physiological techniques including imaging. This article provides a summary of the key findings and recommendations of the group, to equip clinicians to effectively use biomarkers in AKI.

Reversal of cardiac and renal fibrosis by pirfenidone and spironolactone in streptozotocin-diabetic rats

Fibrosis leads to chronic impairment of cardiac and renal function and thus reversal of existing fibrosis may improve function and survival. This project has determined whether pirfenidone, a new antifibrotic compound, and spironolactone, an aldosterone antagonist, reverse both deposition of the major extracellular matrix proteins, collagen and fibronectin, and functional changes in the streptozotocin(STZ)‐diabetic rat. Streptozotocin (65 mg kg−1 i.v.)‐treated rats given pirfenidone (5‐methyl‐1‐phenyl‐2‐[1H]‐pyridone; approximately 200 mg kg−1 day−1 as 0.2–2g 1−1 drinking water) or spironolactone (50 mg kg−1 day−1 s.c.) for 4 weeks starting 4 weeks after STZ showed no attenuation of the increased blood glucose concentrations and increased food and water intakes which characterize diabetes in this model. STZ‐treatment increased perivascular and interstitial collagen deposition in the left ventricle and kidney, and surrounding the aorta. Cardiac, renal and plasma fibronectin concentrations increased in STZ‐diabetic rats. Passive diastolic stiffness increased in isolated hearts from STZ‐diabetic rats. Both pirfenidone and spironolactone treatment attenuated these increases without normalizing the decreased +dP/dtmax of STZ‐diabetic hearts. Left ventricular papillary muscles from STZ‐treated rats showed decreased maximal positive inotropic responses to noradrenaline, EMD 57033 (calcium sensitizer) and calcium chloride; this was not reversed by pirfenidone or spironolactone treatment. STZ‐treatment transiently decreased GFR and urine flow rates in isolated perfused kidneys; pirfenidone but not spironolactone prevented the return to control values. Thus, short‐term pirfenidone and spironolactone treatment reversed cardiac and renal fibrosis and attenuated the increased diastolic stiffness without normalizing cardiac contractility or renal function in STZ‐diabetic rats.

Some biomarkers of acute kidney injury are increased in pre-renal acute injury

Pre-renal acute kidney injury (AKI) is assumed to represent a physiological response to underperfusion. Its diagnosis is retrospective after a transient rise in plasma creatinine, usually associated with evidence of altered tubular transport, particularly that of sodium. In order to test whether pre-renal AKI is reversible because injury is less severe than that of sustained AKI, we measured urinary biomarkers of injury (cystatin C, neutrophil gelatinase-associated lipocalin (NGAL), γ-glutamyl transpeptidase, IL-18, and kidney injury molecule-1 (KIM-1)) at 0, 12, and 24 h following ICU admission. A total of 529 patients were stratified into groups having no AKI, AKI with recovery by 24 h, recovery by 48 h, or the composite of AKI greater than 48 h or dialysis. Pre-renal AKI was identified in 61 patients as acute injury with recovery within 48 h and a fractional sodium excretion <1%. Biomarker concentrations significantly and progressively increased with the duration of AKI. After restricting the AKI recovery within the 48 h cohort to pre-renal AKI, this increase remained significant. The median concentration of KIM-1, cystatin C, and IL-18 were significantly greater in pre-renal AKI compared with no-AKI, while NGAL and γ-glutamyl transpeptidase concentrations were not significant. The median concentration of at least one biomarker was increased in all but three patients with pre-renal AKI. Thus, the reason why some but not all biomarkers were increased requires further study. The results suggest that pre-renal AKI represents a milder form of injury.

Rapid detection of acute kidney injury by plasma cystatin C in the intensive care unit

BACKGROUND Plasma cystatin C (pCysC) has been proposed as an alternative to plasma creatinine (pCr) as a measure of renal function. We compared the detection of functional change by both biomarkers in critically ill patients. METHODS pCysC and pCr were measured on admission to one of two intensive care units (ICU) and then daily over 7 days. Patients were classified according to the analyte that first increased by either ≥25 or ≥50% above the admission value. The proportion of patients in each class was compared using McNemars chi-square test. Sustained acute kidney injury (AKI, a ≥50% increase in pCr from baseline for ≥24 h), dialysis and death within 30 days were recorded. The ability of pCysC and pCr on admission to predict sustained AKI, dialysis or death was assessed from the area under the receiver operator characteristic curve (AUC). RESULTS Of 442 patients, 83 had a ≥50% increase in one analyte, 17 in both and 342 in neither. Comparable numbers for a ≥25% increase were 163 in one analyte, 45 in both and 234 in neither. pCysC increased prior to pCr more frequently than vice versa in both the cohort with a ≥50% increase (P < 0.0001) and with a ≥25% increase (P < 0.0001). pCysC predicted sustained AKI with an AUC of 0.80 [95% confidence interval (CI) = 0.71-0.88]. pCysC and pCr were similarly moderately predictive of death or dialysis with AUCs of 0.61 [95% CI = 0.53-0.68] and 0.60 [95% CI = 0.51-0.67], respectively. CONCLUSION pCysC was an effective and earlier surrogate marker of decreased renal function than pCr in a general ICU population.

Urinary cystatin C is diagnostic of acute kidney injury and sepsis, and predicts mortality in the intensive care unit

IntroductionTo evaluate the utility of urinary cystatin C (uCysC) as a diagnostic marker of acute kidney injury (AKI) and sepsis, and predictor of mortality in critically ill patients.MethodsThis was a two-center, prospective AKI observational study and post hoc sepsis subgroup analysis of 444 general intensive care unit (ICU) patients. uCysC and plasma creatinine were measured at entry to the ICU. AKI was defined as a 50% or 0.3-mg/dL increase in plasma creatinine above baseline. Sepsis was defined clinically. Mortality data were collected up to 30 days. The diagnostic and predictive performances of uCysC were assessed from the area under the receiver operator characteristic curve (AUC) and the odds ratio (OR). Multivariate logistic regression was used to adjust for covariates.ResultsEighty-one (18%) patients had sepsis, 198 (45%) had AKI, and 64 (14%) died within 30 days. AUCs for diagnosis by using uCysC were as follows: sepsis, 0.80, (95% confidence interval (CI), 0.74 to 0.87); AKI, 0.70 (CI, 0.64 to 0.75); and death within 30 days, 0.64 (CI, 0.56 to 0.72). After adjustment for covariates, uCysC remained independently associated with sepsis, AKI, and mortality with odds ratios (CI) of 3.43 (2.46 to 4.78), 1.49 (1.14 to 1.95), and 1.60 (1.16 to 2.21), respectively. Concentrations of uCysC were significantly higher in the presence of sepsis (P < 0.0001) or AKI (P < 0.0001). No interaction was found between sepsis and AKI on the uCysC concentrations (P = 0.53).ConclusionsUrinary cystatin C was independently associated with AKI, sepsis, and death within 30 days.Trial registrationAustralian New Zealand Clinical Trials Registry ACTRN012606000032550.

Test Characteristics of Urinary Biomarkers Depend on Quantitation Method in Acute Kidney Injury

The concentration of urine influences the concentration of urinary biomarkers of AKI. Whether normalization to urinary creatinine concentration, as commonly performed to quantitate albuminuria, is the best method to account for variations in urinary biomarker concentration among patients in the intensive care unit is unknown. Here, we compared the diagnostic and prognostic performance of three methods of biomarker quantitation: absolute concentration, biomarker normalized to urinary creatinine concentration, and biomarker excretion rate. We measured urinary concentrations of alkaline phosphatase, γ-glutamyl transpeptidase, cystatin C, neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, and IL-18 in 528 patients on admission and after 12 and 24 hours. Absolute concentration best diagnosed AKI on admission, but normalized concentrations best predicted death, dialysis, or subsequent development of AKI. Excretion rate on admission did not diagnose or predict outcomes better than either absolute or normalized concentration. Estimated 24-hour biomarker excretion associated with AKI severity, and for neutrophil gelatinase-associated lipocalin and cystatin C, with poorer survival. In summary, normalization to urinary creatinine concentration improves the prediction of incipient AKI and outcome but provides no advantage in diagnosing established AKI. The ideal method for quantitating biomarkers of urinary AKI depends on the outcome of interest.

Back-Calculating Baseline Creatinine with MDRD Misclassifies Acute Kidney Injury in the Intensive Care Unit

BACKGROUND AND OBJECTIVES The purpose of this study was to assess the viability of back-calculation with the Modification of Diet in Renal Disease (MDRD) formula to determine baseline creatinine on the basis of acute kidney injury (AKI) metrics, RIFLE criteria, and Acute Kidney Injury Network (AKIN) criteria for the purpose of clinical trial outcomes or epidemiology. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This study was a retrospective analysis of prospectively collected data from patients with measured baseline creatinines before entry to the intensive care unit (ICU). The AKI status was determined using five different baseline creatinines: the measured creatinine (the standard) and an estimated creatinine determined by back-calculation using MDRD assuming a GFR of 75 ml/min (epCr75), 100 ml/min (epCr100), randomly generating a value on a lognormal curve (epCrRnd), and choosing the lowest creatinine value within the first week in the ICU (epCrlow). A subgroup of patients without chronic kidney disease (CKD) was similarly analyzed. RESULTS Of 224 patients, 70 (31%) had AKI according to RIFLE and 93 (42%) according to AKIN. The epCr75 and epCr100 distributions greatly overestimated the proportion with AKI. The epCrlow overestimated AKI according to AKIN but correctly estimated AKI according to RIFLE. The mean of 1000 epCrRnd distributions correctly estimated AKI according to RIFLE and AKIN. Each estimated distribution performed better in the non-CKD population with the exception of epCrRnd. However, only the epCrlow distribution accurately determined the proportion with AKI. CONCLUSIONS A measured rather than estimated value should be used for baseline creatinine in trials or epidemiologic studies of AKI.