Showing papers in "Clinical Journal of The American Society of Nephrology in 2008"
TL;DR: Concepts regarding bone remodeling, osteoclast and osteoblast function, extracellular matrix, matrix mineralization, and osteocyte function are synthesized in a summary of the currently understood functional determinants of bone strength.
Abstract: This review describes normal bone anatomy and physiology as an introduction to the subsequent articles in this section that discuss clinical applications of iliac crest bone biopsy. The normal anatomy and functions of the skeleton are reviewed first, followed by a general description of the processes of bone modeling and remodeling. The bone remodeling process regulates the gain and loss of bone mineral density in the adult skeleton and directly influences bone strength. Thorough understanding of the bone remodeling process is critical to appreciation of the value of and interpretation of the results of iliac crest bone histomorphometry. Osteoclast recruitment, activation, and bone resorption is discussed in some detail, followed by a review of osteoblast recruitment and the process of new bone formation. Next, the collagenous and noncollagenous protein components and function of bone extracellular matrix are summarized, followed by a description of the process of mineralization of newly formed bone matrix. The actions of biomechanical forces on bone are sensed by the osteocyte syncytium within bone via the canalicular network and intercellular gap junctions. Finally, concepts regarding bone remodeling, osteoclast and osteoblast function, extracellular matrix, matrix mineralization, and osteocyte function are synthesized in a summary of the currently understood functional determinants of bone strength. This information lays the groundwork for understanding the utility and clinical applications of iliac crest bone biopsy.
1,764 citations
TL;DR: The potential role of the immune dysfunction in ESRD as an underlying cause for the high mortality in this patient population is emphasized and the need for more studies in this area is emphasized.
Abstract: End-stage renal disease (ESRD) is associated with significantly increased morbidity and mortality resulting from cardiovascular disease (CVD) and infections, accounting for 50% and 20%, respectively, of the total mortality in ESRD patients. It is possible that these two complications are linked to alterations in the immune system in ESRD, as uremia is associated with a state of immune dysfunction characterized by immunodepression that contributes to the high prevalence of infections among these patients, as well as by immunoactivation resulting in inflammation that may contribute to CVD. This review describes disorders of the innate and adaptive immune systems in ESRD, underlining the specific role of ESRD-associated disturbances of Toll-like receptors. Finally, based on the emerging links between the alterations of immune system, CVD, and infections in ESRD patients, it emphasizes the potential role of the immune dysfunction in ESRD as an underlying cause for the high mortality in this patient population and the need for more studies in this area.
847 citations
TL;DR: Urine NGAL is an early predictive biomarker of AKI severity after CPB and accurate measurements of urine NGAL are obtained using the ARCHITECT platform.
Abstract: Background and objectives: The authors have previously shown that urine neutrophil gelatinase-associated lipocalin (NGAL), measured by a research ELISA, is an early predictive biomarker of acute kidney injury (AKI) after cardiopulmonary bypass (CPB). In this study, whether an NGAL immunoassay developed for a standardized clinical platform (ARCHITECT analyzer®, Abbott Diagnostics Division, Abbott Laboratories, Abbott Park, IL) can predict AKI after CPB was tested.
Design, setting, participants, & measurements: In a pilot study with 136 urine samples (NGAL range, 0.3 to 815 ng/ml) and 6 calibration standards (NGAL range, 0 to 1000 ng/ml), NGAL measurements by research ELISA and by the ARCHITECT® assay were highly correlated (r = 0.99). In a subsequent study, 196 children undergoing CPB were prospectively enrolled and serial urine NGAL measurements obtained by ARCHITECT® assay. The primary outcome was AKI, defined as a ≥50% increase in serum creatinine.
Results: AKI developed in 99 patients (51%), but the diagnosis using serum creatinine was delayed by 2 to 3 d after CPB. In contrast, mean urine NGAL levels increased 15-fold within 2 h and by 25-fold at 4 and 6 h after CPB. For the 2-h urine NGAL measurement, the area under the curve was 0.95, sensitivity was 0.82, and the specificity was 0.90 for prediction of AKI using a cutoff value of 100 ng/ml. The 2-h urine NGAL levels correlated with severity and duration of AKI, length of stay, dialysis requirement, and death.
Conclusions: Accurate measurements of urine NGAL are obtained using the ARCHITECT® platform. Urine NGAL is an early predictive biomarker of AKI severity after CPB.
726 citations
TL;DR: Cystatin C may represent a more adequate alternative to assess renal function in individuals with higher muscle mass when mild kidney impairment is suspected and was significantly related to serum and urinary creatinine but not with cystatin, even after adjustment for protein/meat intake and physical activity.
Abstract: Background and objectives: For addressing the influence of muscle mass on serum and urinary creatinine and serum cystatin C, body composition was assessed by skinfold thickness measurement and bioelectrical impedance analyses.
Design, setting, participants, & measurements: A total of 170 healthy individuals (92 women, 78 men) were classified as sedentary or with mild or moderate/intense physical activity. Blood, 24-h urine samples, and 24-h food recall were obtained from all individuals.
Results: Serum and urinary creatinine correlated significantly with body weight, but the level of correlation with lean mass was even greater. There was no significant correlation between body weight and lean mass with cystatin C. Individuals with moderate/intense physical activity presented significantly lower mean body mass index (23.1 ± 2.5 versus 25.7 ± 3.9 kg/m2) and higher lean mass (55.3 ± 10.0 versus 48.5 ± 10.4%), serum creatinine (1.04 ± 0.12 versus 0.95 ± 0.17 mg/dl), urinary creatinine (1437 ± 471 versus 1231 ± 430 mg/24 h), protein intake (1.4 ± 0.6 versus 1.1 ± 0.6 g/kg per d), and meat intake (0.7 ± 0.3 versus 0.5 ± 0.4 g/kg per d) than the sedentary individuals. Conversely, mean serum cystatin did not differ between these two groups. A multivariate analysis of covariance showed that lean mass was significantly related to serum and urinary creatinine but not with cystatin, even after adjustment for protein/meat intake and physical activity.
Conclusions: Cystatin C may represent a more adequate alternative to assess renal function in individuals with higher muscle mass when mild kidney impairment is suspected.
580 citations
TL;DR: This review focuses on the many new pieces that need to be fit into the complicated puzzle of uremic vascular disease, including persistent inflammation, endothelial dysfunction, oxidative stress, and vascular ossification, which are not only highly prevalent in CKD but also more strongly linked to CVD in these patients than in the general population.
Abstract: Premature cardiovascular disease (CVD), including stroke, peripheral vascular disease, sudden death, coronary artery disease, and congestive heart failure, is a notorious problem in patients with chronic kidney disease (CKD). Because the presence of CVD is independently associated with kidney function decline, it appears that the relationship between CKD and CVD is reciprocal or bidirectional, and that it is this association that leads to the vicious circle contributing to premature death. As randomized, placebo-controlled trials have so far been disappointing and unable to show a survival benefit of various treatment strategies, such a lipid-lowering, increased dialysis dose and normalization of hemoglobin, the risk factor profile seems to be different in CKD compared with the general population. Indeed, seemingly paradoxical associations between traditional risk factors and cardiovascular outcome in patients with advanced CKD have complicated our efforts to identify the real cardiovascular culprits. This review focuses on the many new pieces that need to be fit into the complicated puzzle of uremic vascular disease, including persistent inflammation, endothelial dysfunction, oxidative stress, and vascular ossification. Each of these is not only highly prevalent in CKD but also more strongly linked to CVD in these patients than in the general population. However, a causal relationship between these new markers and CVD in CKD patients remains to be established. Finally, two novel disciplines, proteomics and epigenetics, will be discussed, because these tools may be helpful in the understanding of the discussed vascular risk factors.
539 citations
TL;DR: There has been increasing interest in the identification and validation of novel biomarkers of acute kidney injury that may permit earlier and more accurate diagnosis, and efforts to modernize the approach to its diagnosis are summarized.
Abstract: Acute kidney injury is an increasingly common and potentially catastrophic complication in hospitalized patients. Early observational studies from the 1980s and 1990s established the general epidemiologic features of acute kidney injury: the incidence, prognostic significance, and predisposing medical and surgical conditions. Recent multicenter observational cohorts and administrative databases have enhanced our understanding of the overall disease burden of acute kidney injury and trends in its epidemiology. An increasing number of clinical studies focusing on specific types of acute kidney injury (e.g., in the setting of intravenous contrast, sepsis, and major surgery) have provided further details into this heterogeneous syndrome. Despite our sophisticated understanding of the epidemiology and pathobiology of acute kidney injury, current prevention strategies are inadequate and current treatment options outside of renal replacement therapy are nonexistent. This failure to innovate may be due in part to a diagnostic approach that has stagnated for decades and continues to rely on markers of glomerular filtration (blood urea nitrogen and creatinine) that are neither sensitive nor specific. There has been increasing interest in the identification and validation of novel biomarkers of acute kidney injury that may permit earlier and more accurate diagnosis. This review summarizes the major epidemiologic studies of acute kidney injury and efforts to modernize the approach to its diagnosis.
484 citations
TL;DR: With implementation of early education, referral to a transplant center coincident with creation of vascular access, timely transplant evaluation, and identification of potential living donors, early transplantation can be an option for substantially more patients with chronic kidney disease.
Abstract: Background and objectives: Kidney transplantation is the most desired and cost-effective modality of renal replacement therapy for patients with irreversible chronic kidney failure (end-stage renal disease, stage 5 chronic kidney disease). Despite emerging evidence that the best outcomes accrue to patients who receive a transplant early in the course of renal replacement therapy, only 2.5% of incident patients with end-stage renal disease undergo transplantation as their initial modality of treatment, a figure largely unchanged for at least a decade. Design, setting, participants, & measurements: The National Kidney Foundation convened a Kidney Disease Outcomes Quality Initiative (KDOQI) conference in Washington, DC, March 19 through 20, 2007, to examine the issue. Fifty-two participants representing transplant centers, dialysis providers, and payers were divided into three work groups to address the impact of early transplantation on the chronic kidney disease paradigm, educational needs of patients and professionals, and finances of renal replacement therapy. Results: Participants explored the benefits of early transplantation on costs and outcomes, identified current barriers (at multiple levels) that impede access to early transplantation, and recommended specific interventions to overcome those barriers. Conclusions: With implementation of early education, referral to a transplant center coincident with creation of vascular access, timely transplant evaluation, and identification of potential living donors, early transplantation can be an option for substantially more patients with chronic kidney disease.
450 citations
TL;DR: In patients with end-stage kidney disease, calcitriol and its analogs do not constitute adequate replacement in managing vitamin D needs of such patients, and the safest and most economical way to ensure adequate vitamin D status is to use oral dosing of native vitamin D.
Abstract: Vitamin D functions in the body through both an endocrine mechanism (regulation of calcium absorption) and an autocrine mechanism (facilitation of gene expression). The former acts through circulating calcitriol, whereas the latter, which accounts for more than 80% of the metabolic utilization of the vitamin each day, produces, uses, and degrades calcitriol exclusively intracellularly. In patients with end-stage kidney disease, the endocrine mechanism is effectively disabled; however, the autocrine mechanism is able to function normally so long as the patient has adequate serum levels of 25(OH)D, on which its function is absolutely dependent. For this reason, calcitriol and its analogs do not constitute adequate replacement in managing vitamin D needs of such patients. Optimal serum 25(OH)D levels are greater than 32 ng/mL (80 nmol/L). The consequences of low 25(OH)D status include increased risk of various chronic diseases, ranging from hypertension to diabetes to cancer. The safest and most economical way to ensure adequate vitamin D status is to use oral dosing of native vitamin D. (Both daily and intermittent regimens work well.) Serum 25(OH)D can be expected to rise by about 1 ng/mL (2.5 nmol/L) for every 100 IU of additional vitamin D each day. Recent data indicate that cholecalciferol (vitamin D3) is substantially more potent than ergocalciferol (vitamin D2) and that the safe upper intake level for vitamin D3 is 10,000 IU/d.
405 citations
TL;DR: Serial intradialytic H(2)(15)O positron emission tomography scanning was used to confirm that the development of dialysis-induced RWMAs was associated with reduction in myocardial blood flow (MBF), and stress-induced segmental left ventricular dysfunction correlates with matched reduction in MBF.
Abstract: Background and objectives: Hemodialysis is associated with hemodynamic instability, acute cardiac ischemia, and the development of regional wall motion abnormalities (RWMAs). This study used serial intradialytic H2 15 O positron emission tomography scanning to confirm that the development of dialysis-induced RWMAs was associated with reduction in myocardial blood flow (MBF). Design, setting, participants, & measurements: Four prevalent hemodialysis patients without angiographically significant coronary artery disease had measurements of MBF during standard hemodialysis and biofeedback dialysis. All patients underwent serial measurements of MBF using positron emission tomography. Concurrent echocardiography was used to assess left ventricular function and the development of RWMAs. Hemodynamic variables were measured using continuous pulse wave analysis. Results: Mean prehemodialysis MBF was within the normal range. Global MBF was acutely reduced during hemodialysis. Segmental MBF was reduced to a significantly greater extent in areas that developed RWMAs compared with those that did not. Not all regions with reduced MBF were functionally affected, but a reduction in myocardial blood flow of >30% from baseline was significantly associated with the development of RWMAs. No significant differences in hemodynamic tolerability, RWMA development, or MBF between dialysis modalities were observed. Conclusions: Hemodialysis is associated with repetitive myocardial ischemia, which, in the absence of coronary artery disease, may be due to coronary microvascular dysfunction. Stress-induced segmental left ventricular dysfunction correlates with matched reduction in MBF. Functional poststress recovery is consistent with myocardial stunning induced by hemodialysis. This process may be important in the development of heart failure in long-term hemodialysis patients.
387 citations
TL;DR: This article itself is in a narrative format, from authors who have published a number of meta-analyses in previous years, and contains recommendations based on the author's clinical experience, the breadth to which available literature was identified and compiled, and the reasons that some studies were given more emphasis than others.
Abstract: We live in the information age, and the practice of medicine is becoming increasingly specialized. In the biomedical literature, the number of published studies has dramatically increased: There are now more than 15 million citations in MEDLINE, with 10,000 to 20,000 new citations added each week (1). Multiple relevant studies usually guide most clinical decisions. These studies often vary in their design; methodologic quality; population studied; and the intervention, test, or condition considered. Because even highly cited trials may be challenged or refuted over time (2), clinical decision-making requires ongoing reconciliation of studies that provide different answers to the same question. Both clinicians and researchers can also benefit from a summary of where uncertainty remains. Because it is often impractical for readers to track down and review all of the primary studies (3), review articles are an important source of summarized evidence on a particular topic (4).
Review articles have traditionally taken the form of a narrative review, whereby a content expert writes about a particular field, condition, or treatment (5–7). Narrative reviews have many benefits, including a broad overview of relevant information tempered by years of practical knowledge from an experienced author. Indeed, this article itself is in a narrative format, from authors who have published a number of meta-analyses in previous years.
In some circumstances, a reader wants to become very knowledgeable about specific details of a topic and wants some assurance that the information presented is both comprehensive and unbiased. A narrative review typically uses an implicit process to compile evidence to support the statements being made. The reader often cannot tell which recommendations were based on the author's clinical experience, the breadth to which available literature was identified and compiled, and the reasons that some studies were given more emphasis than others. It …
358 citations
TL;DR: Calciphylaxis should be considered while evaluating skin lesions in patients with predisposing conditions even in the absence of end-stage kidney disease and renal transplantation, suggesting that heterogeneous mechanisms may contribute to its pathogenesis.
Abstract: Background and objectives: Calciphylaxis, or calcific uremic arteriolopathy, is a well-described entity in end-stage kidney disease and renal transplant patients; however, little systematic information is available on calciphylaxis from nonuremic causes. This systematic review was designed to characterize etiologies, clinical features, laboratory abnormalities, and prognosis of nonuremic calciphylaxis. Design, setting, participants, & measurements: A systematic review of literature for case reports and case series of nonuremic calciphylaxis was performed. Cases included met the operational definition of nonuremic calciphylaxis–histopathologic diagnosis of calciphylaxis in the absence of end-stage kidney disease, renal transplantation, or acute kidney injury requiring renal replacement therapy. Results: We found 36 cases (75% women, 63% Caucasian, aged 15 to 82 yr) of nonuremic calciphylaxis. Primary hyperparathyroidism, malignancy, alcoholic liver disease, and connective tissue disease were the most common reported causes. Preceding corticosteroid use was reported for 61% patients. Protein C and S deficiencies were seen in 11% of patients. Skin lesions were morphologically similar to calcific uremic arteriolopathy. Mortality rate was 52%, with sepsis being the leading cause of death. Conclusion: Calciphylaxis should be considered while evaluating skin lesions in patients with predisposing conditions even in the absence of end-stage kidney disease and renal transplantation. Nonuremic calciphylaxis is reported most often in white women. Mineral abnormalities that are invoked as potential causes in calcific uremic arteriolopathy are often absent, suggesting that heterogeneous mechanisms may contribute to its pathogenesis. Nonuremic calciphylaxis is associated with high mortality, and there is no known effective treatment.
TL;DR: Hemodialysis patients with diabetes can be expected to have reduced primary functional patency rates, but if treated adequately, then arteriovenous fistula functionality can be maintained as long as in patients without diabetes.
Abstract: Background and objectives: Vascular access standards are predominantly based on older, single-center reports; however, the hemodialysis population has changed dramatically and primary arteriovenous fistula failure is a huge problem. This prospective, multicenter study used standardized definitions to analyze patency rates and potential risk factors that affect functional patency and late arteriovenous fistula functionality.
Design, setting, participants, & measurements: Eleven centers participated in a guidelines implementation program. All new permanent vascular accesses were included. Patency and functional patency, defined as access survival from creation and from first dialysis use, respectively, were calculated using Kaplan-Meier analysis. Risk factors for primary functional patency loss (intervention-free interval) and secondary failure (abandonment) were determined using regression models.
Results: A total of 491 arteriovenous fistulas were placed in 395 patients. Six-, 12-, and 18-mo secondary patency and functional patency were 75 ± 2.0, 70 ± 2.3, and 67 ± 2.7% and 90 ± 1.9, 88 ± 2.2, and 86 ± 2.7%, respectively. Primary failure rate was 40%. Thrombosis rate was 0.14 per patient-year. Diabetes and arteriovenous fistula surveillance were significantly associated with primary functional patency loss. Preoperative duplex was inversely related to secondary failure. The secondary failure rate per hospital varied from 0 to 39%.
Conclusions: This study showed a marked difference between patency and functional patency, likely to be explained by high primary failure rates. Hemodialysis patients with diabetes can be expected to have reduced primary functional patency rates, but if treated adequately, then arteriovenous fistula functionality can be maintained as long as in patients without diabetes.
TL;DR: Clinical studies showed that it is not purely academic to distinguish between intimal and medial calcification but rather relevant for the clinical presentation, treatment, and prognosis because each type leads to different clinical consequences.
Abstract: Calcification of the vascular tree is common in physiologic and pathologic conditions, i.e., aging, diabetes, dyslipidemia, genetic diseases, and diseases with disturbances of calcium metabolism. In chronic kidney disease, vascular calcification is even more common, develops early, and contributes to the markedly increased cardiovascular risk in this particular population. Pathomorphologically, atherosclerosis (i.e., plaque-forming degenerative changes of the aorta and of large elastic arteries) and arteriosclerosis (i.e., concentric media thickening of muscular arteries) can be distinguished. Increasing knowledge about calcification together with improved imaging techniques provided evidence that also vascular calcification has to be divided into two distinct entities according to the specific sites of calcification within the vascular wall: Patchy calcification of the intima in the vicinity of lipid or cholesterol deposits as present in plaque calcification and calcification of the media in the absence of such lipid or cholesterol deposits, known as Monckeberg-type atherosclerosis. The two types of calcification may vary according to the type of vessel (large elastic versus smaller muscular type artery) and proximal versus distal sites of the arterial tree. Furthermore, clinical studies showed that it is not purely academic to distinguish between intimal and medial calcification but rather relevant for the clinical presentation, treatment, and prognosis because each type leads to different clinical consequences. In vivo studies in animal models provided evidence in favor of common pathomechanisms between vascular calcification and atherosclerosis; however, there is other, strong experimental and clinical evidence that pleads for the continued distinction between intimal and medial calcification.
TL;DR: It is important for the clinician to have a high degree of suspicion for these disorders in cases of high anion gap metabolic acidosis, acute renal failure, or unexplained neurologic disease so that treatment can be initiated early.
Abstract: Alcohol-related intoxications, including methanol, ethylene glycol, diethylene glycol, and propylene glycol, and alcoholic ketoacidosis can present with a high anion gap metabolic acidosis and increased serum osmolal gap, whereas isopropanol intoxication presents with hyperosmolality alone. The effects of these substances, except for isopropanol and possibly alcoholic ketoacidosis, are due to their metabolites, which can cause metabolic acidosis and cellular dysfunction. Accumulation of the alcohols in the blood can cause an increment in the osmolality, and accumulation of their metabolites can cause an increase in the anion gap and a decrease in serum bicarbonate concentration. The presence of both laboratory abnormalities concurrently is an important diagnostic clue, although either can be absent, depending on the time after exposure when blood is sampled. In addition to metabolic acidosis, acute renal failure and neurologic disease can occur in some of the intoxications. Dialysis to remove the unmetabolized alcohol and possibly the organic acid anion can be helpful in treatment of several of the alcohol-related intoxications. Administration of fomepizole or ethanol to inhibit alcohol dehydrogenase, a critical enzyme in metabolism of the alcohols, is beneficial in treatment of ethylene glycol and methanol intoxication and possibly diethylene glycol and propylene glycol intoxication. Given the potentially high morbidity and mortality of these intoxications, it is important for the clinician to have a high degree of suspicion for these disorders in cases of high anion gap metabolic acidosis, acute renal failure, or unexplained neurologic disease so that treatment can be initiated early.
TL;DR: This study demonstrates significant abnormalities of serum and urinary polyclonal FLC in patients with CKD, and provides the basis for studies that assess the contribution of polyclona FLC to progressive renal injury and systemic inflammation in Patients with kidney disease.
Abstract: Background and objectives: Monoclonal free light chains (FLC) frequently cause kidney disease in patients with plasma cell dyscrasias. Polyclonal FLC, however, have not been assessed in patients with chronic kidney disease (CKD) yet could potentially play an important pathologic role. This study describes for the first time polyclonal FLC in patients with CKD. Design, setting, participants, & measurements: A sensitive, quantitative immunoassay was used to analyze serum and urinary polyclonal FLC in 688 patients with CKD of various causes. Results: Serum κ and λ FLC concentrations increased progressively with CKD stage (both P Conclusions: This study demonstrates significant abnormalities of serum and urinary polyclonal FLC in patients with CKD. These data provide the basis for studies that assess the contribution of polyclonal FLC to progressive renal injury and systemic inflammation in patients with kidney disease.
TL;DR: The differential impact of each AKI definition interpretation interpretation on incidence estimation and severity distribution was evaluated and it was found thatAKI definition variation causes interstudy heterogeneity.
Abstract: Background and objectives: Differences in defining acute kidney injury (AKI) may impact incidence ascertainment. We assessed the effects of different AKI definition interpretation methods on epidemiology ascertainment.
Design, setting, participants, & measurements: Two groups were studied at Texas Children's Hospital, Houston, Texas: 150 critically ill children (prospective) and 254 noncritically ill, hospitalized children receiving aminoglycosides (retrospective). SCr was collected for 14 d in the prospective study and 21 d in the retrospective study. Children with known baseline serum creatinine (bSCr) were classified by the pediatric Risk, Injury, Failure, Loss, End-Stage Kidney Disease (pRIFLE) AKI definition using SCr change (pRIFLEΔSCr), estimated creatinine clearance (eCCl) change (pRIFLEΔCCl), and the Acute Kidney Injury Network (AKIN) definition. In subjects without known bSCr, bSCR was estimated as eCCl = 100 (eCCl100) and 120 ml/min per 1.73 m2 (eCCl120), admission SCr (AdmSCr) and lower/upper normative values (NormsMin, NormsMax). The differential impact of each AKI definition interpretation on incidence estimation and severity distribution was evaluated.
Results: pRIFLEΔSCr and AKIN led to identical AKI distributions. pRIFLEΔCCl resulted in 14.5% (critically ill) and 11% (noncritical) more patients diagnosed with AKI compared to other methods (P 0.05). Different bSCr estimates led to differences in AKI incidence, from 12% (AdmSCr) to 87.8% (NormsMin) (P 0.05) in the critically ill group and from 4.6% (eCCl100) to 43.1% (NormsMin) (P 0.05) in the noncritical group.
Conclusions: AKI definition variation causes interstudy heterogeneity. AKI definition should be standardized so that results can be compared across studies.
TL;DR: The committee concluded that epidemiologic studies should include prospective out- and inpatient studies that measure incidence of community and hospital acute kidney injury and post-acute kidney injury chronic kidney disease, and whenever available, use of reliable existing administrative or institutional databases.
Abstract: Background and objectives: The worldwide incidence of acute kidney injury is poorly known because of underreporting, regional disparities, and differences in definition and case mix. New definitions call for revision of the problem with unified criteria. Design, setting, participants, & measurements: This article reports on the research recommendations of an international multidisciplinary committee, assembled to define a research agenda on acute kidney injury epidemiology using a modified three-step Delphi process. Results: Knowledge of incidence and risk factors is crucial because it drives local and international efforts on detection and treatment. Also, notable differences exist between developing and developed countries: Incidence seems higher in the former, but underreporting compounded by age and gender disparities makes available data unreliable. In developing countries, incidence varies seasonally; incidence peaks cause critical shortages in medical and nursing personnel. Finally, in developing countries, lack of systematic evaluation of the role of falciparum malaria, obstetric mechanisms, and hemolytic uremic syndrome on acute kidney injury hampers efforts to prevent acute kidney injury. Conclusions: The committee concluded that epidemiologic studies should include ( 1 ) prospective out- and inpatient studies that measure incidence of community and hospital acute kidney injury and post–acute kidney injury chronic kidney disease; ( 2 ) incidence measurements during seasonal peaks in developing and developed countries; and ( 3 ) whenever available, use of reliable existing administrative or institutional databases. Epidemiologic studies using standardized definitions in community and institutional settings in developing and underdeveloped countries are essential first steps to achieving early detection and intervention and improved patient outcomes.
TL;DR: The "surprise" question is effective in identifying sicker dialysis patients who have a high risk for early mortality and should receive priority for palliative care interventions.
Abstract: Background and objectives: Dialysis patients are increasingly characterized by older age, multiple comorbidities, and shortened life expectancy. This study investigated whether the “surprise” question, “Would I be surprised if this patient died in the next year?” identifies patients who are at high risk for early mortality.
Design, setting, participants, & measurements: This prospective cohort study of 147 patients in three hemodialysis dialysis units classified patients into “yes” and “no” groups on the basis of the “surprise” question response and tracked patient status (alive or dead) at 12 mo. Demographics, Charlson Comorbidity Index score, and Karnofsky Performance Status score were measured.
Results: Initially, 34 (23%) patients were classified in the “no” group. Compared with the 113 patients in the “yes” group, the patients in the “no” group were older (72.5 ± 12.8 versus 64.5 ± 14.9), had a higher comorbidity score (7.1 ± 2.3 versus 5.8 ± 2.1), and had a lower performance status score (69.7 ± 17.1 versus 81.6 ± 15.8). At 12 mo, 22 (15%) patients had died; the mortality rate for the “no” group was 29.4% and for the “yes” group was 10.6%. The odds of dying within 1 yr for the patients in the “no” group were 3.5 times higher than for patients in the “yes” group, (odds ratio 3.507, 95% CI 1.356 to 9.067, P = 0.01).
Conclusions: The “surprise” question is effective in identifying sicker dialysis patients who have a high risk for early mortality and should receive priority for palliative care interventions.
TL;DR: The conclusion is that smoking is an important renal risk factor, and nephrologists have to invest more efforts to motivate patients to stop smoking.
Abstract: Although it is beyond any doubt that smoking is the number one preventable cause of death in most countries, smoking as an independent progression factor in renal disease has been questioned against the background of evidence-based criteria. This is because information from large, randomized, prospective studies that investigate the effects of smoking on renal function in healthy individuals as well as in patients with primary or secondary renal disease are lacking. Since 2003, a substantial number of clinical and experimental data concerning the adverse renal effects of smoking have been published, including large, prospective, population-based, observational studies. These more recent data together with evidence from experimental studies clearly indicate that smoking is a relevant risk factor, conferring a substantial increase in risk for renal function deterioration. This review summarizes the present knowledge about the renal risks of smoking as well as the increased cardiovascular risk caused by smoking in patients with chronic kidney disease. The conclusion is that smoking is an important renal risk factor, and nephrologists have to invest more efforts to motivate patients to stop smoking.
TL;DR: In populations with high cardiovascular risk, especially those with ESRD, aortic PWV measurements provide predictive utility independent of the standard brachial arterial BP measurements, and are of particular interest to nephrologists.
Abstract: Arterial stiffness is recognized increasingly as an important component in the determination of cardiovascular risk, particularly in chronic kidney disease and ESRD populations. Although the technique has been around for nearly 100 yr, in the past 20 to 25 yr, pragmatic noninvasive approaches have allowed the incorporation of arterial stiffness measurements, usually in the form of aortic pulse wave velocity (PWV), into clinical assessment of patients. In populations with high cardiovascular risk, especially those with ESRD, aortic PWV measurements provide predictive utility independent of the standard brachial arterial BP measurements. This review briefly discusses the history of vascular dynamics, the determinants of PWV, and some of the available technologies in current use and concludes with a section on the relevance of arterial stiffness measurements in populations of particular interest to nephrologists.
TL;DR: Even a partial remission in lupus nephritis is associated with a significantly better patient and renal survival compared with no remission.
Abstract: Background and objectives: The value of a complete remission in severe lupus nephritis is well known but little is known about the impact of a partial remission in this patient population. The purpose of this study was to evaluate the long-term prognosis of achieving a complete or partial remission in a well-defined group of patients with severe lupus nephritis.
Design, setting, participants, & measurements: In this study, 86 patients with diffuse lupus glomerulonephritis were reviewed for assessment of the value of a partial remission (50% reduction in baseline proteinuria to ≤1.5 g/d and ≤25% increase in baseline creatinine) and complete remission (proteinuria ≤0.33 g/d and serum creatinine ≤1.4 mg/dl) on outcomes compared with patients who did not attain a remission. These well-characterized patients were entered into a prospective therapeutic trial conducted by the Collaborative Study Group and were followed for more than 10 yr.
Results: All biopsies showed diffuse lupus nephritis. A complete remission was attained in 37 (43%) patients, a partial remission in 21 (24%) patients, and no remission in 28 (32%) patients. Baseline clinical and serologic features were similar among the groups, but patients with a complete remission had a lower serum creatinine and chronicity index compared with patients with partial or no remission. The patient survival at 10 yr was 95% for complete remission, 76% for partial remission, and 46% for no remission. The renal survival at 10 yr was 94% for complete remission, 45% for partial remission, and 19% for no remission, and the patient survival without end-stage renal disease at 10 yr was 92% for complete remission, 43% for partial remission, and 13% for no remission.
Conclusion: Even a partial remission in lupus nephritis is associated with a significantly better patient and renal survival compared with no remission.
TL;DR: It is suggested that subclinical primary hypothyroidism is a relatively common condition among persons with CKD not requiring chronic dialysis, and it is independently associated with progressively lower estimated GFR in a large cohort of unselected outpatient adults.
Abstract: Background and objectives: Subclinical primary hypothyroidism is highly prevalent in the general population, especially in the elderly. However, the prevalence of subclinical primary hypothyroidism in persons with chronic kidney disease (CKD) not requiring chronic dialysis is not well defined. Design, setting, participants, and measurements: Cross-sectional data from 3089 adult outpatients, who were consecutively referred by general practitioners for routine blood testing over the last two years, were analyzed. Glomerular filtration rate (GFR) was estimated by the abbreviated Modification of Diet in Renal Disease equation. Multivariable logistic regression was used to evaluate the independent association between prevalent subclinical primary hypothyroidism and estimated GFR. Results: Among 3089 adult participants, 293 (9.5%) had subclinical primary hypothyroidism and 277 (9%) had an estimated GFR Conclusions: These findings suggest that subclinical primary hypothyroidism is a relatively common condition (∼18%) among persons with CKD not requiring chronic dialysis, and it is independently associated with progressively lower estimated GFR in a large cohort of unselected outpatient adults.
TL;DR: Members of the Istanbul Summit concluded that transplant commercialism, which targets the vulnerable, transplant tourism, and organ trafficking should be prohibited and that the legacy of transplantation is threatened by organ trafficking and transplant tourism.
Abstract: Organ commercialism, which targets vulnerable populations (such as illiterate and impoverished persons, undocumented immigrants, prisoners, and political or economic refugees) in resource-poor countries, has been condemned by international bodies such as the World Health Organization for decades. Yet in recent years, as a consequence of the increasing ease of Internet communication and the willingness of patients in rich countries to travel and purchase organs, organ trafficking and transplant tourism have grown into global problems. For example, as of 2006, foreigners received two-thirds of the 2000 kidney transplants performed annually in Pakistan. The Istanbul Declaration proclaims that the poor who sell their organs are being exploited, whether by richer people within their own countries or by transplant tourists from abroad. Moreover, transplant tourists risk physical harm by unregulated and illegal transplantation. Participants in the Istanbul Summit concluded that transplant commercialism, which targets the vulnerable, transplant tourism, and organ trafficking should be prohibited. And they also urged their fellow transplant professionals, individually and through their organizations, to put an end to these unethical activities and foster safe, accountable practices that meet the needs of transplant recipients while protecting donors. Countries from which transplant tourists originate, as well as those to which they travel to obtain transplants, are just beginning to address their respective responsibilities to protect their people from exploitation and to develop national self-sufficiency in organ donation. The Declaration should reinforce the resolve of governments and international organizations to develop laws and guidelines to bring an end to wrongful practices. \"The legacy of transplantation is threatened by organ trafficking and transplant tourism. The Declaration of Istanbul aims to combat these activities and to preserve the nobility of organ donation. The success of transplantation as a life-saving treatment does not require-nor justify-victimizing the world's poor as the source of organs for the rich\" (Steering Committee of the Istanbul Summit).
TL;DR: Compared with conventional therapy, a cinacalcet-based treatment algorithm increased achievement of KDOQI treatment targets in dialysis patients in whom conventional therapy was no longer effective in controlling this disease.
Abstract: Background and objectives: Cinacalcet, a novel calcimimetic, targets the calcium-sensing receptor to lower parathyroid hormone (PTH), calcium, and phosphorus levels in dialysis patients with secondary hyperparathyroidism (SHPT). This study compared the efficacy of a cinacalcet-based regimen with unrestricted conventional care (vitamin D and phosphate binders) for achieving the stringent National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI) targets for dialysis patients. Study design: In this multicenter, open-label study, hemodialysis patients with poorly controlled SHPT were randomized to receive conventional care (n 184) or a cinacalcet-based regimen (n 368). Doses of cinacalcet, vitamin D sterols, and phosphate binders were adjusted during a 16-wk dose-optimization phase with the use of algorithms that allowed cinacalcet to be used with adjusted doses of vitamin D. The primary end point was the proportion of patients with mean intact PTH <300 pg/ml during a 7-wk efficacy assessment phase. Results: A higher proportion of patients receiving the cinacalcet-based regimen versus conventional care achieved the targets for PTH (71% versus 22%, respectively; P < 0.001), Ca P (77% versus 58%, respectively; P < 0.001), calcium (76% versus 33%, respectively; P < 0.001), phosphorus (63% versus 50%, respectively; P 0.002), and PTH and Ca P (59% versus 16%, respectively, P < 0.001), and allowed a 22% reduction in vitamin D dosage in patients receiving vitamin D at baseline. Achievement of targets was greatest in patients with less severe disease (intact PTH range, 300 to 500 pg/ml) and the cinacalcet dose required was lower in these patients (median 30 mg/d). Conclusions: Compared with conventional therapy, a cinacalcet-based treatment algorithm increased achievement of KDOQI treatment targets in dialysis patients in whom conventional therapy was no longer effective in controlling this disease.
TL;DR: Given the high risk of vascular calcification in those patients with chronic kidney disease, the importance of understanding warfarin's effect on VKDPs is paramount, and recognizing the importance in vascular biology will stimulate new areas of research and offer potential therapeutic interventions.
Abstract: Vitamin K-dependent proteins (VKDPs) require carboxylation to become biologically active. Although the coagulant factors are the most well-known VKDPs, there are many others with important physiologic roles. Matrix Gla Protein (MGP) and Growth Arrest Specific Gene 6 (Gas-6) are two particularly important VKDPs, and their roles in vascular biology are just beginning to be understood. Both function to protect the vasculature; MGP prevents vascular calcification and Gas-6 affects vascular smooth muscle cell apoptosis and movement. Unlike the coagulant factors, which undergo hepatic carboxylation, MGP and Gas-6 are carboxylated within the vasculature. This peripheral carboxylation process is distinct from hepatic carboxylation, yet both are inhibited by warfarin administration. Warfarin prevents the activation of MGP and Gas-6, and in animals, induces vascular calcification. The relationship of warfarin to vascular calcification in humans is not fully known, yet observational data suggest an association. Given the high risk of vascular calcification in those patients with chronic kidney disease, the importance of understanding warfarin's effect on VKDPs is paramount. Furthermore, recognizing the importance of VKDPs in vascular biology will stimulate new areas of research and offer potential therapeutic interventions.
TL;DR: Stopping ACEI or ARB before cardiac surgery may reduce the incidence of AKI, and preoperative use of ACEI/ARB is associated with a 27.6% higher risk for AKI postoperatively.
Abstract: Background and objectives: Acute kidney injury (AKI) occurs commonly after cardiac surgery. Most patients who undergo cardiac surgery receive long-term treatment with angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB). The aim of this study was to determine whether long-term use of ACEI/ARB is associated with an increased incidence of AKI after cardiac surgery.
Design, setting, participants, & measurements: This was a retrospective cohort study of 1358 adult patients who underwent cardiac surgery between January 1, 2001, and December 31, 2005, in two tertiary care hospitals in Buffalo, NY. The incidence of AKI was determined after cardiac surgery. Clinical data were collected using a standardized form that included comorbid condition, use of ACEI/ARB, and intraoperative and postoperative complications.
Results: Overall, 40.2% of patients developed AKI. Preoperative variables that were significantly associated with development of AKI included increasing age; nonwhite race; combined valve surgery and coronary artery bypass grafting compared with coronary artery bypass grafting alone; American Society of Anesthesiologists (ASA) Risk Score category 4/5 compared with 2 to 3; presence of diabetes, congestive heart failure, or neurologic disease at baseline; use of ACEI/ARB; and emergency surgery. Intra- and postoperative factors that were associated with postoperative AKI were hypotension during surgery, use of vasopressors, and postoperative hypotension. Multiple regression logistic model confirmed an independent and significant association of AKI and preoperative use of ACEI/ARB. This was confirmed using a bivariate-probit and propensity score model that adjusts for confounding by indication of use and selection bias.
Conclusions: Preoperative use of ACEI/ARB is associated with a 27.6% higher risk for AKI postoperatively. Stopping ACEI or ARB before cardiac surgery may reduce the incidence of AKI.
TL;DR: Acute rejection and new-onset diabetes have a similar impact on long-term transplant survival but lead to transplant failure through different mechanisms, and targeted therapeutic strategies to minimize the impact of various early posttransplantation complications may lead to improved long- term outcomes.
Abstract: Background and objectives: Development of new therapeutic strategies to improve long-term transplant outcomes requires improved understanding of the mechanisms by which these complications limit long-term transplant survival. Design, setting, participants, & measurements: The association of acute rejection and new-onset diabetes was determined in the first posttransplantation year with the outcomes of transplant failure from any cause, death-censored graft loss, and death with a functioning graft in 27,707 adult recipients of first kidney-only transplants, with graft survival of at least 1 yr, performed between 1995 and 2002 in the United States. Results: In multivariate analyses, patients who developed acute rejection or new-onset diabetes had a similar risk for transplant failure from any cause, but the mechanisms of transplant failure were different: Acute rejection was associated with death-censored graft loss but only weakly associated with death with a functioning graft. In contrast new-onset diabetes was not associated with death-censored graft loss but was associated with an increased risk for death with a functioning graft. Conclusions: Acute rejection and new-onset diabetes have a similar impact on long-term transplant survival but lead to transplant failure through different mechanisms. The mechanisms by which new-onset diabetes leads to transplant failure should be prospectively studied. Targeted therapeutic strategies to minimize the impact of various early posttransplantation complications may lead to improved long-term outcomes.
TL;DR: Real-time, noninvasive novel methods may help to differentiate between evolving tubular damage and altered hemodynamics and in the design of appropriate preventive interventions.
Abstract: Background and objectives: Renal parenchymal Po2 declines after the administration of iodinated radiocontrast agents, reaching critically low levels of approximately 10 mmHg in medullary structures. Design, setting, participants, & measurements: In this review, the causes of renal parenchymal hypoxia and its potential role in the pathogenesis of contrast nephropathy are appraised. Results: Commonly associated predisposing factors are associated with a propensity to enhance renal hypoxia. Indeed, animal models of radiocontrast nephropathy require the induction of such predisposing factors, mimicking clinical scenarios that lead to contrast nephropathy in high-risk individuals. In these models, in association with medullary hypoxic damage, a transient local cellular hypoxia response is noted, initiated at least in part by hypoxia-inducible factors. Some predisposing conditions that are distinguished by chronically aggravated medullary hypoxia, such as tubulointerstitial disease and diabetes, are characterized by a priori upregulation of hypoxia-inducible factors, which seems to confer tolerance against radiocontrast-related hypoxic tubular damage. Renal dysfunction under such circumstances likely reflects to some extent altered intrarenal hemodynamics, rather than acute tubular injury. Conclusions: Real-time, noninvasive novel methods may help to differentiate between evolving tubular damage and altered hemodynamics and in the design of appropriate preventive interventions.
TL;DR: Clinically significant CIAKI following nonemergent computed tomography is uncommon among outpatients with mild baseline kidney disease, and these findings have important implications for providers ordering and performing computed tomographic and for future clinical trials of CIAKI.
Abstract: Background and objectives: Most studies of contrast-induced acute kidney injury (CIAKI) have focused on patients undergoing angiographic procedures. The incidence and outcomes of CIAKI in patients undergoing nonemergent, contrast-enhanced computed tomography in the inpatient and outpatient setting were assessed.
Design, setting, participants, & measurements: Patients with estimated glomerular filtration rates (GFRs) <60 ml/min per 1.73 m2 undergoing nonemergent computed tomography with intravenous iodinated radiocontrast at an academic VA Medical Center were prospectively identified. Serum creatinine was assessed 48 to 96 h postprocedure to quantify the incidence of CIAKI, and the need for postprocedure dialysis, hospital admission, and 30-d mortality was tracked to examine the associations of CIAKI with these medical outcomes.
Results: A total of 421 patients with a median estimated GFR of 53 ml/min per 1.73 m2 were enrolled. Overall, 6.5% of patients developed an increase in serum creatinine ≥25%, and 3.5% demonstrated a rise in serum creatinine ≥0.5 mg/dl. Although only 6% of outpatients received preprocedure and postprocedure intravenous fluid, 45 ml/min per 1.73 m2 manifested an increase in serum creatinine ≥0.5 mg/dl. None of the study participants required postprocedure dialysis. Forty-six patients (10.9%) were hospitalized and 10 (2.4%) died by 30-d follow-up; however, CIAKI was not associated with these outcomes.
Conclusions: Clinically significant CIAKI following nonemergent computed tomography is uncommon among outpatients with mild baseline kidney disease. These findings have important implications for providers ordering and performing computed tomography and for future clinical trials of CIAKI.
TL;DR: Lower erythropoietin responsiveness is a strong, independent predictor of mortality risk and should be considered when evaluating associations between clinical outcomes and potential prognostic indicators, such as Epoetin alfa dose and achieved hemoglobin values.
Abstract: Background and objectives: Among hemodialysis patients, achieved hemoglobin is associated with Epoetin alfa dose and erythropoietin responsiveness. A prospective erythropoietin responsiveness measure was developed and its association with mortality evaluated.
Design, setting, participants, & measurements: Data from 321 participants were used and randomized to the hematocrit normalization arm of the Normal Hematocrit Cardiac Trial. Subjects were to receive a 50% Epoetin alfa dose increase at randomization. The prospective erythropoietin responsiveness measure was defined as the ratio of weekly hematocrit change (over the 3 wk after randomization) per Epoetin alfa dose increase (1000 IU/wk) corresponding to the mandated 50% dose increase at randomization. The distribution of responsiveness was divided into quartiles. Over a 1-yr follow-up, Cox proportional hazard modeling evaluated associations between this responsiveness measure and mortality.
Results: Erythropoietin responsiveness values ranged from −2.1% to 2.4% per week per 1000 IU. Although subjects were similar across response quartiles, mortality ranged between 14% and 34% among subjects in the highest and lowest response quartiles (P = 0.0004), respectively. After adjusting for baseline prognostic indicators, highest versus lowest responsiveness was associated with a hazard ratio of 0.41 (95% confidence interval, 0.20 to 0.87).
Conclusion: Lower erythropoietin responsiveness is a strong, independent predictor of mortality risk and should be considered when evaluating associations between clinical outcomes and potential prognostic indicators, such as Epoetin alfa dose and achieved hemoglobin values.