Evi Nagler

Urinary and serum biomarkers for the diagnosis of acute kidney injury: an in-depth review of the literature

BACKGROUND Acute kidney injury (AKI) remains associated with high morbidity and mortality, despite progress in medical care. Although the RIFLE (Risk, Injury, Failure, Loss, End-Stage Kidney Disease) and AKIN (Acute Kidney Injury Network) criteria, based on serum creatinine and urine output, were a step forward in diagnosing AKI, a reliable tool to differentiate between true parenchymal and pre-renal azotaemia in clinical practice is still lacking. In the last decade, many papers on the use of new urinary and serum biomarkers for the diagnosis and prognostication of AKI have been published. Thus, the question arises which biomarker is a reliable differential diagnostic tool under which circumstances. METHODS We searched Medline from inception to April 2012 using medical subject heading and text words for AKI and biomarkers [neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), Cystatin C, interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-18 (IL-18), N-acetyl-glucosaminidase (NAG), glutathione transferases (GST) and liver fatty acid binding protein (LFABP)] to identify relevant papers in five different settings (paediatrics, cardiac surgery, emergency department, critically ill and contrast-induced nephropathy). RESULTS We included 87 relevant papers, reporting on 74 studies. Depending upon the setting, 7-27 different definitions of AKI were used. Reported diagnostic performance of the different biomarkers was variable from poor to excellent, and no consistent generalizable conclusions can be drawn on their diagnostic value. CONCLUSIONS Early diagnosing of AKI in clinical conditions by using new serum and urinary biomarkers remains cumbersome, especially in those settings where timing and aetiology of AKI are not well defined. Putting too much emphasis on markers that have not convincingly proven reliability might lead to incorrect interpretation of clinical trials. Further research in this field is warranted before biomarkers can be introduced in clinical practice.

The Uremic Toxicity of Indoxyl Sulfate and p-Cresyl Sulfate: A Systematic Review

A growing number of publications supports a biologic effect of the protein-bound uremic retention solutes indoxyl sulfate and p-cresyl sulfate. However, the use of unrealistically high free concentrations of these compounds and/or inappropriately low albumin concentrations may blur the interpretation of these results. Here, we performed a systematic review, selecting only studies in which, depending on the albumin concentration, real or extrapolated free concentrations of indoxyl sulfate and p-cresyl sulfate remained in the uremic range. The 27 studies retrieved comprised in vitro and animal studies. A quality score was developed, giving 1 point for each of the following criteria: six or more experiments, confirmation by more than one experimental approach, neutralization of the biologic effect by counteractive reagents or antibodies, use of a real-life model, and use of dose-response analyses in vitro and/or animal studies. The overall average score was 3 of 5 points, with five studies scoring 5 of 5 points and six studies scoring 4 of 5 points, highlighting the superior quality of a substantial number of the retrieved studies. In the 11 highest scoring studies, most functional deteriorations were related to uremic cardiovascular disease and kidney damage. We conclude that our systematic approach allowed the retrieval of methodologically correct studies unbiased by erroneous conditions related to albumin binding. Our data seem to confirm the toxicity of indoxyl sulfate and p-cresyl sulfate and support their roles in vascular and renal disease progression.

Hypomagnesemia and the risk of death and GFR decline in chronic kidney disease.

BACKGROUND Hypomagnesemia predicts cardiovascular morbidity and mortality in the general population and accelerated loss of kidney function in renal transplant recipients and diabetics. It is associated with risk factors for cardiovascular and renal injury such as hyperaldosteronism, endothelial dysfunction, oxidative stress, insulin resistance, and hypertension. We aimed to establish the prognostic significance of hypomagnesemia for all-cause mortality and decline in estimated glomerular filtration rate (eGFR) in chronic kidney disease. METHODS Baseline parameters and serial follow-up measurements of serum creatinine were obtained in 1650 patients with chronic kidney disease and follow-up in a tertiary hospital between January 2002 and June 2011. We used Cox proportional hazards regression to assess the predictive value of magnesium for all-cause mortality and a random-effects mixed linear model for longitudinal analysis of the effect of serum magnesium on eGFR decline. RESULTS After a median follow-up of 5.1 years, 284 deaths occurred. Higher magnesium was associated with reduced mortality (adjusted hazard ratio 0.930 per 0.1 mg/dL increase; 95% confidence interval [CI], 0.887-0.974; P = .002) after adjustment for potential confounders including age, sex, diabetes, kidney function, and hypertension. Patients with low (<1.8 mg/dL) versus high (>2.2 mg/dL) serum magnesium had a 61% increased mortality risk (adjusted hazard ratio 1.613; 95% CI, 1.113-2.338; P = .012). On average, eGFR changed by 0.934 per year (95% CI, 0.927-0.941; P <.0001) or an annual decrease of 6.6%. After adjustment for age, sex, diabetes, and hypertension, this change was modified by a factor of 1.033 (95% CI, 1.003-1.065; P = .032) per 1-mg/dL increase in baseline magnesium, corresponding to an annual eGFR decrease of 3.5%. The effect of magnesium lost significance after adjustment for additional covariates, including diuretics. CONCLUSION Hypomagnesemia predicts mortality and kidney function decline in chronic kidney disease patients. Confounding factors and treatment effects may affect these associations. Its potential as a modifiable risk factor remains to be established.

High-Dose Adjuvant Radiotherapy After Radical Prostatectomy With or Without Androgen Deprivation Therapy

PURPOSE To retrospectively evaluate the outcome and toxicity in patients receiving high-dose (>69 Gy) adjuvant radiotherapy (HD-ART) and the impact of androgen deprivation therapy (ADT). METHODS AND MATERIALS Between 1999 and 2008, 225 node-negative patients were referred for HD-ART with or without ADT to two large academic institutions. Indications for HD-ART were extracapsular extension, seminal vesicle invasion (SVI), and/or positive surgical margins at radical prostatectomy (RP). A dose of at least 69.1 Gy was prescribed to the prostate bed and seminal vesicle bed. The ADT consisted of a luteinizing hormone-releasing hormone analog. The duration and indication of ADT was left at the discretion of the treating physician. The effect of HD-ART and ADT on biochemical (bRFS) and clinical (cRFS) relapse-free survival was examined through univariate and multivariate analysis, with correction for known patient- and treatment-related variables. Interaction terms were introduced to evaluate effect modification. RESULTS After a median follow-up time of 5 years, the 7-year bRFS and cRFS were 84% and 88%, respectively. On multivariate analysis, the addition of ADT was independently associated with an improved bRFS (hazard ratio [HR] 0.4, p = 0.02) and cRFS (HR 0.2, p = 0.008). Higher Gleason scores and SVI were associated with decreased bRFS and cRFS. A lymphadenectomy at the time of RP independently improved cRFS (HR 0.09, p = 0.009). The 7-year probability of late Grade 2-3 toxicity was 29% and 5% for genitourinary (GU) and gastrointestinal (GI) symptoms, respectively. The absolute incidence of Grade 3 toxicity was <1% and 10% for GI and GU symptoms, respectively. The study is limited by its retrospective design and the lack of a standardized use of ADT. CONCLUSIONS This retrospective study shows significantly improved bRFS and cRFS rates with the addition of ADT to HD-ART, with low Grade 3 gastrointestinal toxicity and 10% Grade 3 genitourinary toxicity.

The effect of magnesium supplements on early post-transplantation glucose metabolism: a randomized controlled trial

Post‐transplantation hypomagnesemia is common and predicts diabetes. Magnesium improves glycemic control in diabetics and insulin sensitivity in insulin resistant subjects. We aimed to assess the effectiveness of oral magnesium for improving glycemic control and insulin sensitivity at 3 months post‐transplantation. We conducted a single‐center, open‐label, randomized parallel group study. We included adults with serum magnesium <1.7 mg/dl within 2 weeks after kidney transplantation. We randomized participants to 450 mg magnesium oxide up to three times daily or no treatment. The primary endpoint was the mean difference in fasting glycemia. Secondary endpoints were the mean difference in area under the curve (AUC) of glucose during an oral glucose tolerance test and insulin resistance measured by Homeostasis Model of Assessment‐Insulin Resistance (HOMA‐IR). Analyses were on intention‐to‐treat basis. In patients randomized to magnesium oxide (N = 27) versus no treatment (N = 27), fasting glycemia on average was 11.5 mg/dl lower (95% CI 1.7 to 21.3; P = 0.02). There was no difference between the two groups neither for 2 h AUC, where the mean value was 1164 mg/dl/min (95% CI −1884 to 4284; P = 0.45) lower in the treatment group nor for HOMA‐IR. Magnesium supplements modestly improved fasting glycemia without effect on insulin resistance. Higher baseline glycemia among patients in the control group may have driven the positive outcome (ClinicalTrials.gov number: NCT01889576).

European Renal Best Practice (ERBP) Guideline development methodology: towards the best possible guidelines

The prime mission of European Renal Best Practice (ERBP) is to improve the outcome of patients with kidney disease in a sustainable way through enhancing the availability of the knowledge on the management of these patients in a format that stimulates its use in clinical practice in Europe. A key activity is to produce clinical practice guidelines to help clinicians make the healthcare decisions they face. To further improve the quality and validity of its clinical practice guidelines, ERBP has revised its guideline development process. The present document outlines the principles of ERBPs 10-step approach. Important features include standard procedures for selecting topics, for assembling the guideline development group, for choosing and formulating questions, for finding, appraising and summarizing the evidence, for generating recommendations, for preparing reports and organizing peer review. ERBP has adopted the Grading of Recommendations Assessment, Development and Evaluation system for rating the quality of the evidence and strength of recommendations and has addressed implementation in the development process by integrating the GuideLine Implementability Appraisal tool. Ultimately, it is anticipated that these changes will not only further improve the quality of the guideline development process, but also enhance the quality of care and improve outcomes of patients with kidney disease across Europe.

Providing guidance in the dark: rare renal diseases and the challenge to improve the quality of evidence

Among renal diseases, over 100 conditions meet the epidemiological criteria to be defined as rare, including disorders in development, transport and metabolism. Clinical management of rare diseases is likely to be less investigated than that of common disorders and for this reason the scientific evidence to support clinical practice is limited. Furthermore, no specific and validated methods for designing, carrying out or analyzing clinical trials in small populations exist with important consequences for evidence-based medicine. In this paper we aim at discussing the inherent difficulty in finding evidence in rare renal diseases, providing some suggestions on how the quality of evidence and the guidance in these diseases can be improved.

Why creating standardized core outcome sets for chronic kidney disease will improve clinical practice.

Chronic kidney disease (CKD) is common and is associated with increased mortality, morbidity and cost. However, insufficient high-quality trial data are available to answer many relevant clinical questions in this field. In addition, a wide range of variable outcomes are used in studies, and often they are incompletely reported. Furthermore, there is a lack of patient-relevant outcomes, such as mortality, morbidity, quality of life, pain, need for dialysis or costs. Common problems with outcome reporting are as follows: choosing the wrong domains to measure; within domains, choosing the wrong measures (invalid surrogates, composite, non-patient relevant); within measures, choosing the wrong/variable metrics; and within metrics, choosing variable presentation methods. With this article, we aim to underline why standardized outcome reporting is key to achieving evidence-based guidance and improving clinical care for patients; highlight the frameworks available for achieving core outcome sets; and starting from these frameworks, we propose steps needed to develop a core outcome set in the field of CKD. We hope that standardized core outcome sets for nephrology will lead to the most important outcome of guideline production, improving outcomes for our patients.

Clinical practice recommendations for native vitamin D therapy in children with chronic kidney disease Stages 2–5 and on dialysis

Vitamin D deficiency is widely prevalent and often severe in children and adults with chronic kidney disease (CKD). Although native vitamin D {25-hydroxyvitamin D [25(OH)D]} is thought to have pleiotropic effects on many organ systems, its skeletal effects have been most widely studied. The 25(OH)D deficiency is causally linked with rickets and fractures in healthy children and those with CKD, contributing to the CKD-mineral and bone disorder (MBD) complex. There are few studies to provide evidence for vitamin D therapy or guidelines for its use in CKD. A core working group (WG) of the European Society for Paediatric Nephrology (ESPN) CKD-MBD and Dialysis WGs have developed recommendations for the evaluation, treatment and prevention of vitamin D deficiency in children with CKD. We present clinical practice recommendations for the use of ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3) in children with CKD Stages 2-5 and on dialysis. A parallel document addresses treatment recommendations for active vitamin D analogue therapy. The WG has performed an extensive literature review to include meta-analyses and randomized controlled trials in healthy children as well as children and adults with CKD, and prospective observational studies in children with CKD. The Grading of Recommendation, Assessment, Development and Evaluation (GRADE) system has been used to develop and grade the recommendations. In the absence of applicable study data, the opinion of experts from the ESPN CKD-MBD and Dialysis WGs is provided, but clearly GRADE-ed as such and must be carefully considered by the treating physician, and adapted to individual patient needs as appropriate.

Composing a new song for trials: the Standardized Outcomes in Nephrology (SONG) initiative

Randomized trials provide the most reliable evidence about the safety and effectiveness of interventions to improve health care and patient outcomes. Unfortunately, the potential for trials to inform treatment decisions remains limited because the outcomes reported often do not resonate with what is directly meaningful and relevant to patients and their clinicians [1–3]. Further, inconsistent reporting of outcomes across trials prevents assessment of the comparative effect of interventions [4]. Outcome reporting bias, whereby authors cherry-pick the outcomes they report on the basis of favourable results, may also occur when there is not a standardized list of outcomes measured and reported [5, 6]. Collectively these problems may undermine the reliability of published trials, leading to inefficient use of scarce research and health care resources and unintended harm to patients [6]. Such dissonance in outcomes reported in trials is widespread and evident across all medical specialties. The growing recognition of the problem has prompted large-scale efforts to establish core outcome sets. Core outcome sets are an agreed standardized set of outcomes for a specific clinical area that are to be reported as a minimum in all trials in that area [7]. Outcomes are selected because they are critically important to all stakeholders—namely patients, their clinicians and policymakers— for decision making. Core outcome sets are not designed to be comprehensive or exclusive. Typically they include only three to five outcomes. Other outcomes that are identified to be important (i.e. to some stakeholder groups) may also be recommended for some trials (Figure 1). The designated primary outcome of any given trial may be outside the core outcome set and researchers may also opt to add other, trial-specific outcomes, chosen for reasons including responsiveness to the intervention and feasibility. Attempts to standardize outcomes began 50 years ago when the World Health Organization published recommendations for the minimum requirements for data collection in cancer trials [8]. In the 1990s, the Outcome Measures in Rheumatology (OMERACT) initiative was formed, and is perhaps the most widely recognized and largest initiative in the field of core outcome development. OMERACT engages patients and health professionals to standardize outcome measures for trials in rheumatology [9] and has pioneered methodologies for developing core outcome sets. The uptake of the OMERACT core outcome sets has improved the consistency of outcomes reported in trials [10]. In the past decade, core outcome sets in diverse medical specialties, including cardiology, dermatology, surgery, oncology, women’s health and respiratory disease, have progressively been developed [7, 9–11]. The use of core outcome sets is also increasingly being advocated by funders to ensure the relevance and potential impact of research. In the UK, funding organizations, including the National Institute for Health Research and the Health Research Board (Ireland), advise researchers to include core outcome sets if they are available and highlight the Core Outcome Measures in Effectiveness (COMET) database of core outcomes as a key resource [7]. The COMET initiative was recently launched to facilitate the development, implementation and evaluation of core outcome sets [7]. There has been a long-standing need in nephrology to develop core outcomes [12–14]. More than 14 000 randomized trials are available in the Cochrane Kidney and Transplant Specialised Register [15] and a search of ClinicalTrials.gov trials for ‘kidney disease’ yields >3000 ongoing trials. Despite this considerable investment in trials in nephrology, improvements in outcomes for patients with kidney disease have been modest at best. Across all stages of chronic kidney disease (CKD), patients still have a markedly higher risk of mortality and serious comorbidities, including cardiovascular disease, diabetes, cancer and infection, compared with the general population [16–18]. Patients with CKD have poor quality of life, particularly if they are on dialysis, to the extent that many patients || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || ||