T. Keefe Davis

Cardiovascular risk in chronic kidney disease (CKD): the CKD-mineral bone disorder (CKD-MBD)

Recent advances in our understanding of the excess mortality of chronic kidney disease (CKD) due to cardiovascular complications, obtained through observational studies, demonstrate that vascular calcification and hyperphosphatemia are major cardiovascular risk factors. Mechanistic studies demonstrate that these two risk factors are related and that hyperphosphatemia directly stimulates vascular calcification. The role of hyperphosphatemia in stimulating vascular calcification in CKD is associated with a block to the skeletal reservoir function in phosphate balance due to excess bone resorption. This has led to the realization that renal osteodystrophy is linked to vascular calcification by disordered mineral homeostasis (phosphate) and that a multiorgan system fails in CKD, leading to cardiovascular mortality. In children with renal disease, the multiorgan system fails, just as in adults, but the outcomes have been less well studied, and perceptions of differences from adults are possibly incorrect. Vascular calcification and cardiovascular mortality are less prevalent among pediatric patients, but they are present. However, CKD-induced vascular disease causes stiffness of the arterial tree causing, in turn, systolic hypertension and left ventricular hypertrophy as early manifestations of the same pathology in the adult. Because of the role of the skeleton in these outcomes, renal osteodystrophy has been renamed as the CKD mineral bone disorder (CKD-MBD). This review, which focuses on the pediatric patient population, describes our current state of knowledge with regards to the pathophysiology of the CKD-MBD, including the new discoveries related to early stages of CKD. As a new necessity, cardiovascular function issues are incorporated into the CKD-MBD, and new advances in our knowledge of this critical component of the disorder will lead to improved outcomes in CKD.

Treatment of Shiga Toxin–Producing Escherichia coli Infections

The management of Shiga toxin-producing Escherichia coli (STEC) infections is reviewed. Certain management practices optimize the likelihood of good outcomes, such as avoidance of antibiotics during the pre-hemolytic uremic syndrome phase, admission to hospital, and vigorous intravenous volume expansion using isotonic fluids. The successful management of STEC infections is based on recognition that a patient might have an STEC infection, and appropriate use of the microbiology laboratory. The timeliness of STEC identification cannot be overemphasized, because it avoids therapies prompted by inappropriate additional testing and directs the clinician to focus on effective management strategies. The opportunities during STEC infections to avert the worst outcomes are brief, and this article emphasizes practical matters relevant to making a diagnosis, anticipating the trajectory of illness, and optimizing care.

Incidence and outcomes of neonatal acute kidney injury (AWAKEN): a multicentre, multinational, observational cohort study

Background Single-center studies suggest that neonatal acute kidney injury (AKI) is associated with poor outcomes. However, inferences regarding the association between AKI, mortality, and hospital length of stay are limited due to the small sample size of those studies. In order to determine whether neonatal AKI is independently associated with increased mortality and longer hospital stay, we analyzed the Assessment of Worldwide Acute Kidney Epidemiology in Neonates (AWAKEN) database. Methods All neonates admitted to 24 participating neonatal intensive care units from four countries (Australia, Canada, India, United States) between January 1 and March 31, 2014, were screened. Of 4273 neonates screened, 2022 (47·3%) met study criteria. Exclusion criteria included: no intravenous fluids ≥48 hours, admission ≥14 days of life, congenital heart disease requiring surgical repair at <7 days of life, lethal chromosomal anomaly, death within 48 hours, inability to determine AKI status or severe congenital kidney abnormalities. AKI was defined using a standardized definition —i.e., serum creatinine rise of ≥0.3 mg/dL (26.5 mcmol/L) or ≥50% from previous lowest value, and/or if urine output was <1 mL/kg/h on postnatal days 2 to 7. Findings Incidence of AKI was 605/2022 (29·9%). Rates varied by gestational age groups (i.e., ≥22 to <29 weeks =47·9%; ≥29 to <36 weeks =18·3%; and ≥36 weeks =36·7%). Even after adjusting for multiple potential confounding factors, infants with AKI had higher mortality compared to those without AKI [(59/605 (9·7%) vs. 20/1417 (1·4%); p< 0.001; adjusted OR=4·6 (95% CI=2·5–8·3); p=<0·0001], and longer hospital stay [adjusted parameter estimate 8·8 days (95% CI=6·1–11·5); p<0·0001]. Interpretation Neonatal AKI is a common and independent risk factor for mortality and longer hospital stay. These data suggest that neonates may be impacted by AKI in a manner similar to pediatric and adult patients. Funding US National Institutes of Health, University of Alabama at Birmingham, Cincinnati Children’s, University of New Mexico.

Assessment of Worldwide Acute Kidney Injury Epidemiology in Neonates: Design of a Retrospective Cohort Study

Introduction Acute kidney injury (AKI) affects ~30% of hospitalized neonates. Critical to advancing our understanding of neonatal AKI is collaborative research among neonatologists and nephrologists. The Neonatal Kidney Collaborative (NKC) is an international, multidisciplinary group dedicated to investigating neonatal AKI. The AWAKEN study (Assessment of Worldwide Acute Kidney injury Epidemiology in Neonates) was designed to describe the epidemiology of neonatal AKI, validate the definition of neonatal AKI, identify primary risk factors for neonatal AKI, and investigate the contribution of fluid management to AKI events and short-term outcomes. Methods and analysis The NKC was established with at least one pediatric nephrologist and neonatologist from 24 institutions in 4 countries (USA, Canada, Australia, and India). A Steering Committee and four subcommittees were created. The database subcommittee oversaw the development of the web-based database (MediData Rave™) that captured all NICU admissions from 1/1/14 to 3/31/14. Inclusion and exclusion criteria were applied to eliminate neonates with a low likelihood of AKI. Data collection included: (1) baseline demographic information; (2) daily physiologic parameters and care received during the first week of life; (3) weekly “snapshots”; (4) discharge information including growth parameters, final diagnoses, discharge medications, and need for renal replacement therapy; and (5) all serum creatinine values. Ethics and dissemination AWAKEN was proposed as human subjects research. The study design allowed for a waiver of informed consent/parental permission. NKC investigators will disseminate data through peer-reviewed publications and educational conferences. Discussion The purpose of this publication is to describe the formation of the NKC, the establishment of the AWAKEN cohort and database, future directions, and a few “lessons learned.” The AWAKEN database includes ~325 unique variables and >4 million discrete data points. AWAKEN will be the largest, most inclusive neonatal AKI study to date. In addition to validating the neonatal AKI definition and identifying risk factors for AKI, this study will uncover variations in practice patterns related to fluid provision, renal function monitoring, and involvement of pediatric nephrologists during hospitalization. The AWAKEN study will position the NKC to achieve the long-term goal of improving the lives, health, and well-being of newborns at risk for kidney disease.

Shiga Toxin/Verocytotoxin-Producing Escherichia coli Infections: Practical Clinical Perspectives

Escherichia coli strains that produce Shiga toxins/verotoxins are rare, but important, causes of human disease. They are responsible for a spectrum of illnesses that range from the asymptomatic to the life-threatening hemolytic-uremic syndrome; diseases caused by E. coli belonging to serotype O157:H7 are exceptionally severe. Each illness has a fairly predictable trajectory, and good clinical practice at one phase can be inappropriate at other phases. Early recognition, rapid and definitive microbiology, and strategic selection of tests increase the likelihood of good outcomes. The best management of these infections consists of avoiding antibiotics, antimotility agents, and narcotics and implementing aggressive intravenous volume expansion, especially in the early phases of illness.

Stage specific requirement of Gfrα1 in the ureteric epithelium during kidney development

Glial cell line-derived neurotrophic factor (GDNF) binds a coreceptor GDNF family receptor α1 (GFRα1) and forms a signaling complex with the receptor tyrosine kinase RET. GDNF-GFRα1-RET signaling activates cellular pathways that are required for normal induction of the ureteric bud (UB) from the Wolffian duct (WD). Failure of UB formation results in bilateral renal agenesis and perinatal lethality. Gfrα1 is expressed in both the epithelial and mesenchymal compartments of the developing kidney while Ret expression is specific to the epithelium. The biological importance of Gfrα1s wider tissue expression and its role in later kidney development are unclear. We discovered that conditional loss of Gfrα1 in the WD epithelium prior to UB branching is sufficient to cause renal agenesis. This finding indicates that Gfrα1 expressed in the nonepithelial structures cannot compensate for this loss. To determine Gfrα1s role in branching morphogenesis after UB induction we used an inducible Gfrα1-specific Cre-deletor strain and deleted Gfrα1 from the majority of UB tip cells post UB induction in vivo and in explant kidney cultures. We report that Gfrα1 excision from the epithelia compartment after UB induction caused a modest reduction in branching morphogenesis. The loss of Gfrα1 from UB-tip cells resulted in reduced cell proliferation and decreased activated ERK (pERK). Further, cells without Gfrα1 expression are able to populate the branching UB tips. These findings delineate previously unclear biological roles of Gfrα1 in the urinary tract and demonstrate its cell-type and stage-specific requirements in kidney development.

Citrate anticoagulation during continuous renal replacement therapy in pediatric critical care.

Objective: To provide the pediatric intensivist an in-depth understanding of citrate as regional anticoagulant during continuous renal replacement therapy. Data Sources and Data Selection: We searched the PubMed.gov database using the initial key words: citrate anticoagulation [title] AND continuous; citrate [title] AND pediatric AND continuous; prospective pediatric renal replacement AND citrate; and regional citrate anticoagulation. Additional searchers were performed using EMBASE, CINAHL, and SCOPUS with similar keywords and limits. Further articles were gathered from bibliographic references of relevant studies and reviews. Only articles published in English were reviewed. Data Extraction and Data Synthesis: In the pediatric population, there are no prospective interventional or randomized studies comparing regional versus systemic anticoagulation. However, there are 11 (retrospective and prospective observational studies) in the pediatric population using citrate anticoagulation. These studies have shown that regional citrate anticoagulation in the pediatric population can be effective, provide equivalent circuit survival, and decrease bleeding compared with heparin anticoagulation. In the adult population, there are six prospective randomized controlled trials comparing the efficacy of regional citrate anticoagulation versus heparin. Two systematic reviews with meta-analysis of these six trials have been performed. The adult data on the use of regional citrate anticoagulation during continuous renal replacement therapy show a decreased risk of bleeding and at the least equivalent circuit survival as compared to heparin. Current pediatric and adult studies support regional citrate anticoagulation as an effective alternative to systemic heparin anticoagulation in most patient populations. Conclusions: Continuous renal replacement therapy is the most common modality of renal replacement in the critical care setting. Regional anticoagulation is an ideal option in a critically ill child after recent surgery or with coagulopathy. Therefore, regional citrate anticoagulation in the pediatric critical care population requiring renal replacement therapy is commonly employed. Complications of citrate anticoagulation can be avoided with a greater understanding of the properties and clearance of citrate. Continued reporting of observational data and the development of prospective multicenter trials using citrate anticoagulation are needed to ensure safe and standardized care in the pediatric population.

Posaconazole-induced hypertension and hypokalemia due to inhibition of the 11β-hydroxylase enzyme

ABSTRACT Posaconazole is an antifungal therapy reported to cause incident hypertension. Hypokalemia is also a known side effect. The combination of hypertension and hypokalemia suggests mineralocorticoid excess. We present the case of a 15-year-old adolescent male with hypertensive urgency while on prophylactic posaconazole therapy for a combined immunodeficiency. We identify the mechanism of posaconazole-induced hypertension to be inhibition of the 11β-hydroxylase enzyme, resulting in elevated levels of the mineralocorticoid receptor activator deoxycorticosterone. Loss of function of the 11β-hydroxylase enzyme is responsible for a rare form of congenital adrenal hyperplasia and can be associated with life-threatening adrenal crisis.

Smoking guns: Answers

Toxicology studies identified AB-FUBINACA, a fifth generation synthetic cannabinoid (SC), in the urine (450 ng/mL) and serum (52 ng/mL). Acute kidney injury (AKI) secondary to SCs was brought to international attention in a report from the U.S. Centers for Disease Control and Prevention in February 2013 [1] which detailed 16 cases of AKI after SC use in six states. A case series of four patients from Alabama, all from the same county, also implicated SCs as a cause of AKI [2]. An additional case has since been reported [3]. This is the first report of a fifth generation SC associated with AKI. SCs, commonly referred to as “Spice,” are designed to bind to the same cannabinoid receptors (designated CB1 and CB2) as the active compound in marijuana, delta-9 tetrahydrocannabinol (THC). Many SCs demonstrate a high affinity for CB1 and CB2 despite having markedly different chemical structures from THC; consequently, these compounds are also referred to as “synthetic marijuana” or cannabimimetics. SCs are designed and synthesized in clandestine laboratories. Plant material/inactive vegetable matter is soaked in solvent containing the dissolved SC or the SC is sprayed directly onto the matter [1, 4]. This material is then dried and smoked. The U.S Drug Enforcement Administration (DEA) has placed multiple SCs into Schedule I of the Controlled Substance Act (CSA), including AB-FUBINACA [5–7]. However, illicit use continues as new drugs are constantly being designed, and many of the older compounds remain commercially available under the guise of herbal incense, bath additives, or air fresheners with the label “not for human consumption.” The illegal use is further encouraged by affordability, expectation of an intense high, and avoidance of detection by commonly used urine drug tests. The synthetic drug industry is a growing market. In the high school age group, 8–11 % of seniors have reported use [8]. There are countless street and commercial names for SCcontaining products (Table 1)—with these names having no correlation with the presence of a particular SC. These drugs are made in laboratories with no quality or safety controls, and thus there is great variability amongst these products in terms of ingredients, potentially toxic preservatives, adulterants, and concentration of active SC [4]. There is no assurance that This article refers to the article that can be found at http://dx.doi.org/10. 1007/s00467-014-2978-1.

Pediatric Hematuria Remains a Clinical Dilemma

Hematuria is blood in the urine. A strict clinical definition is the presence of 5 or more red blood cells (RBCs) per high-power (40×) field. It can further be subclassified relative to appearance (gross vs microscopic), duration (transient, intermittent, or persistent), and/or symptomatic versus asymptomatic. Studies of school age children have shown that hematuria is relatively common, with a prevalence of up to 6%. Transient hematuria is the most common, but persistent hematuria does affect about 0.3% of the population. The American Academy of Pediatrics (AAP) no longer recommends annual screening urinalysis, and therefore, hematuria usually comes to attention when gross hematuria occurs or during evaluation for urinary symptoms. However, this is not always the case, for it is not uncommon for an annual physical exam sheet provided by a school district or employer to have a section requesting documentation of a urinalysis. This often prompts testing rather than a rebuttal referencing the AAP guidelines. Urine can vary greatly in color and smell because of its specific gravity and constituents. Clear colored urine is associated with high water content and, therefore, a low osmolality and low specific gravity. Dark yellow or orange urine is often a simple sign of dehydration and a practical illustration of the kidney’s ability to reabsorb water, excreting urine with a high osmolality and high specific gravity. Gross hematuria is usually appreciated as bright red in color or as “tea colored.” Red urine, however, does not necessarily mean hematuria. There are a number of possible causes of discolored urine not caused by hematuria (Table 1). The urine dipstick is the most common initial test used to diagnose hematuria. A urine dipstick positive for blood must be further examined for intact RBCs and differentiated from pigmenturia—that is, hemoglobinuria or myoglobinuria. The urine dipstick detects heme peroxidase activity of RBCs, but both hemoglobin and myoglobin cause positive results. Hemoglobin is a large multimeric protein found exclusively in red cells, used by the body for oxygen transport from the lungs to tissue. Urinary hemoglobin may be derived from either intact urinary RBCs or intravascular hemolysis and filtration of free hemoglobin. Myoglobin is a heme-containing protein involved in oxidative phosphorylation and is released from muscle during injury. The management of hemoglobinuria and myoglobinuria is based on treating the primary process and temporarily increasing the solubility of the proteins in the urine. This is typically done by increasing the pH of the urine, attempting to decrease precipitation and cast formation, thereby avoiding oxidative and endoplasmic reticulum stress.