Urinary Trace Elements Are Biomarkers for Early Detection of Acute Kidney Injury.

Introduction: Acute kidney injury (AKI) is common in hospitalized patients and associated with poor outcomes. Current methods for identifying AKI (rise in serum creatinine [sCr] or fall in urine output [UO]) are inadequate and delay detection. Early detection of AKI with easily measurable biomarkers might improve outcomes by facilitating early implementation of AKI care pathways. Methods: From a porcine model of AKI, we identified trace elements (TEs) in urine that were associated with subsequent development of AKI. We tested these putative biomarkers in 2 observational cohort studies of patients at high risk of AKI: 151 patients undergoing cardiac surgery and 150 patients admitted to a general adult intensive care unit (ICU). Results: In adults admitted to the ICU, urinary cadmium (Cd) (adjusted for urinary creatinine) had area under the receiver operating characteristic curve (AUROC) 0.70 and negative predictive value (NPV) 89%; copper (Cu) had AUROC 0.76 and NPV 91%. In humans (but not pigs), urinary zinc (Zn) was also associated with AKI and, in the ICU study, had AUROC 0.67 and NPV 80%. In patients undergoing cardiac surgery, Zn had AUROC 0.77 and NPV 91%; urinary Cd and Cu had poor AUROC but NPV of 93% and 95%, respectively. In control studies, we found that the urinary biomarkers are stable at room temperature for at least 14 days and are not affected by other confounding factors, such as chronic kidney disease (CKD). Conclusion: Urinary Cd, Cu, and Zn are novel biomarkers for early detection of AKI. Urinary trace metals have advantages over proteins as AKI biomarkers because they are stable at room temperature and have potential for cheap point-of-care testing using electrochemistry.

Definition of hourly urine output influences reported incidence and staging of acute kidney injury.

BACKGROUND: Acute kidney injury (AKI) is commonly defined using the KDIGO system, which includes criteria based on reduced urine output (UO). There is no consensus on whether UO should be measured using consecutive hourly readings or mean output. This makes KDIGO UO definition and staging of AKI vulnerable to inconsistency which has implications both for research and clinical practice. The objective of this study was to investigate whether the way in which UO is defined affects incidence and staging of AKI. METHODS: We conducted a retrospective analysis of two single centre observational studies investigating (i) patients undergoing cardiac surgery and (ii) patients admitted to general intensive care units (ICU). AKI was identified using KDIGO serum creatinine (SCr) criteria and two methods of UO (UOcons: UO meeting KDIGO criteria in each consecutive hour; UOmean: mean hourly UO meeting KDIGO criteria). RESULTS: Data from 151 CICU and 150 ICU admissions were analysed. Incidence of AKI using SCr alone was 23.8% in CICU and 32% in ICU. Incidence increased in both groups when UO was considered, with inclusion of UOmean more than doubling reported incidence of AKI (CICU: UOcons 39.7%, UOmean 72.8%; ICU: UOcons 51.3%, UOmean 69.3%). In both groups UOcons led to a larger increase in KDIGO stage 1 but UOmean increased the incidence of KDIGO stage 2. CONCLUSIONS: We demonstrate a serious lack of clarity in the internationally accepted AKI definition leading to significant variability in reporting of AKI incidence.

Hyperosmolar dehydration: A predictor of kidney injury and outcome in hospitalised older adults.

BACKGROUND & AIMS: Hospitalised older adults are vulnerable to dehydration. However, the prevalence of hyperosmolar dehydration (HD) and its impact on outcome is unknown. Serum osmolality is not measured routinely but osmolarity, a validated alternative, can be calculated using routinely measured serum biochemistry. This study aimed to use calculated osmolarity to measure the prevalence of HD (serum osmolarity >300 mOsm/l) and assess its impact on acute kidney injury (AKI) and outcome in hospitalised older adults. METHODS: This retrospective cohort study used data from a UK teaching hospital retrieved from the electronic database relating to all medical emergency admissions of patients aged ≥ 65 years admitted between 1st May 2011 and 31st October 2013. Using these data, Charlson comorbidity index (CCI), National Early Warning Score (NEWS), length of hospital stay (LOS) and mortality were determined. Osmolarity was calculated using the equation of Krahn and Khajuria. RESULTS: A total of 6632 patients were identified; 27% had HD, 39% of whom had AKI. HD was associated with a median (Q1, Q3) LOS of 5 (1, 12) days compared with 3 (1, 9) days in the euhydrated group, P < 0.001. Adjusted Cox-regression analysis demonstrated that patients with HD were four-times more likely to develop AKI 12-24 h after admission [Hazards Ratio (95% Confidence Interval) 4.5 (3.5-5.6), P < 0.001], and had 60% greater 30-day mortality [1.6 (1.4-1.9), P < 0.001], compared with those who were euhydrated. CONCLUSION: HD is common in hospitalised older adults and is associated with increased LOS, risk of AKI and mortality. Further work is required to assess the validity of osmolality or osmolarity as an early predictor of AKI and the impact of HD on outcome prospectively.

Micronutrient and Amino Acid Losses During Renal Replacement Therapy for Acute Kidney Injury.

INTRODUCTION: Malnutrition is common in patients with acute kidney injury (AKI), particularly in those requiring renal replacement therapy (RRT). Use of RRT removes metabolic waste products and toxins, but it will inevitably also remove useful molecules such as micronutrients, which might aggravate malnutrition. The RRT modalities vary in mechanism of solute removal; for example, intermittent hemodialysis (IHD) uses diffusion, continuous veno-venous hemofiltration (CVVH) uses convection, and sustained low-efficiency diafiltration (SLEDf) uses a combination of these. METHODS: We assessed micronutrient and amino acid losses in 3 different RRT modalities in patients with AKI (IHD, n = 27; SLEDf, n = 12; CVVH, n = 21) after correction for dialysis dose and plasma concentrations. RESULTS: Total losses were affected by modality; generally CVVH >> SLEDf > IHD (e.g., amino acid loss was 18.69 ± 3.04, 8.21 ± 4.07, and 5.13 ± 3.1 g, respectively; P < 0.001). Loss of specific trace elements (e.g., copper and zinc) during RRT was marked, with considerable heterogeneity between RRT types (e.g., +849 and +2325 µg/l lost during SLEDf vs. IHD, respectively), whereas effluent losses of copper and zinc decreased during CVVH (effect size relative to IHD, -3167 and -1442 µg/l, respectively). B vitamins were undetectable in effluent, but experimental modeling estimated 40% to 60% loss within the first 15 minutes of RRT. CONCLUSION: Micronutrient and amino acid losses are marked during RRT in patients with AKI, with variation between RRT modalities and micronutrients.

Acute and chronic kidney disease in elderly patients with hip fracture: prevalence, risk factors and outcome with development and validation of a risk prediction model for acute kidney injury.

BACKGROUND: Hip fracture is a common injury in older people with a high rate of postoperative morbidity and mortality. This patient group is also at high risk of acute kidney injury (AKI) and chronic kidney disease (CKD), but little is known of the impact of kidney disease on outcome following hip fracture. METHODS: An observational cohort of consecutive patients with hip fracture in a large UK secondary care hospital. Predictive modelling of outcomes using development and validation datasets. Inclusion: all patients admitted with hip fracture with sufficient serum creatinine measurements to define acute kidney injury. Main outcome measures - development of acute kidney injury during admission; mortality (in hospital, 30-365 day and to follow-up); length of hospital stay. RESULTS: Data were available for 2848 / 2959 consecutive admissions from 2007-2011; 776 (27.2%) male. Acute kidney injury occurs in 24%; development of acute kidney injury is independently associated with male sex (OR 1.48 (1.21 to 1.80), premorbid chronic kidney disease stage 3B or worse (OR 1.52 (1.19 to 1.93)), age (OR 3.4 (2.29 to 5.2) for >85 years) and greater than one major co-morbidities (OR 1.61 (1.34 to 1.93)). Acute kidney injury of any stage is associated with an increased hazard of death, and increased length of stay (Acute kidney injury: 19.1 (IQR 13 to 31) days; no acute kidney injury 15 (11 to 23) days). A simplified predictive model containing Age, CKD stage (3B-5), two or more comorbidities, and male sex had an area under the ROC curve of 0.63 (0.60 to 0.67). CONCLUSIONS: Acute kidney injury following hip fracture is common and associated with worse outcome and greater hospital length of stay. With the number of people experiencing hip fracture predicted to rise, recognition of risk factors and optimal perioperative management of acute kidney injury will become even more important.

Diagnosis and Management of Iron Deficiency in CKD: A Summary of the NICE Guideline Recommendations and Their Rationale.

The UK-based National Institute for Health and Care Excellence (NICE) has updated its guidance on iron deficiency and anemia management in chronic kidney disease. This report outlines the recommendations regarding iron deficiency and their rationale. Serum ferritin alone or transferrin saturation alone are no longer recommended as diagnostic tests to assess iron deficiency. Red blood cell markers (percentage hypochromic red blood cells, reticulocyte hemoglobin content, or reticulocyte hemoglobin equivalent) are better than ferritin level alone at predicting responsiveness to intravenous iron. When red blood cell markers are not available, a combination of transferrin saturation < 20% and ferritin level < 100ng/mL is an alternative. In comparisons of the cost-effectiveness of different iron status testing and treatment strategies, using percentage hypochromic red blood cells > 6% was the most cost-effective strategy for both hemodialysis and nonhemodialysis patients. A trial of oral iron replacement is recommended in people not receiving an erythropoiesis-stimulating agent (ESA) and not on hemodialysis therapy. For children receiving ESAs, but not treated by hemodialysis, oral iron should be considered. In adults and children receiving ESAs and/or on hemodialysis therapy, intravenous iron should be offered. When giving intravenous iron, high-dose low-frequency administration is recommended. For all children and for adults receiving in-center hemodialysis, low-dose high-frequency administration may be more appropriate.

Remote effects of acute kidney injury in a porcine model.

Acute kidney injury (AKI) is a common and serious condition with no specific treatment. An episode of AKI may affect organs distant from the kidney, further increasing the morbidity associated with AKI. The mechanism of organ cross talk after AKI is unclear. The renal and immune systems of pigs and humans are alike. Using a preclinical animal (porcine) model, we tested the hypothesis that early effects of AKI on distant organs is by immune cell infiltration, leading to inflammatory cytokine production, extravasation, and edema. In 29 pigs exposed to either sham surgery or renal ischemia-reperfusion (control, n = 12; AKI, n = 17), we assessed remote organ (liver, lung, brain) effects in the short (from 2- to 48-h reperfusion) and longer term (5 wk later) using immunofluorescence (for leukocyte infiltration, apoptosis), a cytokine array, tissue elemental analysis (e.g., electrolytes), blood hematology and chemistry (e.g., liver enzymes), and PCR (for inflammatory markers). AKI elicited significant, short-term (∼24 h) increments in enzymes indicative of acute liver damage (e.g. , AST: ALT ratio; P = 0.02) and influenced tissue biochemistry in some remote organs (e.g., lung tissue [Ca(2+)] increased; P = 0.04). These effects largely resolved after 48 h, and no further histopathology, edema, apoptosis, or immune cell infiltration was noted in the liver, lung, or hippocampus in the short and longer term. AKI has subtle biochemical effects on remote organs in the short term, including a transient increment in markers of acute liver damage. These effects resolved by 48 h, and no further remote organ histopathology, apoptosis, edema, or immune cell infiltration was noted.

Micronutrient and amino acid losses in acute renal replacement therapy.

PURPOSE OF REVIEW: A wide range of renal replacement therapies is now available to support patients with acute kidney injury. These treatments utilize diffusion, convection or a combination of these mechanisms to remove metabolic waste products from the bloodstream. It is inevitable that physiologically important substances including micronutrients will also be removed. Here we review current knowledge of the extent of micronutrient loss, how it varies between treatment modalities and its clinical significance. RECENT FINDINGS: Very few studies have specifically investigated micronutrient loss in renal replacement therapy for acute kidney injury. Recent data suggest that trace elements and amino acids are lost during intermittent dialysis, hybrid therapies such as sustained low-efficiency diafiltration and continuous therapies. Extent of micronutrient loss appears to vary with treatment type, with continuous convection-based treatments probably causing greatest losses. SUMMARY: Patients with acute kidney injury are at high risk of disease-related malnutrition. The use of renal replacement therapy, although often essential for life support, results in loss of micronutrients into the filtrate or dialysate. Losses are probably greater with continuous convective treatments, but it is not yet known whether these losses are clinically significant or whether their replacement would improve patient outcomes.

The definition of acute kidney injury and its use in practice.

Acute kidney injury (AKI) is a common syndrome that is independently associated with increased mortality. A standardized definition is important to facilitate clinical care and research. The definition of AKI has evolved rapidly since 2004, with the introduction of the Risk, Injury, Failure, Loss, and End-stage renal disease (RIFLE), AKI Network (AKIN), and Kidney Disease Improving Global Outcomes (KDIGO) classifications. RIFLE was modified for pediatric use (pRIFLE). They were developed using both evidence and consensus. Small rises in serum creatinine are independently associated with increased mortality, and hence are incorporated into the current definition of AKI. The recent definition from the international KDIGO guideline merged RIFLE and AKIN. Systematic review has found that these definitions do not differ significantly in their performance. Health-care staff caring for children or adults should use standard criteria for AKI, such as the pRIFLE or KDIGO definitions, respectively. These efforts to standardize AKI definition are a substantial advance, although areas of uncertainty remain. The new definitions have enabled the use of electronic alerts to warn clinicians of possible AKI. Novel biomarkers may further refine the definition of AKI, but their use will need to produce tangible improvements in outcomes and cost effectiveness. Further developments in AKI definitions should be informed by research into their practical application across health-care providers. This review will discuss the definition of AKI and its use in practice for clinicians and laboratory scientists.

A real-time electronic alert to improve detection of acute kidney injury in a large teaching hospital.

BACKGROUND: Acute kidney injury (AKI) is a common and serious problem in hospitalized patients. Early detection is critical for optimal management but in practice is currently inadequate. To improve outcomes in AKI, development of early detection tools is essential. METHODS: We developed an automated real-time electronic alert system employing algorithms which combined internationally recognized criteria for AKI [Risk, Injury, Failure, Loss, End-stage kidney disease (RIFLE) and Acute Kidney Injury Network (AKIN)]. All adult patients admitted to Nottingham University Hospitals were included. Where a patient's serum creatinine increased sufficiently to define AKI, an electronic alert was issued, with referral to an intranet-based AKI guideline. Incidence of AKI Stages 1-3, in-hospital mortality, length of stay and distribution between specialties is reported. RESULTS: Between May 2011 and April 2013, 59,921 alerts resulted from 22,754 admission episodes, associated with 15,550 different patients. Overall incidence of AKI for inpatients was 10.7%. Highest AKI stage reached was: Stage 1 in 7.2%, Stage 2 in 2.2% and Stage 3 in 1.3%. In-hospital mortality for all AKI stages was 18.5% and increased with AKI stage (12.5, 28.4, 35.7% for Stages 1, 2 and 3 AKI, respectively). Median length of stay was 9 days for all AKI. CONCLUSIONS: This is the first fully automated real time AKI e-alert system, using AKIN and RIFLE criteria, to be introduced to a large National Health Service hospital. It has provided one of the biggest single-centre AKI datasets in the UK revealing mortality rates which increase with AKI stage. It is likely to have improved detection and management of AKI. The methodology is transferable to other acute hospitals.

Remote conditioning or erythropoietin before surgery primes kidneys to clear ischemia-reperfusion-damaged cells: a renoprotective mechanism?

Acute kidney injury is common, serious with no specific treatment. Ischemia-reperfusion is a common cause of acute kidney injury (AKI). Clinical trials suggest that preoperative erythropoietin (EPO) or remote ischemic preconditioning may have a renoprotective effect. Using a porcine model of warm ischemia-reperfusion-induced AKI (40-min bilateral cross-clamping of renal arteries, 48-h reperfusion), we examined the renoprotective efficacy of EPO (1,000 iu/kg iv.) or remote ischemic preconditioning (3 cycles, 5-min inflation/deflation to 200 mmHg of a hindlimb sphygmomanometer cuff). Ischemia-reperfusion induced significant kidney injury at 24 and 48 h (χ(2), 1 degree of freedom, >10 for 6/7 histopathological features). At 2 h, a panel of biomarkers including plasma creatinine, neutrophil gelatinase-associated lipocalin, and IL-1ß, and urinary albumin:creatinine could be used to predict histopathological injury. Ischemia-reperfusion increased cell proliferation and apoptosis in the renal cortex but, for pretreated groups, the apoptotic cells were predominantly intratubular rather than interstitial. At 48-h reperfusion, plasma IL-1ß and the number of subcapsular cells in G2-M arrest were reduced after preoperative EPO, but not after remote ischemic preconditioning. These data suggest an intrarenal mechanism acting within cortical cells that may underpin a renoprotective function for preoperative EPO and, to a limited extent, remote ischemic preconditioning. Despite equivocal longer-term outcomes in clinical studies investigating EPO as a renoprotective agent in AKI, optimal clinical dosing and administration have not been established. Our data suggest further clinical studies on the potential renoprotective effect of EPO and remote ischemic preconditioning are justified.

How acute kidney injury is investigated and managed in UK intensive care units--a survey of current practice.

BACKGROUND: Optimal management of acute kidney injury (AKI) remains controversial, particularly with respect to acutely unwell patients in the intensive care unit (ICU). This is likely to be attributable to the currently poor evidence base. Attempts to introduce guidance and consistency have been made over recent years, such as the AKI Network (AKIN) staging system and, in the UK, recommendations from the 2009 National Confidential Enquiry into Patient Outcome and Death (NCEPOD) report into AKI. We wished to ascertain how AKI is investigated and managed in intensive care units in the UK, and whether these recent initiatives have made any difference to clinical practice. METHODS: This is an online survey of all general adult UK ICUs between December 2009 and May 2010. RESULTS: One hundred and eighty-eight out of two hundred and thirty-three units (80%) started the survey; 167 (72%) completed it. Only 19.2% of respondents routinely use AKIN or Risk, Injury, Failure, Loss, End-stage kidney disease (RIFLE) criteria for diagnosis and staging of AKI. A nephrologist is never or rarely consulted about patients with AKI in over 40% of the units. Only 46.4% have 24-h access to a renal ultrasound service. Continuous venovenous haemofiltration (CVVH) is the most commonly used form of renal replacement therapy (RRT) but intermittent haemodialysis (IHD) is used infrequently. Continuous RRTs (CRRTs) are managed almost exclusively by intensivists, whereas IHD is managed predominantly by nephrologists. The most frequently used criteria for initiating RRT are hyperkalaemia, fluid overload and pH. Most units have a standard RRT protocol and 35 mL/kg/h is the most frequently prescribed dose of CVVH. Only 51% of the units assess the delivered dose of RRT. CONCLUSIONS: Considerable variation exists in the investigation and management of AKI in UK ICUs. Despite increasing recognition of the importance of AKI, few ICUs are aware of RIFLE and AKIN criteria.

Polarisation, key to good localisation.

Polarisation of cells is crucial for vectorial transport of ions and solutes. In literature, however, proteins specifically targeted to the apical or basolateral membrane are often studied in non-polarised cells. To investigate whether these data can be extrapolated to expression in polarised cells, we studied several membrane-specific proteins. In polarised MDCK cells, the Aquaporin-2 water channel resides in intracellular vesicles and apical membrane, while the vasopressin-type 2 receptor, anion-exchanger 1 (AE1) protein and E-Cadherin mainly localise to the basolateral membrane. In non-polarised MDCK cells, however, Aquaporin-2 localises, besides plasma membrane, mainly in the Golgi complex, while the others show a dispersed staining throughout the cell. Moreover, while AQP2 mutants in dominant nephrogenic diabetes insipidus are missorted to different organelles in polarised cells, they all predominantly localise to the Golgi complex in non-polarised MDCK cells. Additionally, the maturation of V2R, and likely its missorting, is affected in transiently-transfected compared to stably-transfected cells. In conclusion, we show that the use of stably-transfected polarised cells is crucial in interpreting the processing and the localisation of membrane targeted proteins.

A novel missense mutation in AE1 causing autosomal dominant distal renal tubular acidosis retains normal transport function but is mistargeted in polarized epithelial cells.

Mutations in SLC4A1, encoding the chloride-bicarbonate exchanger AE1, cause distal renal tubular acidosis (dRTA), a disease of defective urinary acidification by the distal nephron. In this study we report a novel missense mutation, G609R, causing dominant dRTA in affected members of a large Caucasian pedigree who all exhibited metabolic acidosis with alkaline urine, prominent nephrocalcinosis, and progressive renal impairment. To investigate the potential disease mechanism, the consequent effects of this mutation were determined. We first assessed anion transport function of G609R by expression in Xenopus oocytes. Western blotting and immunofluorescence demonstrated that the mutant protein was expressed at the oocyte cell surface. Measuring chloride and bicarbonate fluxes revealed normal 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid-inhibitable anion exchange, suggesting that loss-of-function of kAE1 cannot explain the severe disease phenotype in this kindred. We next expressed epitope-tagged wild-type or mutant kAE1 in Madin-Darby canine kidney cells. In monolayers grown to polarity, mutant kAE1 was detected subapically and at the apical membrane, as well as at the basolateral membrane, in contrast to the normal basolateral appearance of wild-type kAE1. These findings suggest that the seventh transmembrane domain that contains Gly-609 plays an important role in targeting kAE1 to the correct cell surface compartment. They confirm that dominant dRTA is associated with non-polarized trafficking of the protein, with no significant effect on anion transport function in vitro, which remains an unusual mechanism of human disease.

Non-polarized targeting of AE1 causes autosomal dominant distal renal tubular acidosis.

Autosomal dominant distal renal tubular acidosis (ddRTA) is caused by mutations in SLC4A1, which encodes the polytopic chloride-bicarbonate exchanger AE1 that is normally expressed at the basolateral surface of alpha-intercalated cells in the distal nephron. Here we report that, in contrast with many disorders in which mutant membrane proteins are retained intracellularly and degraded, ddRTA can result from aberrant targeting of AE1 to the apical surface.