Jordan Yz Li

Review: The role of microRNAs in kidney disease.

MicroRNAs (miRNAs) are short non‐coding RNAs that modulate physiological and pathological processes by inhibiting target gene expression via blockade of protein translation or by inducing mRNA degradation. These miRNAs potentially regulate the expression of thousands of proteins. As a result, miRNAs have emerged rapidly as a major new area of biomedical research with relevance to kidney disease. MiRNA expression has been shown to differ between the kidney and other organs as well as between different kidney regions. Furthermore, miRNAs have been found to be functionally important in models of podocyte development, diabetic nephropathy and polycystic kidney disease. Of particular interest, podocyte‐specific deletion of Dicer, a key enzyme in the biogenesis of miRNA, results in proteinuria and severe renal impairment in mice. One miRNA (miR‐192) can also act as an effector of transforming growth factor‐β activity in the high‐glucose environment of diabetic nephropathy. Differential expression of miRNAs has been reported in kidney allograft rejection. It is anticipated that future studies involving miRNAs will generate new insights into the complex pathophysiology underlying various kidney diseases, generate diagnostic biomarkers and might be of value as therapeutic targets for progressive kidney diseases. The purpose of this review is to highlight key miRNA developments in kidney diseases and how this might influence the diagnosis and management of patients with kidney disease in the future.

Exosomes and the kidney: blaming the messenger.

Exosomes are membrane‐bound vesicles of endosomal origin, present in a wide range of biological fluids, including blood and urine. They range between 30 and 100 nm in diameter, and consist of a limiting lipid bilayer, transmembrane proteins and a hydrophilic core containing proteins, mRNAs and microRNAs (miRNA). Exosomes can act as extracellular vehicles by which cells communicate, through the delivery of their functional cargo to recipient cells, with many important biological, physiological and pathological implications. The exosome release pathway contributes towards protein secretion, antigen presentation, pathogen transfer and cancer progression. Exosomes and exosome‐mediated signalling have been implicated in disease processes such as atherosclerosis, calcification and kidney diseases. Circulating levels of exosomes and extracellular vesicles can be influenced by the progression of renal disease. Advances in methods for purification and analysis of exosomes are leading to potential diagnostic and therapeutic avenues for kidney diseases. This review will focus on biophysical properties and biogenesis of exosomes, their pathophysiological roles and their potential as biomarkers and therapeutics in kidney diseases.

Bilateral basal ganglia lesions in patients with end-stage diabetic nephropathy.

Summary:  Acute movement disorder associated with reversible bilateral basal ganglia lesions is an increasingly recognized syndrome in patients with end‐stage renal disease, especially in the setting of concurrent diabetes mellitus. We report an elderly man with end‐stage diabetic nephropathy treated by daily automated peritoneal dialysis who developed subacute symptoms of gait disturbance, dysarthria, dysphagia and lethargy. Computed tomography and magnetic resonance imaging of the head revealed bilateral symmetrical basal ganglia lesions. Repeat imaging 3 weeks later showed that these lesions had regressed spontaneously. However, his neurological symptoms improved slowly. These findings were similar to 23 other cases in the literature. Review of these cases shows that clinical features were predominantly bradykinesia, gait disturbance and concurrent metabolic acidosis (observed in 90% of cases). The pathogenesis of this condition has not been clearly defined, but uraemia may be an aggravating factor in predisposed patients, particularly in the presence of diabetic microvascular disease. There is no specific treatment for this condition; supportive measures are the mainstay of management. In the majority of patients, neurological improvement lags behind regression of basal ganglia lesions seen with neuroimaging, and the long‐term outcome is variable.

Characteristics and outcomes of discharges against medical advice among hospitalised patients

Discharge against medical advice (DAMA) occurs when an in‐patient chooses to leave the hospital before discharge is recommended by the treating clinicians. The long‐term outcomes of patients who DAMA are not well documented.

Dipping your feet in the water: podocytes in urine

Podocyte injury and loss plays an important role in the pathogenesis and progression of many kidney diseases. Studies have shown that podocyte-related markers and products can be detected in the urine of patients with glomerular diseases such as focal segmental glomerulosclerosis, IgA nephropathy, lupus nephritis, diabetic nephropathy and pre-eclampsia. Therefore, detecting the loss of podocytes in the urine provides a useful noninvasive technique of gathering information about the disease type and/or activity of glomerular diseases. Currently, urine podocyte-related protein markers, mRNA, microRNA and exosomes have been used with varying degrees of success to study glomerular diseases. The determination of urinary podocyte loss may become an important noninvasive tool in the evaluation of glomerular diseases.

Human leucocyte antigen DQ alpha heterodimers and human leucocyte antigen DR alleles in tubulointerstitial nephritis and uveitis syndrome.

Tubulointerstitial nephritis and uveitis (TINU) syndrome is a rare clinical entity of acute interstitial nephritis (AIN) associated with uveitis. First described in 1975 by Dobrin et al., over 200 cases have been reported. Although the pathogenesis of TINU syndrome is unknown, the current view is that it is the result of an autoimmune process. Both cell-mediated immune responses and autoantibody production have been implicated. The association between TINU and human leucocyte antigen (HLA) phenotypes (DQ and DR) alleles has been the subject of several small studies. The authors review the literature and present two cases of definite TINU in an Australian population in which the same HLA DQA1*01, DQB1*05 and DRB1*01 haplotype was identified.

Bilateral basal ganglia lesions in patients with end-stage diabetic nephropathy (Brief Communication)

Summary:  Acute movement disorder associated with reversible bilateral basal ganglia lesions is an increasingly recognized syndrome in patients with end‐stage renal disease, especially in the setting of concurrent diabetes mellitus. We report an elderly man with end‐stage diabetic nephropathy treated by daily automated peritoneal dialysis who developed subacute symptoms of gait disturbance, dysarthria, dysphagia and lethargy. Computed tomography and magnetic resonance imaging of the head revealed bilateral symmetrical basal ganglia lesions. Repeat imaging 3 weeks later showed that these lesions had regressed spontaneously. However, his neurological symptoms improved slowly. These findings were similar to 23 other cases in the literature. Review of these cases shows that clinical features were predominantly bradykinesia, gait disturbance and concurrent metabolic acidosis (observed in 90% of cases). The pathogenesis of this condition has not been clearly defined, but uraemia may be an aggravating factor in predisposed patients, particularly in the presence of diabetic microvascular disease. There is no specific treatment for this condition; supportive measures are the mainstay of management. In the majority of patients, neurological improvement lags behind regression of basal ganglia lesions seen with neuroimaging, and the long‐term outcome is variable.

Emergency department lengths of stay: characteristics favouring a delay to the admission decision as distinct from a delay while awaiting an inpatient bed

A prolonged stay for a patient within the emergency department (ED) can adversely affect the outcome of their ensuing hospital admission.

Human cytomegalovirus encoded microRNAs: hitting targets

Human cytomegalovirus (HCMV) infection is of particular concern in immunodeficient individuals notably transplant recipients, leading to increased morbidity and mortality. HCMV is predicted to encode multiple microRNAs (miRNAs) and several have been characterized in vitro. Furthermore, these miRNAs have been shown to target human and viral mRNAs. Pathways involved in human cellular targets have key roles in vesicle trafficking, immune evasion and cell cycle control. This demonstration of viral miRNA targets provides novel insights into viral pathogenesis. This review details the evidence for the existence of HCMV-encoded miRNA and their targets. HCMV miRNA in blood and other tissues is a potential diagnostic tool and blocking the effects of specific HCMV-encoded miRNA with sequence specific antagomirs is a potential new therapy.

THE SURVIVAL OF PATIENTS WITH NOT-FOR-RESUSCITATION ORDERS

BACKGROUND Studies have shown higher in-hospital mortality rates in patients with not-for-resuscitation (NFR) decisions. Long-term survival of these patients after their discharge from acute care is largely unknown as is communication of such decisions to primary care givers through letters or discharge summaries. AIM To evaluate the in-hospital mortality and post-discharge survival of general medical patients with documented resuscitation decisions as well as the prevalence of these decisions being communicated to primary health care providers through discharge summaries. DESIGN Retrospective cross-sectional study. METHODS The medical records of 618 general medical patients admitted to an Australian tertiary referral teaching hospital between January and December 2007 were reviewed to determine the documentation of resuscitation decisions. Mortality rates in-hospital and up to 5 years post-discharge were assessed in relation to the nature of any resuscitation decisions. Communication of these decisions in the discharge summaries was also evaluated. RESULTS One hundred and thirty-six (22%) patients had resuscitation decisions documented of whom 91 (67%) did not want resuscitation (NFR). For this NFR group, the in-hospital mortality rate was 20%, and their cumulative 1- and 5-year mortality rates were 53 and 85%, respectively. Of the 112 patients with resuscitation decisions who survived to discharge, 104 of them (93%) had discharge summaries completed but only 9 (8.4%) had resuscitation decisions documented in those discharge summaries. CONCLUSION Many general medical patients with a documented NFR decision survive beyond 1 year after their index admission. The rate of communication of resuscitation decisions in hospital discharge summaries is low.