Fabry disease is a rare, X-linked, lysosomal storage disease caused by mutations in the gene encoding the enzyme alpha-galactosidase A. Complete or partial deficiency in this enzyme leads to intracellular accumulation of globotriaosylceramide (Gb3) and related glycosphingolipids in many cell types throughout the body, including the kidney. Progressive accumulation of Gb3 in podocytes, epithelial cells and the tubular cells of the distal tubule and loop of Henle contribute to the renal symptoms of Fabry disease, which manifest as proteinuria and reduced glomerular filtration rate leading to chronic kidney disease and progression to end-stage renal disease. Early diagnosis and timely initiation of treatment of Fabry renal disease is an important facet of disease management. Initiating treatment with enzyme replacement therapy (ERT; agalsidase alfa, Replagal®, Shire; agalsidase beta, Fabrazyme®, Genzyme) as part of a comprehensive strategy to prevent complications of the disease, may be beneficial in stabilizing renal function or slowing its decline. Early initiation of ERT may also be more effective than initiating therapy in patients with more advanced disease. Several strategies are required to complement the use of ERT and treat the myriad of associated symptoms and organ involvements. In particular, patients with renal Fabry disease are at risk of cardiovascular events, such as high blood pressure, cardiac arrhythmias and stroke. This review discusses the management of renal involvement in Fabry disease, including diagnosis, treatments, and follow-up, and explores recent advances in the use of biomarkers to assist with diagnosis, monitoring disease progression and response to treatment.
Fabry disease; Diagnosis; Management; Nephropathy; Enzyme replacement therapy
Metabolic acidosis is a common complication of chronic kidney disease. Accumulating evidence identifies acidosis not only as a consequence of, but as a contributor to, kidney disease progression. Several mechanistic pathways have been identified in this regard. The dietary acid load, even in the absence of overt acidosis, may have deleterious effects. Several small trials now suggest that the treatment of acidosis with oral alkali can slow the progression of kidney disease.
Bicarbonate; Dietary acid; Net endogenous acid production; Sodium bicarbonate; Alkali; Ammonia; Complement; Endothelin; Aldosterone
The inflammasome is a large, multiprotein complex that drives proinflammatory cytokine production in response to infection and tissue injury. Pattern recognition receptors that are either membrane bound or cytoplasmic trigger inflammasome assembly. These receptors sense danger signals including damage-associated molecular patterns and pathogen-associated molecular patterns (DAMPS and PAMPS respectively). The best-characterized inflammasome is the NLRP3 inflammasome. On assembly of the NLRP3 inflammasome, post-translational processing and secretion of pro-inflammatory cytokines IL-1β and IL-18 occurs; in addition, cell death may be mediated via caspase-1. Intrinsic renal cells express components of the inflammasome pathway. This is most prominent in tubular epithelial cells and, to a lesser degree, in glomeruli. Several primary renal diseases and systemic diseases affecting the kidney are associated with NLRP3 inflammasome/IL-1β/IL-18 axis activation. Most of the disorders studied have been acute inflammatory diseases. The disease spectrum includes ureteric obstruction, ischaemia reperfusion injury, glomerulonephritis, sepsis, hypoxia, glycerol-induced renal failure, and crystal nephropathy. In addition to mediating renal disease, the IL-1/ IL-18 axis may also be responsible for development of CKD itself and its related complications, including vascular calcification and sepsis. Experimental models using genetic deletions and/or receptor antagonists/antiserum against the NLRP3 inflammasome pathway have shown decreased severity of disease. As such, the inflammasome is an attractive potential therapeutic target in a variety of renal diseases.
Inflammasome; NLRP3; Renal disease; IL-1β; IL-18; PAMPs; DAMPs; P2X7R
Several reports show that patients with chronic disease who are empowered with information technology (IT) tools for monitoring, training and self-management have improved outcomes, however there are few such applications employed in kidney disease. This review explores the current and potential uses of health IT platforms to advance kidney disease care by offering innovative solutions to inform, engage and communicate with individuals with CKD.
Chronic kidney disease; Health information technology; Mobile health; Patient safety
Uric acid is the end product of purine metabolism in humans. High levels are causative in gout and urolithiasis. Hyperuricaemia has also been implicated in the pathophysiology of hypertension, chronic kidney disease (CKD), congestive heart failure (CHF), the metabolic syndrome, type 2 diabetes mellitus (T2DM), and atherosclerosis, with or without cardiovascular events. This article briefly reviews uric acid metabolism and summarizes the current literature on hyperuricaemia in cardiovascular disease and related co-morbidities, and emerging treatment options.
Uric acid; Urate; Hypertension; Chronic kidney disease; Congestive heart failure; Type 2 diabetes mellitus; Metabolic syndrome; Cardiovascular events; Atherosclerosis
In recent years, the imbalance in phosphate homeostasis in patients with end-stage renal disease (ESRD) has been the subject of much research. It appears that, while hyperphosphatemia may be a tangible indicator of deteriorating kidney function, lack of phosphate homeostasis may also be associated with the increased risk of cardiovascular events and mortality that has become a hallmark of ESRD. The need to maintain phosphorus concentrations within a recommended range is reflected in evidence-based guidelines. However, these do not reflect serum phosphorus concentrations achieved by most patients in clinical practice. Given this discrepancy, it is important to consider ways in which dietary restriction of phosphorus intake and, in particular, use of phosphate binders in patients with ESRD can be made more effective. Poor adherence is common in patients with ESRD and has been associated with inadequate control of serum phosphorus concentrations. Studies indicate that, among other factors, major reasons for poor adherence to phosphate binder therapy include high pill burden and patients’ lack of understanding of their condition and its treatment. This review examines available evidence, seeking to understand fully the reasons underlying poor adherence in patients with ESRD and consider possible strategies for improving adherence in clinical practice.
Adherence; Chronic kidney disease; Hyperphosphatemia; Phosphate binder; Pill burden
Focal segmental glomerulosclerosis (FSGS) is a kidney disease with progressive glomerular scarring and a clinical presentation of nephrotic syndrome. FSGS is a common primary glomerular disorder that causes renal dysfunction which progresses slowly over time to end-stage renal disease. Most cases of FSGS are idiopathic Although kidney transplantation is a potentially curative treatment, 40% of patients have recurrence of FSGS after transplantation. In this review a brief summary of the pathogenesis causing FSGS in humans is given, and a variety of animal models used to study FSGS is discussed. These animal models include the reduction of renal mass by resecting 5/6 of the kidney, reduction of renal mass due to systemic diseases such as hypertension, hyperlipidemia or SLE, drug-induced FSGS using adriamycin, puromycin or streptozotocin, virus-induced FSGS, genetically-induced FSGS such as via Mpv-17 inactivation and α-actinin 4 and podocin knockouts, and a model for circulating permeability factors. In addition, an animal model that spontaneously develops FSGS is discussed. To date, there is no exact understanding of the pathogenesis of idiopathic FSGS, and there is no definite curative treatment. One requirement facilitating FSGS research is an animal model that resembles human FSGS. Most animal models induce secondary forms of FSGS in an acute manner. The ideal animal model for primary FSGS, however, should mimic the human primary form in that it develops spontaneously and has a slow chronic progression. Such models are currently not available. We conclude that there is a need for a better animal model to investigate the pathogenesis and potential treatment options of FSGS.
Focal segmental glomerulosclerosis; Animal model; Remnant kidney; Adriamycin; Puromycin aminonucleoside-induced nephrosis; hiv; Mpv-17; α-actinin 4
Cardiovascular deaths account for about 40% of all deaths of patients with chronic kidney disease (CKD), particularly those on dialysis, while sudden cardiac death (SCD) might be responsible for as many as 60% of SCD in patients undergoing dialysis. Studies have demonstrated a number of factors occurring in hemodialysis (HD) that could lead to cardiac arrhythmias. Patients with CKD undergoing HD are at high risk of ventricular arrhythmia and SCD since changes associated with renal failure and hemodialysis-related disorders overlap. Antiarrhythmic therapy is much more difficult in patients with CKD, but the general principles are similar to those in patients with normal renal function - at first, the cause of arrhythmias should be found and eliminated. Also the choice of therapy is narrowed due to the altered pharmacokinetics of many drugs resulting from renal failure, neurotoxicity of certain drugs and their complex interactions. Cardiac pacing in elderly patients is a common method of treatment. Assessment of patients’ prognosis is important when deciding whether to implant complex devices. There are reports concerning greater risk of surgical complications, which depends also on the extent of the surgical site. The decision concerning implantation of a pacing system in patients with CKD should be made on the basis of individual assessment of the patient.
Arrhythmias; Chronic kidney disease; Renal failure; Sudden cardiac death
Ideally, care prior to the initiation of dialysis should increase the likelihood that patients start electively outside of the hospital setting with a mature arteriovenous fistula (AVF) or peritoneal dialysis (PD) catheter. However, unplanned dialysis continues to occur in patients both known and unknown to nephrology services, and in both late and early referrals. The objective of this article is to review the clinical and socioeconomic outcomes of unplanned dialysis initiation. The secondary objective is to explore the potential cost implications of reducing the rate of unplanned first dialysis in Canada.
MEDLINE and EMBASE from inception to 2008 were used to identify studies examining the clinical, economic or quality of life (QoL) outcomes in patients with an unplanned versus planned first dialysis. Data were described in a qualitative manner.
Eight European studies (5,805 patients) were reviewed. Duration of hospitalization and mortality was higher for the unplanned versus planned population. Patients undergoing a first unplanned dialysis had significantly worse laboratory parameters and QoL. Rates of unplanned dialysis ranged from 24-49%. The total annual burden to the Canadian healthcare system of unplanned dialysis in 2005 was estimated at $33 million in direct hospital costs alone. Reducing the rate of unplanned dialysis by one-half yielded savings ranging from $13.3 to $16.1 million.
The clinical and socioeconomic impact of unplanned dialysis is significant. To more consistently characterize the unplanned population, the term suboptimal initiation is proposed to include dialysis initiation in hospital and/or with a central venous catheter and/or with a patient not starting on their chronic modality of choice. Further research and implementation of initiatives to reduce the rate of suboptimal initiation of dialysis in Canada are needed.