The first reports connecting uremic inflammation with a wasted and atherogenic phenotype and poor outcome initiated in the late 1990s. Since then, about 3500 publications appear on Medline, reflecting the exponential interest that this topic has evoked in nephrology. What was described as a “novel” risk factor 10 years ago has now evolved into an established finding in patients with end‐stage renal disease (ESRD). The purpose of this review is to summarize the main advances contributing to our current understanding of the complex inflammatory processes present in ESRD. Causes and consequences of inflammation, genetic heritability of the inflammatory response, implications on outcome prognostication, and contemporary therapeutic evidence are some of the various topics discussed.
Dialysis patients have extraordinarily high mortality rates. The death rate for all US dialysis patients in 2004 was 230 per 1000 patient-years. Cardiac disease is the major cause of death in dialysis patients and accounts for 43% of all-cause mortality. In the United States Renal Data System database 62% of cardiac deaths (or 27% of all deaths) are attributable to arrhythmic mechanisms. The estimated rate of sudden cardiac death in US dialysis patients in 2002 was 7% per year. There are several plausible explanations for the special vulnerability of dialysis patients to sustaining sudden cardiac death. Obstructive coronary artery disease, coupled with diminished tolerance to myocardial ischemia (in the setting of myocardial fibrosis and left ventricular hypertrophy), rapid electrolyte shifts in hemodialysis patients, and derangements in autonomic function may all contribute to this heightened risk of sudden cardiac death. This review focuses on the epidemiology of sudden cardiac death in dialysis patients, underlying mechanisms of sudden death, and potential interventions to reduce the risk of sudden cardiac death in dialysis patients (including medical therapy and defibrillators). It is unlikely that one single therapeutic intervention will prevent sudden cardiac death in dialysis patients; but a more modest (and attainable) goal is the implementation of multiple strategies to reduce the risk of sudden cardiac death in this special high-risk population.
An arteriovenous fistula (AVF) is the optimal vascular access for hemodialysis (HD), because it is associated with prolonged survival, fewer infections, lower hospitalization rates, and reduced costs. The AVF First breakthrough initiative (FFBI) has made dramatic progress, effectively promoting the increase in the national AVF prevalence since the program’s inception from 32% in May 2003 to nearly 60% in 2011. Central venous catheter (CVC) use has stabilized and recently decreased slightly for prevalent patients (treated more than 90 days), while CVC usage in the first 90 days remains unacceptably high at nearly 80%. This high prevalence of CVC utilization suggests important specific improvement goals for FFBI. In addition to the current 66% AVF goal, the initiative should include specific CVC usage target(s), based on the KDOQI goal of less than 10% in patients undergoing HD for more than 90 days, and a substantially improved initial target from the current CVC proportion. These specific CVC targets would be disseminated through the ESRD networks to individual dialysis facilities, further emphasizing CVC avoidance in the transition from advanced CKD to chronic kidney failure, while continuing to decrease CVC by prompt conversion of CVC‐based hemodialysis patients to permanent vascular access, utilizing an AVF whenever feasible.
A significant number of dietary restrictions are imposed traditionally and uniformly on maintenance dialysis patients, whereas there is very little data to support their benefits. Recent studies indicate that dietary restrictions of phosphorus may lead to worse survival and poorer nutritional status. Restricting dietary potassium may deprive dialysis patients of heart‐healthy diets and lead to intake of more atherogenic diets. There is little data about the survival benefits of dietary sodium restriction, and limiting fluid intake may inherently lead to lower protein and calorie consumption, when in fact dialysis patients often need higher protein intake to prevent and correct protein‐energy wasting. Restricting dietary carbohydrates in diabetic dialysis patients may not be beneficial in those with burnt‐out diabetes. Dietary fat including omega‐3 fatty acids may be important caloric sources and should not be restricted. Data to justify other dietary restrictions related to calcium, vitamins, and trace elements are scarce and often contradictory. The restriction of eating during hemodialysis treatment is likely another incorrect practice that may worsen hemodialysis induced hypoglycemia and nutritional derangements. We suggest careful relaxation of most dietary restrictions and adoption of a more balanced and individualized approach, thereby easing some of these overzealous restrictions that have not been proven to offer major advantages to patients and their outcomes and which may in fact worsen patients' quality of life and satisfaction. This manuscript critically reviews the current paradigms and practices of recommended dietary regimens in dialysis patients including those related to dietary protein, carbohydrate, fat, phosphorus, potassium, sodium, and calcium, and discusses the feasibility and implications of adherence to ardent dietary restrictions and future research.
Patients with chronic kidney disease (CKD) have a much higher risk of cardiovascular diseases than the general population. Endothelial dysfunction, which participates in accelerated atherosclerosis, is a hallmark of CKD. Patients with CKD display impaired endothelium‐dependent vasodilatation, elevated soluble biomarkers of endothelial dysfunction, and increased oxidative stress. They also present an imbalance between circulating endothelial populations reflecting endothelial injury (endothelial microparticles and circulating endothelial cells) and repair (endothelial progenitor cells). Endothelial damage induced by a uremic environment suggests an involvement of uremia‐specific factors. Several uremic toxins, mostly protein‐bound, have been shown to have specific endothelial toxicity: ADMA, homocysteine, AGEs, and more recently, p‐cresyl sulfate and indoxyl sulfate. These toxins, all poorly removed by hemodialysis therapies, share mechanisms of endothelial toxicity: they promote pro‐oxidant and pro‐inflammatory response and inhibit endothelial repair. This article (i) reviews the evidence for endothelial dysfunction in CKD, (ii) specifies the involvement of protein‐bound uremic toxins in this dysfunction, and (iii) discusses therapeutic strategies for lowering uremic toxin concentrations or for countering the effects of uremic toxins on the endothelium.
Vascular access dysfunction is one of the leading causes of morbidity and mortality among end‐stage renal disease patients. Vascular access dysfunction exists in all three types of available accesses: arteriovenous fistulas, arteriovenous grafts, and tunneled catheters. To improve clinical research and outcomes in hemodialysis (HD) access dysfunction, the development of a multidisciplinary network of collaborative investigators with various areas of expertise, and common standards for terminology and classification in all vascular access types, is required. The North American Vascular Access Consortium (NAVAC) is a newly formed multidisciplinary and multicenter network of experts in the area of HD vascular access, who include nephrologists and interventional nephrologists from the United States and Canada with: (1) a primary clinical and research focus in HD vascular access dysfunction, (2) national and internationally recognized experts in vascular access, and (3) a history of productivity measured by peer‐reviewed publications and funding among members of this consortium. The consortium’s mission is to improve the quality and efficiency in vascular access research, and impact the research in the area of HD vascular access by conducting observational studies and randomized controlled trials. The purpose of the consortium’s initial manuscript is to provide working and standard vascular access definitions relating to (1) epidemiology, (2) vascular access function, (3) vascular access patency, and (4) complications in vascular accesses relating to each of the vascular access types.
In this review, a systematic literature search and meta‐analysis were performed to assess the effects of hemodiafiltration (HDF) on clinical outcome, as compared with hemodialysis (HD). Furthermore, the relation between the convection volume in HDF and clinical outcome was studied. The literature search identified six randomized controlled trials (RCTs). In a meta‐analysis of these RCTs, HDF treatment was related to a decreased risk of mortality (RR: 0.84; 95% CI 0.73–0.96) and cardiovascular death (RR: 0.73; 95% CI 0.57–0.92). Post hoc analyses of the three largest RCTs suggested an inverse relation between the magnitude of convection volume and mortality risk. The evidence presented in this analysis supports a wider acceptance of HDF.
Acquired immunity disturbances in hemodialysis(HD) patients are many and diverse. They are caused by uremia per se, the HD procedure, chronic renal failure complications, and therapeutic interventions for their treatment. Current data suggest that acquired immunity disturbances in HD patients concern mainly the T-lymphocyte and the antigen-presenting cell(APC). The T-lymphocyte-dependent immune response is deficient, predisposing to infections and inadequate response to vaccinations. In addition, APCs are preactivated, which seems to be responsible for the malnutrition-inflammation-atherosclerosis syndrome, and also affects T-lymphocyte function. At the molecular level it is assumed that the interaction between the APC and the T-lymphocyte is impaired. This disturbance is likely to concern the signal that results from the interaction between the major histocompatibility complex: peptide complex on A-PC surfaces and T-cell receptors on T-lymphocyte surfaces, or the signal that results from the interaction among the co-receptors of these two cells. The aim of the present review was to collect and classify the available clinical and experimental data in this area. Although many pieces are still missing from the puzzle, a better understanding of the responsible molecular mechanisms, will potentially lead to increased survival and a better quality of life in HD patients.
Hypoalbuminemia is the result of the combined effects of inflammation and inadequate protein and caloric intake in patients with chronic disease such as chronic renal failure. Inflammation and malnutrition both reduce albumin concentration by decreasing its rate of synthesis, while inflammation alone is associated with a greater fractional catabolic rate (FCR) and, when extreme, increased transfer of albumin out of the vascular compartment. A vicious cascade of events ensues in which inflammation induces anorexia and reduces the effective use of dietary protein and energy intake and augments catabolism of the key somatic protein, albumin. Hypoalbuminemia is a powerful predictor of mortality in patients with chronic renal failure, and the major cause of death in this population is due to cardiovascular events. Inflammation is associated with vascular disease and likely causes injury to the vascular endothelium, and hypoalbuminemia as two separate expressions of the inflammatory process. Albumin has a myriad of important physiologic effects that are essential for normal health. However, simply administering albumin to critically ill patients with hypoalbuminemia has not been shown to improve survival or reduce morbidity. Thus the inference from these clinical studies suggests that the cause of hypoalbuminemia, rather than low albumin levels specifically, is responsible for morbidity and mortality.
Diabetes mellitus is the leading cause of end‐stage renal disease (ESRD) in the U.S. and many countries globally. The role of improved glycemic control in ameliorating the exceedingly high mortality risk of diabetic dialysis patients is unclear. The treatment of diabetes in ESRD patients is challenging, given changes in glucose homeostasis, the unclear accuracy of glycemic control metrics, and the altered pharmacokinetics of glucose‐lowering drugs by kidney dysfunction, the uremic milieu, and dialysis therapy. Up to one‐third of diabetic dialysis patients may experience spontaneous resolution of hyperglycemia with hemoglobin A1c (HbA1c) levels <6%, a phenomenon known as “Burnt‐Out Diabetes,” which remains with unclear biologic plausibility and undetermined clinical implications. Conventional methods of glycemic control assessment are confounded by the laboratory abnormalities and comorbidities associated with ESRD. Similar to more recent approaches in the general population, there is concern that glucose normalization may be harmful in ESRD patients. There is uncertainty surrounding the optimal glycemic target in this population, although recent epidemiologic data suggest that HbA1c ranges of 6% to 8%, as well as 7% to 9%, are associated with increased survival rates among diabetic dialysis patients. Lastly, many glucose‐lowering drugs and their active metabolites are renally metabolized and excreted, and hence, require dose adjustment or avoidance in dialysis patients.
In December 2002, all U.S. chronic hemodialysis centers were surveyed regarding selected patient care practices and dialysis-associated diseases. The results were compared with similar surveys conducted in previous years. In 2002, 85% of hemodialysis centers were free-standing and 81% operated for profit; the proportion of centers operating for profit has increased each year since 1985. During 1995-2002, the percentage of patients who received dialysis through central catheters increased from 13% to 26%; this trend is worrisome, as infections and antimicrobial use are higher among patients receiving dialysis through catheters. However, during the same period, the percentage of patients receiving dialysis through fistulas increased from 22% to 33%. The percentage of centers reporting one or more patients infected or colonized with vancomycin-resistant enterococci (VRE) increased from 12% in 1995 to 30% in 2002. During 1997-2002, the percentage of patients vaccinated against hepatitis B virus (HBV) infection increased from 47% to 56% and the percentage of staff vaccinated increased from 87% to 90%. In 2002, routine testing for antibody to hepatitis C virus (anti-HCV) was performed on patients at 64% of centers; anti-HCV was found in 7.8% of patients. In 2001, the Centers for Disease Control (CDC) published Recommendations for Preventing Transmission of Infections among Chronic Hemodialysis Patients. Centers were surveyed regarding their awareness of the recommendations and about a variety of infection control practices. In general, the incidence of HBV and HCV was not substantially different for the infection control practices evaluated, including where staff obtain clean supplies for patient treatment, reuse of unused and unopened supplies, and practices for changing external transducer filters/protectors. However, in 2002, the incidence of HBV infection was higher among patients in centers where injectable medications were prepared on a medication cart or medication area located in the treatment area compared to a dedicated medication room. Also, those centers that used a disposable container versus a nondisposable container for priming the dialyzer had a significantly lower incidence of HCV.
Each year approximately 13,000 Veterans transition to maintenance dialysis, mostly in the traditional form of thrice‐weekly hemodialysis from the start. Among >6000 dialysis units nationwide, there are currently approximately 70 Veterans Affairs (VA) dialysis centers. Given this number of VA dialysis centers and their limited capacity, only 10% of all incident dialysis Veterans initiate treatment in a VA center. Evidence suggests that, among Veterans, the receipt of care within the VA system is associated with favorable outcomes, potentially because of the enhanced access to healthcare resources. Data from the United States Renal Data System Special Study Center “Transition‐of‐Care‐in‐CKD” suggest that Veterans who receive dialysis in a VA unit exhibit greater survival compared with the non‐VA centers. Substantial financial expenditures arise from the high volume of outsourced care and higher dialysis reimbursement paid by the VA than by Medicare to outsourced providers. Given the exceedingly high mortality and abrupt decline in residual kidney function (RKF) in the first dialysis year, it is possible that incremental transition to dialysis through an initial twice‐weekly hemodialysis regimen might preserve RKF, prolong vascular access longevity, improve patients’ quality of life, and be a more patient‐centered approach, more consistent with “personalized” dialysis. Broad implementation of incremental dialysis might also result in more Veterans receiving care within a VA dialysis unit. Controlled trials are needed to examine the safety and efficacy of incremental hemodialysis in Veterans and other populations; the administrative and health care as well as provider structure within the VA system would facilitate the performance of such trials.
Calcium, phosphorus, and magnesium homeostasis is altered in chronic kidney disease (CKD). Hypocalcemia, hyperphosphatemia, and hypermagnesemia are not seen until advanced CKD because adaptations develop. Increased parathyroid hormone (PTH) secretion maintains serum calcium normal by increasing calcium efflux from bone, renal calcium reabsorption, and phosphate excretion. Similarly, renal phosphate excretion in CKD is maintained by increased secretion of fibroblast growth factor 23 (FGF23) and PTH. However, the phosphaturic effect of FGF23 is reduced by downregulation of its cofactor Klotho necessary for binding FGF23 to FGF receptors. Intestinal phosphate absorption is diminished in CKD due in part to reduced levels of 1,25 dihydroxyvitamin D. Unlike calcium and phosphorus, magnesium is not regulated by a hormone, but fractional excretion of magnesium increases as CKD progresses. As 60–70% of magnesium is reabsorbed in the thick ascending limb of Henle, activation of the calcium‐sensing receptor by magnesium may facilitate magnesium excretion in CKD. Modification of the TRPM6 channel in the distal tubule may also have a role. Besides abnormal bone morphology and vascular calcification, abnormalities in mineral homeostasis are associated with increased cardiovascular risk, increased mortality and progression of CKD.
Acute kidney injury (AKI) is one of the most common serious complications for all hospital admissions, with its incidence increasing among hospitalized patients, particularly those in the intensive care unit. Despite significant improvements in critical care and dialysis technology, AKI is associated with an increased risk of short‐ and long‐term mortality, prolonged hospital stays, and dialysis dependence. These risks are particularly relevant for critically ill patients with AKI severe enough to require renal replacement therapy (RRT). No specific pharmacologic treatment has been established to treat AKI. Hence, the mainstay treatment for patients with AKI is RRT even though there are still several problematic issues regarding its use including RRT modality, dose, and timing. Recently, the impact of AKI on an increased risk of progression to chronic kidney disease (CKD) and end‐stage renal disease requiring dialysis or transplantation is attracting increased attention.
Intradialytic hypotension (IDH), a common complication of ultrafiltration during hemodialysis therapy, is associated with high mortality and morbidity. IDH, defined as a nadir systolic blood pressure of less than 90 mm Hg on more than 30% of treatments, is a relevant definition and is correlated with mortality. Risk factors for IDH include patient demographics, anti‐hypertensive medication use, larger interdialytic weight gain, and dialysis prescription features as dialysate sodium, high ultrafiltration rate, and dialysate temperature. A high frequency of IDH events carries a substantial death risk. An ultrafiltration rate >10 mL/h/kg, and even more so >13 mL/h/kg, is highly predictive of cardiovascular and all‐cause mortality. Evidence suggests that IDH causes acute reversible segmental myocardial hypoperfusion and contractile dysfunction (myocardial stunning), which can result in long‐term loss of myocardial contractility, leading to premature death. IDH also has negative end‐organ effects on the brain and gut, contributing to mortality through stroke, and endotoxin translocation with associated inflammation and protein‐energy wasting. Given strong association of IDH and dialysis mortality, a paradigm shift to its approach is urgently needed. Randomized controlled trials are required to prospectively test drugs and monitoring devices which may reduce IDH.
Oxidative stress (OS) is the result of prooxidant molecules overwhelming the antioxidant defense mechanisms. Hemodialysis (HD) constitutes a state of elevated inflammation and OS, due to loss of antioxidants during dialysis and activation of white blood cells triggering production of reactive oxygen species. Dialysis vintage, dialysis methods, and type and condition of vascular access, biocompatibility of dialyzer membrane and dialysate, iron administration, and anemia all can play a role in aggravating OS, which in turn has been associated with increased morbidity and mortality. Oral or intravenous administration of antioxidants may detoxify the oxidative molecules and at least in part repair OS‐mediated tissue damage. Lifestyle interventions and optimization of a highly biocompatible HD procedure might ameliorate OS development in dialysis.
The optimal vascular access for elderly patients remains a challenge due to the difficulty balancing the benefits and risks in a population with increased comorbidity and decreased survival. Age is commonly associated with failure to mature in fistula and decreased rates of primary and secondary patency in both fistula and grafts. In the elderly, at 1 and 2 years, primary patency rates range from 43% to 74% and from 29% to 67%, respectively. Secondary patency rates at 1 and 2 years range from 56% to 82% and 44% to 67%, respectively. Cumulative fistula survival is no better than grafts survival when primary failures are included. Several observational studies consistently demonstrate a lower adjusted mortality among those using a fistula compared with a catheter; however, catheter use in the elderly is increasing in most countries with the exception of Japan. Both guidelines and quality initiatives do not acknowledge the trade‐offs involved in managing the elderly patients with multiple chronic conditions and limited life expectancy or the value that patients place on achieving these outcomes. The framework for choice of vascular access presented in this article considers: (1) likelihood of disease progression before death, (2) patient life expectancy, (3) risks and benefits by vascular access type, and (4) patient preference. Future studies evaluating the timing and type of vascular access with careful assessments of complications, functionality, cost benefit, and patients’ preference will provide relevant information to individualize and optimize care to improve morbidity, mortality, and quality of life in the elderly patient.
A literature review performed by the EXtracorporeal TReatments In Poisoning (EXTRIP) workgroup highlighted deficiencies in the existing literature, especially the reporting of case studies. Although general reporting guidelines exist for case studies, there are none in the specific field of extracorporeal treatments in toxicology. Our goal was to construct and propose a checklist that systematically outlines the minimum essential items to be reported in a case study of poisoned patients undergoing extracorporeal treatments. Through a modified two‐round Delphi technique, panelists (mostly chosen from the EXTRIP workgroup) were asked to vote on the pertinence of a set of items to identify those considered minimally essential for reporting complete and accurate case reports. Furthermore, independent raters validated the clarity of each selected items between each round of voting. All case reports containing data on extracorporeal treatments in poisoning published in Medline in 2011 were reviewed during the external validation rounds. Twenty‐one panelists (20 from the EXTRIP workgroup and an invited expert on pharmacology reporting guidelines) participated in the modified Delphi technique. This group included journal editors and experts in nephrology, clinical toxicology, critical care medicine, emergency medicine, and clinical pharmacology. Three independent raters participated in the validation rounds. Panelists voted on a total of 144 items in the first round and 137 items in the second round, with response rates of 96.3% and 98.3%, respectively. Twenty case reports were evaluated at each validation round and the independent raters' response rate was 99.6% and 98.8% per validation round. The final checklist consists of 114 items considered essential for case study reporting. This methodology of alternate voting and external validation rounds was useful in developing the first reporting guideline for case studies in the field of extracorporeal treatments in poisoning. We believe that this guideline will improve the completeness and transparency of published case reports and that the systematic aggregation of information from case reports may provide early signals of effectiveness and/or harm, thereby improving healthcare decision‐making.
Morbidity and mortality related to chronic kidney disease remain unacceptably high, despite tremendous progress in its prevention and treatment. In an ongoing quest to improve outcome in chronic kidney disease patients, the colon might be an appealing, but largely underexplored, therapeutic target. A clear bi‐directional functional relationship exists between the colon and kidney, also referred as to the colo–renal axis. Uremia has an important impact on the colonic microbiome. The microbiome, in turn, is an important source of uremic toxins, with p‐cresyl sulfate and indoxyl sulfate as important prototypes. These co‐metabolites accumulate in the face of a falling kidney function, and may accelerate the progression of renal and cardiovascular disease. Several therapeutic interventions, including prebiotics and adsorbants, specifically target these colon‐derived uremic toxins originating from bacterial metabolism. As kidney function declines, the colon also gains importance in the homeostasis and disposal of potassium and oxalate. Their colonic secretion may be increased by drugs increasing the expression of cAMP and by probiotics (e.g., Oxalobacter formigenes).
Chronic, low‐grade inflammation is a common comorbid condition in chronic kidney disease (CKD), and particularly in chronic dialysis patients. In this review, we consider the question of whether inflammation affects outcomes in dialysis patients. Levels of proinflammatory cytokines, as well as C‐reactive protein, are elevated in chronic dialysis patients. Multiple factors likely contribute to chronic inflammatory activation in kidney disease patients including the uremic milieu, lifestyle and epigenetic influences, infectious and thrombotic events, the dialysis process, and dysbiosis. Increased inflammatory markers in both CKD and chronic dialysis patients are associated with adverse clinical outcomes including all‐cause mortality, cardiovascular events, kidney disease progression, protein energy wasting and diminished motor function, cognitive impairment, as well as other adverse consequences including CKD‐mineral and bone disorder, anemia, and insulin resistance. Strategies that have been shown to reduce chronic systemic inflammation in CKD and chronic dialysis patients include both pharmacological and nonpharmacological interventions. However, despite evidence that systemic inflammatory markers can be lowered in kidney disease patients treated with various strategies, evidence that this improves clinical outcomes is largely unavailable and represents an important future research direction. Overall, there is strong observational evidence that inflammation is high in chronic dialysis patients and that this is independently associated with numerous adverse clinical outcomes. Targeting inflammation represents a potentially novel and attractive strategy if it can indeed improve adverse outcomes common in this population.