Urinary Netrin-1 Is an Early Predictive Biomarker of Acute Kidney Injury after Cardiac Surgery

Background and objectives: Netrin-1, a laminin-related axon guidance molecule, is highly induced and excreted in the urine after acute kidney injury (AKI) in animals. Here, we determined the utility of urinary netrin-1 levels to predict AKI in humans undergoing cardiopulmonary bypass (CPB).Design, setting, participants, & measurements: Serial urine samples were analyzed by enzyme-linked immunosorbent assay for netrin-1 in 26 patients who developed AKI (defined as a 50% or greater increase in serum creatinine after CPB) and 34 controls (patients who did not develop AKI after CPB).Results: Using serum creatinine, AKI was detected on average only 48 hours after CPB. In contrast, urine netrin-1 increased at 2 hours after CPB, peaked at 6 hours (2462 ± 370 pg/mg creatinine), and remained elevated up to 48 hours after CPB. The predictive power of netrin-1 as demonstrated by area under the receiver-operating characteristics curve for diagnosis of AKI at 2, 6, and 12 hours after CPB was 0.74, 0.86, and 0.89, respectively. The 6-hour urine netrin-1 measurement strongly correlated with duration and severity of AKI, as well as length of hospital stay (all P < 0.05). Adjusting for CPB time, the 6-hour netrin-1 remained a powerful independent predictor of AKI, with an odds ratio of 1.20 (95% confidence interval: 1.08 to 1.41; P = 0.006).Conclusion: Our results suggest that netrin-1 is an early, predictive biomarker of AKI after CPB and may allow for the reliable early diagnosis and prognosis of AKI after CPB, before the rise in serum creatinine.The incidence of acute kidney injury (AKI) is increasing worldwide, affecting about 6% of all hospitalized patients in whom it is an independent predictor of mortality and morbidity (1–3). In the critical care setting, the prevalence of AKI requiring dialysis is about 6%, with a mortality rate exceeding 60% (4). Once established, the treatment is largely supportive, at an annual cost surpassing $10 billion in the United States alone (5). The diagnosis currently depends on detection of reduced kidney function by the rise in serum creatinine concentration, which is a delayed and unreliable measure in the acute setting (5). Ironically, experimental studies have identified interventions that may prevent or treat AKI if instituted early in the disease process, well before the serum creatinine rises (6). The lack of early predictive biomarkers has impaired our ability to translate these promising findings to human AKI.Cardiopulmonary bypass (CPB) surgery is the most frequent major surgical procedure performed in hospitals worldwide, with well over a million operations undertaken each year. AKI is a frequent and serious complication encountered in 30% to 40% of adults and children after CPB (7–14). AKI requiring dialysis occurs in up to 5% of these patients, in whom the mortality rate approaches 80%, and is indeed the strongest independent risk factor for death (15). However, even a minor degree of postoperative AKI as manifested by only a 0.2 to 0.3 mg/dl rise in serum creatinine from baseline is also associated with a significant increase in mortality (16,17). Additionally, AKI after cardiac surgery is associated with adverse outcomes, such as prolonged intensive care and hospital stay, dialysis dependency, and increased long-term mortality (18). Infants and children with congenital heart diseases may be especially vulnerable to developing AKI, because many require multiple surgeries for step-by-step repair of complex congenital anomalies (8–14). These patients comprise an important population for the initial validation of AKI biomarkers because they do not exhibit common comorbid variables that complicate similar studies in adults, such as diabetes, hypertension, atherosclerosis, and nephrotoxin use (19).Experimental studies aimed at a better understanding of the early adaptive response of the stressed kidney have recently yielded several candidate genes and proteins that are serendipitously emerging as noninvasive candidate biomarkers of AKI (20,21). One example of such a protein is netrin. The netrins were discovered more than a decade ago as neuronal guidance cues (22). Netrins are molecules with a distinctive domain organization that belong to the laminin-related family of axon-guidance molecules (23). Recent studies indicate various other roles for netrins beyond axonal guidance, including development of mammary gland, lung, pancreas, and blood vessels; inhibition of leukocyte migration during sepsis; mitogenesis; and chemoattraction of endothelial cells (23,24). The kidney has one of the highest levels of netrin-1 expression, and administration of recombinant netrin-1 before ischemia reperfusion reduces kidney injury and inflammation (25). Preclinical studies also indicate that netrin-1 protein is markedly induced in kidney tubule cells and appears in the urine early (within 1 to 3 hours) after murine renal ischemic injury as well as other forms of AKI (26). Therefore, the objective of this study was to determine whether urinary netrin-1 levels predict the development of AKI in pediatric patients undergoing CPB.     

Urinary Biomarkers in the Clinical Prognosis and Early Detection of Acute Kidney Injury

Background and objectives: Several novel urinary biomarkers have shown promise in the early detection and diagnostic evaluation of acute kidney injury (AKI). Clinicians have limited tools to determine which patients will progress to more severe forms of AKI at the time of serum creatinine increase. The diagnostic and prognostic utility of novel and traditional AKI biomarkers was evaluated during a prospective study of 123 adults undergoing cardiac surgery.Design, setting, participants, & measurements: Urinary neutrophil gelatinase-associated lipocalin (NGAL), cystatin C (CyC), kidney injury molecule-1 (KIM-1), hepatocyte growth factor (HGF), π-glutathione-S-transferase (π-GST), α-GST, and fractional excretions of sodium and urea were all measured at preoperative baseline, postoperatively, and at the time of the initial clinical diagnosis of AKI. Receiver operator characteristic curves were generated and the areas under the curve (AUCs) were compared.Results: Forty-six (37.4%) subjects developed AKI Network stage 1 AKI; 9 (7.3%) of whom progressed to stage 3. Preoperative KIM-1 and α-GST were able to predict the future development of stage 1 and stage 3 AKI. Urine CyC at intensive care unit (ICU) arrival best detected early stage 1 AKI (AUC = 0.70, P < 0.001); the 6-hour ICU NGAL (AUC = 0.88; P < 0.001) best detected early stage 3 AKI. π-GST best predicted the progression to stage 3 AKI at the time of creatinine increase (AUC = 0.86; P = 0.002).Conclusion: Urinary biomarkers may improve the ability to detect early AKI and determine the clinical prognosis of AKI at the time of diagnosis.Acute kidney injury (AKI) is a common and serious complication of cardiothoracic surgery (1); depending on the definition of AKI used, it may occur in over 40% of adults, with 1% to 5% requiring renal replacement therapy (RRT) (2–9). Recently, standardized clinical definitions of AKI have been implemented through the use of the RIFLE (Risk, Injury, Failure, Loss, and ESRD) and AKIN (Acute Kidney Injury Network) criteria (10,11). However, these criteria are still very much dependent on delayed serum creatinine elevations, the current gold standard for the diagnosis of AKI. Furthermore, as a functional marker of glomerular filtration, serum creatinine is not ideally suited to diagnose AKI caused by renal tubular injury, rather than reversible prerenal azotemia (10).In recent years, several novel human biomarkers have been demonstrated to detect acute tubular injury and have shown promise in their ability to precede and/or complement serum creatinine in the diagnosis of AKI (12–15). Cardiac surgery has long been used to study AKI because of the ability to prospectively follow patients before and after a well timed renal insult; for this reason, several urinary proteins have been shown to serve as biomarkers of AKI after cardiac surgery, including neutrophil gelatinase-associated lipocalin (NGAL) (16–20), cystatin C (CyC) (19,21), kidney injury molecule-1 (KIM-1) (18,21), interleukin-18 (IL-18) (22), and α-glutathione-S-transferase (α-GST) (23,24). Limited data are available comparing the ability of these markers to predict renal outcomes at the time of AKI diagnosis. In fact, nephrologists have limited tools in their arsenal to assess the presence and severity of renal tubular injury at the time of AKI diagnosis. Although urinalysis with microscopy has been shown to be of some utility in the differential diagnosis of AKI in a generalized hospital-based cohort (25), data supporting its use in the specific setting of cardiac surgery are lacking (24). Similarly, diagnostic mainstays of AKI evaluation such as the fractional excretion of sodium (FENa) have long been shown to be suboptimal tools in the complex setting of cardiac surgery AKI (24), in which volume status, fluid responsiveness, and diuretic use confound inferences regarding the relationship between tubular function and injury (26,27). Additionally, although recent data support the utility of the fractional excretion of urea (FEUrea) as a diagnostic tool in AKI (28), not all data support its use (29). Furthermore, very little is known about the utility of FENa or FEUrea compared with the novel urinary biomarkers discussed above for the differential diagnosis and prognostic evaluation of AKI.In this study, we assessed the diagnostic utility of urinary NGAL, CyC, KIM-1, hepatocyte growth factor (HGF), α-GST (a proximal tubular damage marker), π-GST (a marker specific to distal tubule damage), FENa, and FEUrea as biomarkers for the detection of early and severe AKI after adult cardiac surgery. These novel biomarkers can be thought of as falling into two categories: constitutive markers (proteins/enzymes that are normally present in renal tubular cells and not normally found in the urine in significant concentration but are released into the urine in direct response to cellular injury), and inducible biomarkers (proteins that are not normally found in high concentrations in renal tubular cells or urine until their production is directly upregulated in response to cellular injury). CyC, α-GST, and π-GST are constitutive proteins that are extruded into urine in the presence of site-specific renal tubular injury (CyC and α-GST are proximal and π-GST is distal); intracellular GSTs are released into urine by damaged tubular cells, whereas injured proximal tubules fail to reabsorb filtered CyC. In contrast, KIM-1 and NGAL are inducible biomarkers, gene products that are increased in direct response to nephron damage (30,31). We also evaluated the ability of these markers to predict the severity/stage of AKI at the time of clinical diagnosis by serum creatinine increase. We performed all of the above analyses for those subjects who developed AKI as defined by the AKIN (11). Recent data demonstrate that urine NGAL after cardiac surgery varies with baseline renal function (32); as such, a secondary analysis of baseline GFR was conducted for the aforementioned panel of biomarkers (32). Finally, we interpreted the data for all novel biomarker concentrations adjusted and unadjusted for dilution by indexing to urinary creatinine, but for brevity''s sake, we only report the indexed values unless otherwise noted.     

Serum Cystatin C Is an Early Predictive Biomarker of Acute Kidney Injury after Pediatric Cardiopulmonary Bypass

Background and objectives: Acute kidney injury (AKI) is a frequent complication of cardiopulmonary bypass (CPB). Serum creatinine (SCr), the current standard, is an inadequate marker for AKI since a delay occurs before SCr rises. Biomarkers that are sensitive and rapidly measurable could allow early intervention and improve patient outcomes. We investigated the value of serum cystatin C as an early biomarker for AKI after pediatric CPB.Design, setting, participants, & measurements: We analyzed data from 374 prospectively enrolled children undergoing CPB. Serum samples were obtained before and at 2, 12, and 24 hours after CPB. Cystatin C was quantified by nephelometry. The primary outcome was AKI, defined as a ≥50% increase in SCr. Secondary outcomes included severity and duration of AKI, hospital length of stay, and mortality. A multivariable stepwise logistic regression analysis was used to assess predictors of AKI.Results: One hundred nineteen patients (32%) developed AKI using SCr criteria. Serum cystatin C concentrations were significantly increased in AKI patients at 12 hours after CPB (P < 0.0001) and remained elevated at 24 hours (P < 0.0001). Maximal sensitivity and specificity for prediction of AKI occurred at a 12-hour cystatin C cut-off of 1.16 mg/L. The 12-hour cystatin C strongly correlated with severity and duration of AKI as well as length of hospital stay. In multivariable analysis, 12-hour cystatin C remained a powerful independent predictor of AKI.Conclusion: Serum cystatin C is an early predictive biomarker for AKI and its clinical outcomes after pediatric CPB.Acute kidney injury (AKI) occurs commonly world-wide, affecting 2% to 5% of hospitalized patients and independently predicting mortality and morbidity (1). Once established, the treatment of AKI is largely supportive, at an annual cost surpassing $10 billion in the US alone (2). The diagnosis currently depends on detection of reduced kidney function by a rise in serum creatinine (SCr) concentration, which is a delayed and unreliable measure in the acute setting (3). Notably, experimental studies have identified interventions that may prevent or treat AKI if instituted early in the disease process, well before the SCr rises (4). The lack of early predictive biomarkers has impaired our ability to translate these promising findings to human AKI.Cardiac surgery with cardiopulmonary bypass (CPB) is the most frequent major surgical procedure performed in hospitals worldwide, with well over a million operations undertaken each year. AKI is a common and serious complication encountered in 30% to 40% of adults and children after CPB (5,6). AKI requiring dialysis occurs in up to 5% of these cases, in whom the mortality rate approaches 80% (6). However, even minor degrees of postoperative AKI as manifest by only a 0.2 to 0.3 mg/dl rise in SCr from baseline and often thought to be clinically unimportant, portend a significant increase in short-term mortality in adults (7). AKI after cardiac surgery is also associated with a number of adverse outcomes, including prolonged intensive care and hospital stays, diminished quality of life, and increased long-term mortality (8). Infants and children with congenital heart disease may be especially vulnerable to developing AKI since many require multiple surgeries for stepwise repair of complex congenital anomalies. These patients represent an ideal group for the validation of AKI biomarkers since confounding co-morbid conditions, such as advanced age, pre-existing renal insufficiency, hypertension, atherosclerotic vascular disease, and diabetes are usually absent.Serum cystatin C has been validated as a marker to estimate GFR in several patient populations, including kidney transplants (9) and critically ill patients (10), and more recently has shown promise as an early biomarker of AKI after adult cardiac surgery (11). Cystatin C is an endogenous cysteine proteinase inhibitor produced by nucleated cells at a constant rate. It is freely filtered at the glomerulus, reabsorbed and catabolized, but is not secreted by the tubules. Importantly, cystatin C is readily measurable using clinical laboratory platforms and does not increase with urinary tract infection or in chronic nonrenal disease, such as malignancy.For this study, we sought to (1) determine the accuracy of early serum cystatin C measurements for the prediction of AKI after pediatric CPB; (2) determine the relationship between cystatin C measurements and renal outcomes (duration and severity of AKI); and (3) determine the relationship between cystatin C measurements and clinical outcomes (mortality and length of hospital stay).     

The Origin of Multiple Molecular Forms in Urine of HNL/NGAL

Background and objectives: Several molecular forms of human neutrophil lipocalin/neutrophil gelatinase-associated lipocalin (HNL/NGAL), a novel biomarker for acute kidney injury (AKI), have been found in urine. The origin of these different forms and the effect of antibody configuration on assay performances were investigated in this report.Design, setting, participants, & measurements: The molecular forms of HNL/NGAL from human neutrophils and present in urine obtained from cardiac surgery patients and patients with urinary tract infection (UTI), as well as secreted from HK-2 cells, were studied by Western blotting. The levels of HNL/NGAL in urine were measured by ELISAs. Kidney injury was simulated by incubation of HK-2 cells under stressful conditions.Results: The major molecular form of HNL/NGAL secreted by neutrophils is dimeric, whereas the major form secreted by HK-2 cells is monomeric. This was reflected by a predominance of the monomeric form in urine from patients with AKI and the dimeric form in patients with UTIs. The epitope specificities of the antibody used in the ELISAs had a profound effect on assay performance and paralleled differences of the antibodies to identify the different forms of urine HNL/NGAL.Conclusions: The monomeric form is the predominant form secreted by tubular epithelial cells, and the dimeric form is the predominant form secreted by neutrophils. The development of molecular form-specific assays for HNL/NGAL may be a means to identify the origin of HNL/NGAL in urine and construct more specific tools for the diagnosis of AKI.Human neutrophil lipocalin(HNL) (1), also named neutrophil gelatinase-associated lipocalin (NGAL) (2), is a ubiquitous glycoprotein originally isolated from human neutrophils and localized in their specific granules. HNL/NGAL exists as a 25-kD monomer, or as a 45-kD disulfide-linked homodimer, and it is covalently conjugated with gelatinase (matrix metalloproteinase 9) via an intermolecular disulfide bridge as a 135-kD heterodimeric form (2).Although HNL/NGAL was originally identified in and purified from human neutrophils, it is also expressed in kidney, liver, and epithelial cells under certain conditions (3,4). Pathologic or stressful conditions such as inflammation, infection, cancer, intoxication, ischemia, kidney injury, and cardiac surgery can induce the upregulation of the synthesis of HNL/NGAL (5–13). In addition, several studies have shown that upregulation of HNL/NGAL in human cell lines (A459 (14), MCF-7 (15), and HepG2 (11)) is induced by oxidative stress, cytokines, or other stimuli.HNL/NGAL has recently been highlighted as a novel and early biomarker of acute kidney injury (AKI) (12,13,16–19). Thus, the levels of HNL/NGAL were significantly increased in serum/plasma and urine after cardiac surgery and paralleled reduction in renal function (12,16,19). Several immunoassays have been developed for the measurement of HNL/NGAL. The assays are based on different formats and include RIA (20), Western blotting (21), ELISA (22,23), Triage device (24), and the Architect platform (16). Several research groups used one of these assays to determine the levels of HNL/NGAL in urine and drew the conclusion that HNL/NGAL is a biomarker of AKI (12,13,16–18). Our previous results indicated that the antibody configuration had an effect on the clinical performance of the assay (19,25). We also reported, for the first time, the existence of several molecular forms of HNL/NGAL in urine obtained from patients after cardiac surgery and that the presence of dimeric and monomeric forms and their ratios changed after operation (19). The source of the different molecular forms of HNL/NGAL and what they might reflect has not yet been elucidated. The aim of this report was therefore to study the possible cellular source of these different molecular forms and to investigate the possible effect of these different forms on the assay performances of HNL/NGAL assays using several different monoclonal and polyclonal antibodies with different epitope specificities.     

Off-Pump Coronary Artery Bypass Surgery and Acute Kidney Injury: A Meta-Analysis of Randomized Controlled Trials

Background and objectives: Off-pump coronary artery bypass grafting (CABG) has been advocated to cause less inflammation, morbidity, and mortality than the more traditional on-pump technique. This meta-analysis compares these two surgical techniques with respect to causing acute kidney injury (AKI).Design, setting, participants, & measurements: This study searched for randomized controlled trials in MEDLINE and abstracts from the proceedings of scientific meetings through February 2010. Included were trials comparing off-pump to on-pump CABG that reported the incidence of AKI, as defined by a mixture of criteria including biochemical parameter/urine output/dialysis requirement. Mortality was evaluated among the studies that reported kidney-related outcomes. For primary and subgroup analyses, fixed-effect meta-analyses of odds ratios (OR) were performed.Results: In 22 identified trials (4819 patients), the weighted incidence of AKI in the on-pump CABG group was 4.0% (95% confidence interval [CI] 1.8%, 8.5%), dialysis requirement 2.4% (95% CI 1.6%, 3.7%), and mortality 2.6% (95% CI 1.6%, 4.0%). By meta-analysis, off-pump CABG was associated with a 40% lower odds of postoperative AKI (OR 0.60; 95% CI 0.43, 0.84; P = 0.003) and a nonsignificant 33% lower odds for dialysis requirement (OR 0.67; 95% CI 0.40, 1.12; P = 0.12). Within the selected trials, off-pump CABG was not associated with a significant decrease in mortality.Conclusions: Off-pump CABG may be associated with a lower incidence of postoperative AKI but may not affect dialysis requirement, a serious complication of cardiac surgery. However, the different definitions of AKI used in individual trials and methodological concerns preclude definitive conclusions.First introduced in the 1960s (1–3), coronary artery bypass grafting (CABG) remains the standard of care for symptomatic patients with three-vessel or left main coronary artery disease (4,5). For the past 30 years, CABG has been performed primarily with the use of an extracorporeal cardiopulmonary bypass (CPB) machine (on-pump) requiring cannulation of the heart and aorta, crossclamping of the ascending aorta, and the induction of cardioplegic arrest. However, in the 1990s, interest emerged in performing off-pump CABG (6,7) with the hope of reducing postoperative complications associated with the use of CPB, including the generalized systemic inflammatory response (8) and acute organ dysfunction such as cerebral dysfunction (9), myocardial depression (10), and prolonged mechanical ventilation (11).Acute kidney injury (AKI) is a serious complication of on-pump CABG, ranging from small postoperative increases in serum creatinine observed in 5% to 20% of patients (12,13) to severe forms requiring dialysis developing in 1% of patients (14,15). Whether defined by various serum creatinine increments or dialysis requirement, AKI has been linked to excessive in-hospital morbidity and mortality (12,14) and increased resource consumption (16,17). With an estimated 176,000 cardiac bypass procedures performed in 2007 (18), preventing AKI postoperatively is an important goal.Previously published studies comparing the effect of off-pump versus on-pump CABG on kidney end points have yielded conflicting results. Although six meta-analyses have examined this question, results were inconclusive (19,20) or the data synthesis included studies of various designs with a mixture of randomized controlled trials (RCTs) and observational studies (21–24). To shed further light on this question, we conducted a comprehensive meta-analysis restricted to all RCTs published to date, comparing the effect of off-pump versus on-pump CABG on development of AKI including dialysis requirement.     

Preexisting Chronic Kidney Disease: A Potential for Improved Outcomes from Acute Kidney Injury

Background and objectives: Acute kidney injury (AKI) is associated with adverse outcomes in critically ill patients. The influence of preexisting chronic kidney disease (CKD) on AKI outcomes is unclear.Design, setting, participants, & measurements: We analyzed data from a prospective observational cohort study of AKI in critically ill patients who received nephrology consultation: the Program to Improve Care in Acute Renal Disease. In-hospital mortality rate, length of stay, and dialysis dependence were compared in patients with and without a prior history of CKD, defined by an elevated serum creatinine, proteinuria, and/or abnormal renal ultrasound within a year before hospitalization. We hypothesized that patients with AKI and prior history of CKD would have lower mortality rates, shorter lengths of stay, and higher rates of dialysis dependence than patients without prior history of CKD.Results: Patients with AKI and a prior history of CKD were older and underwent nephrology consultation earlier in the course of AKI. In-hospital mortality rate was lower (31 versus 40%, P = 0.04), and median intensive care unit length of stay was 4.6 d shorter (14.7 versus 19.3 d, P = 0.001) in patients with a prior history of CKD. Among dialyzed survivors, patients with prior CKD were also more likely to be dialysis dependent at hospital discharge. Differences in outcome were most evident in patients with lower severity of illness.Conclusions: Among critically ill patients with AKI, those with prior CKD experience a lower mortality rate but are more likely to be dialysis dependent at hospital discharge. Future studies should determine optimal strategies for managing AKI with and without a prior history of CKD.Acute kidney injury (AKI) is associated with adverse outcomes, particularly in critically ill patients. In-hospital mortality rates range from 30 to 80%, depending on the clinical setting and definitions used. Several studies have shown that underlying chronic kidney disease (CKD) markedly increases the risk of AKI and that the risk increases proportional to the CKD stage (1–4). Additionally, data from the United States Renal Data System showed that the percentage of incident ESRD patients who experienced an episode of AKI in the previous 2 yr has doubled over the past 10 yr (4). Among hospitalized Medicare beneficiaries, patients with CKD have a 10-fold higher incidence of AKI. It is unclear whether patients with AKI and prior CKD experience a different disease course and outcomes than those without prior CKD, because data from several studies are conflicting (5–7). Most studies have suggested that patients with prior CKD are more likely to remain dialysis dependent after an episode of dialysis-requiring AKI (5,8,9). The association between prior CKD and mortality has been variably described. Recent studies suggest that prior CKD may be associated with lower mortality in dialyzed intensive care unit (ICU) patients (5,6,10). In this analysis, we explored whether prior CKD modified the association between AKI and outcomes (mortality, ICU and hospital length of stay, and dialysis dependence) in critically ill patients enrolled in a prospective observational multicenter cohort study (11). We hypothesized that patients with AKI who had a prior history of CKD would have lower mortality rates, shorter lengths of stay, and higher rates of dialysis dependence than patients with AKI with no prior history of CKD.     

Predictors of Health Utility among 60-Day Survivors of Acute Kidney Injury in the Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network Study

Background and objectives: Health-related quality of life (HRQOL) after acute kidney injury (AKI) is an area of great importance to patients. It was hypothesized that HRQOL after AKI would relate to intensity of dialysis during AKI and dialysis dependence at follow-up.Design, setting, participants, & measurements: The Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network Study was a multicenter, prospective, randomized trial of intensive versus less intensive renal replacement therapy in critically ill patients with AKI. Of 1124 participants, 415 survived at least 60 days and completed the Health Utilities Index (HUI), which measures 8 health attributes and calculates an overall HRQOL score, also called a utility score. How strongly pre–intensive care unit (ICU) health, severity of illness, hospital course, intensity of dialysis, and outcome were associated with 60-day HUI scores was assessed, after adjustment for demographics.Results: The overall HUI score was 0.40 ± 0.37, indicating severely compromised health utility and was associated with only admission from home and hospital and ICU length of stay (LOS). Ambulation was better among those with a shorter hospital and ICU LOS. Better cognition was associated with dialysis independence and with fewer comorbid chronic illnesses. Emotion was associated with only hospital LOS. Pain was associated with ICU LOS.Conclusions: Health utility was low in this cohort of patients after AKI, and intensity of dialysis did not affect subsequent health utility. The effects of a lengthy hospitalization generally outweighed the effects of delayed recovery of kidney function on HRQOL after AKI.A cute kidney injury (AKI) is common among hospitalized patients and is particularly prevalent among patients cared for in the intensive care unit (ICU) setting (1–3). AKI has been associated with increased morbidity, mortality, and costs (1–4). It remains unclear to what extent treatment of or recovery from AKI influences health-related quality of life in survivors of AKI. There have been several reports of health-related quality of life (HRQOL) among survivors of AKI in the ICU (5–10). However, many of these studies are limited by small sample size and low response rate. In addition, follow-up times are variable among and sometimes within studies, ranging from 3 months to several years. Several measures of HRQOL have been used, including the Medical Outcomes Study Short Form 36-item health survey (SF-36) (9), EuroQol (EQ-5D) (5), and Nottingham Health Profile (6,8,10), and also health utilities by time trade-off (7) or visual analog scale (5) and Activities of Daily Living (7,8). Perhaps because of this variability, results are mixed. On balance, limitations in mobility were fairly common, ranging from 29 to 60% (6,8). However, patients generally reported a favorable health status, with 62 to 77% of patients reporting “good” or “excellent” health status (7,10). Health utility on the EQ-5D index was 0.68 compared with an age- and sex-matched norm of 0.86 (5), but in the same study utility by visual analog scale was not different from the general population. Health utility by the time trade-off method was reported by Hamel et al. to be 0.84, but no normative data were presented (7).The availability of HRQOL data in a large cohort of survivors of AKI requiring renal replacement therapy (RRT) provides a unique opportunity to study HRQOL and its potential determinants in this population. The Veterans Affairs/National Institutes of Health (VA/NIH) Acute Renal Failure Trial Network (ATN) study (ClinicalTrials.gov, {"type":"clinical-trial","attrs":{"text":"NCT00076219","term_id":"NCT00076219"}}NCT00076219) was a multicenter randomized trial of intensive versus less intensive renal replacement therapy in critically ill patients with acute kidney injury conducted between November 2003 and July 2007 at 27 VA and university-affiliated medical centers (11,12). Although the major goals of the ATN study were to assess the effects of treatment assignment on 60-day mortality, in-hospital mortality, and recovery of renal function, HRQOL was also assessed at 60 days among survivors with the intention of establishing the effect of dialysis intensity on HRQOL and of assigning health utilities to facilitate performance of cost-effectiveness analysis.We hypothesized that study treatment assignment and ongoing dialysis dependence at 60 days would be potential determinants of HRQOL. Although intensive dialysis did not lead to shorter hospital stays or more rapid recovery of renal function (12), both of which might have contributed to improved HRQOL at 60 days, we postulated that better control of uremia could have direct effects on HRQOL. In addition, given that patients receiving maintenance dialysis routinely report impaired HRQOL (13–15), we also hypothesized that ongoing need for dialysis would be an important determinant of HRQOL at 60 days.     

Cystatin C as a Marker of Acute Kidney Injury in the Emergency Department

Background and objectives: The diagnosis of acute kidney injury (AKI) is usually based on changes in serum creatinine, which is a poor marker of early renal dysfunction. The discriminative and predictive abilities of serum and urinary cystatin C were examined for the prediction of AKI.Design, setting, participants, & measurements: In this prospective cohort study, serum and urinary cystatin C were serially measured in a heterogeneous group of patients (n = 616) presenting to a tertiary care emergency department. The primary outcome was AKI, classified according to RIFLE and AKIN criteria. The secondary outcome was an adjudication based on clinical criteria to AKI, prerenal azotemia, chronic kidney disease (CKD), and normal kidney function.Results: Patients were adjudicated to have AKI in 21.1%, prerenal azotemia in 25.8%, CKD in 2.4%, and normal kidney function in 50.7%. For the diagnosis of AKI, the discriminatory ability of urinary creatinine and cystatin C was marginal. Both serum cystatin C and serum creatinine (at presentation and 6 hours later) showed high discriminatory ability for the diagnosis of AKI. However, only serum cystatin C attained a significant early predictive power (Hosmer-Lemeshow P value > 0.05). Serum cystatin C could differentiate between AKI and prerenal azotemia, but not between AKI and CKD.Conclusions: Serum cystatin C is an early, predictive biomarker of AKI, which outperforms serum creatinine in the heterogeneous emergency department setting. However, neither biomarker discriminated between AKI and CKD. Additional biomarkers continue to be needed for improved specificity in the diagnosis of community-acquired AKI.The incidence of acute kidney injury (AKI) is increasing globally, affecting about 6% of all hospitalized patients in whom it is an independent predictor of mortality and morbidity (1). Much is now known about the epidemiology of AKI in the hospital-acquired and critical care settings (2). AKI occurring in a community setting is also common but quite distinct, and published data are scarce. Community-acquired renal dysfunction encountered in the emergency department (ED) is frequently caused by volume depletion, whereas hospital-acquired AKI often accompanies other organ disease processes and complicates their management and outcomes (3). In the ED, the clinician''s priorities are (1) to detect AKI early so that preventive and therapeutic approaches may be implemented in a timely manner, and (2) to differentiate between prerenal azotemia (preR), chronic kidney disease (CKD), and intrinsic AKI. Unfortunately, neither is possible with serum creatinine (SCr) measurements, since changes in SCr lag behind both renal injury and renal recovery, and are influenced by several nonrenal factors (4,5).A number of novel plasma and urinary biomarkers have recently been proposed for the early diagnosis of AKI and its clinical outcomes in a variety of clinical settings (6,7). Among these, cystatin C appears to be a useful detection marker for AKI (8). It is a low molecular weight cysteine proteinase that is stably produced by all nucleated cells in a constitutive fashion. It is freely filtered by the renal glomeruli and totally reabsorbed in the proximal tubule, without secretion. Serum concentration of cystatin C is thus determined primarily by GFR. Cystatin C is not normally found in urine in significant amounts (9). Elevated urinary levels of cystatin C may reflect tubular dysfunction independent of GFR (10,11) and may provide an early indication of AKI in the cardiac surgery (12) and critically ill (13) patients. Multiple studies evaluating serum cystatin C (SCysC) as a GFR marker have shown that it performs at least as well as SCr in the population at large, and it is superior to SCr in specific patient populations (14). SCysC has also been proposed as an early biomarker of AKI in the intensive care (15,16), cardiac surgery (17), and radiocontrast administration (18) settings.The aim of this prospective cohort study was to evaluate the accuracy of SCysC and urinary cystatin C (UCysC) as early biomarkers of AKI in an unselected, heterogeneous group of patients admitted to the ED in a large tertiary care hospital. The primary end point was a diagnosis of AKI fulfilling the SCr-based RIFLE (19) and AKIN (20) criteria. The secondary end point was the differentiation between preR, intrinsic AKI, and CKD at the time of presentation to the ED.     

Renal Involvement in Primary Sj?gren's Syndrome: A Clinicopathologic Study

Background & objectives: Renal pathology and clinical outcomes in patients with primary Sjögren''s syndrome (pSS) who underwent kidney biopsy (KB) because of renal impairment are reported.Design, setting, participants, & measurements: Twenty-four of 7276 patients with pSS underwent KB over 40 years. Patient cases were reviewed by a renal pathologist, nephrologist, and rheumatologist. Presentation, laboratory findings, renal pathology, initial treatment, and therapeutic response were noted.Results: Seventeen patients (17 of 24; 71%) had acute or chronic tubulointerstitial nephritis (TIN) as the primary lesion, with chronic TIN (11 of 17; 65%) the most common presentation. Two had cryoglobulinemic GN. Two had focal segmental glomerulosclerosis. Twenty patients (83%) were initially treated with corticosteroids. In addition, three received rituximab during follow-up. Sixteen were followed after biopsy for more than 12 mo (median 76 mo; range 17 to 192), and 14 of 16 maintained or improved renal function through follow-up. Of the seven patients presenting in stage IV chronic kidney disease, none progressed to stage V with treatment.Conclusions: This case series supports chronic TIN as the predominant KB finding in patients with renal involvement from pSS and illustrates diverse glomerular lesions. KB should be considered in the clinical evaluation of kidney dysfunction in pSS. Treatment with glucocorticoids or other immunosuppressive agents appears to slow progression of renal disease. Screening for renal involvement in pSS should include urinalysis, serum creatinine, and KB where indicated. KB with characteristic findings (TIN) should be considered as an additional supportive criterion to the classification criteria for pSS because it may affect management and renal outcome.Primary Sjögren''s syndrome (pSS) is a progressive autoimmune disorder involving the exocrine glands (1), typically presenting with keratoconjunctivitis and xerostomia (2). It is characterized pathologically by a predominant lymphocytic infiltrate around epithelial ducts of exocrine glands on salivary gland biopsy (3). Extraglandular manifestations of pSS, once thought to be uncommon, occur in up to 25% of patients. Patients can be afflicted by severe interstitial lung disease (4), cutaneous vasculitis (5), peripheral neuropathy (6), and hematologic complications such as lymphoma (7). They are also at increased risk for celiac sprue (8) and complications from Helicobacter pylori infection (9) such as mucosa-associated lymphatic tissue (MALT)-type lymphoma.Much of our understanding of the clinical presentation of renal involvement in pSS is based on case reports (10–26) and small retrospective cohorts (27–29). Tubulointerstitial nephritis (TIN) remains the most common presentation of renal involvement in pSS and CD4/CD8 T cell subsets are reported to predominate (27,30). This is often characterized by a distal (type I) renal tubular acidosis (RTA) and less commonly proximal (type II) RTA (Fanconi syndrome) (11,31–33). GN is thought to be a rare occurrence, with only case reports available in the literature (10,12–23), and tends to be a late development (34) in the course of the disease.We examined the renal pathologic findings and clinical trends of all patients with pSS who underwent kidney biopsy (KB) at Mayo Clinic since 1967 and assembled a case series of patients with pSS with renal pathologic disease evaluated by renal biopsy at a single center in the United States. This case series aimed to describe the common clinical presentations of renal disease in pSS, the array of pathologic findings of renal involvement in pSS, and trends during follow-up and treatment.     

Elevated Urinary IL-18 Levels at the Time of ICU Admission Predict Adverse Clinical Outcomes

Background and objectives: Urine IL-18 (uIL-18) has demonstrated moderate capacity to predict acute kidney injury (AKI) and adverse outcomes in defined settings. Its ability to predict AKI and provide prognostic information in broadly selected, critically ill adults remains unknown.Design, setting, participants, & measurements: The study prospectively evaluated the capacity of uIL-18 measured within 24 hours of intensive care unit (ICU) admission to predict AKI, death, and receipt of acute dialysis in a large mixed-adult ICU population.Results: Of 451 patients, 86 developed AKI within 48 hours of enrollment and had higher median uIL-18 levels [426 (interquartile range [IQR]: 152 to 1183) pg/mg creatinine] compared with those without AKI [248 (IQR: 120 to 559) pg/mg]. The area under the receiver operating characteristic curve for uIL-18 predicting subsequent AKI within 24 hours was 0.62 (95% CI: 0.54 to 0.69) and improved modestly to 0.67 (95% CI: 0.53 to 0.81) in patients whose enrollment eGFR was ≥75 ml/min per 1.73 m². The highest median uIL-18 levels were observed in patients with sepsis at enrollment [508 (IQR: 230 to 1281) pg/mg], those receiving acute dialysis [571 (IQR: 161 to 1614) pg/mg] or dying [532 (IQR: 210 to 1614) pg/mg] within 28 days of ascertainment. After adjustment for a priori selected clinical predictors, uIL-18 remained independently predictive of composite outcome of death or acute dialysis within 28 days of ascertainment (odds ratio, 1.86 [95% CI: 1.31 to 2.64]).Conclusions: uIL-18 did not reliably predict AKI development, but did predict poor clinical outcomes in a broadly selected, critically ill adult population.The successful translation of promising preclinical treatments for acute kidney injury (AKI) has been hindered by a lack of early, accurate, and reliable indicators of injury. Furthermore, the discovery and validation of biologic markers able to differentiate between patients with mild or reversible forms of AKI and those that will progress to dialysis or not survive may also assist in risk-stratification for clinical trials. Recent efforts to identify biologic markers with early diagnostic and prognostic potential have yielded several candidates (1), including neutrophil gelatinase-associated lipocalin (NGAL) (2), liver fatty acid binding protein (L-FABP) (3), kidney injury molecule 1 (KIM-1) (4), cystatin C (5), and IL-18 (urine IL-18 [uIL-18]) (6,7).IL-18, a proinflammatory cytokine of the IL-1 superfamily, is found in monocytes, fibroblasts, and proximal renal tubular epithelial cells (8). The ability of IL-18 to mediate ischemic proximal tubular injury in mice and proinflammatory responses via its actions on the Toll-like receptor 4 has provided a rationale for its use as a human AKI biomarker (9,10). Previous studies have explored the ability of uIL-18 levels to predict AKI among children undergoing cardiopulmonary bypass (11), adults receiving a kidney transplant (12), and in children requiring mechanical ventilation (13). More recently, early translational studies in humans with limited sample sizes have demonstrated that uIL-18 levels can provide important prognostic information for AKI patients after cardiac surgery (11), 3-month graft function in kidney transplant patients (11), and survival in acute respiratory distress syndrome (ARDS) and in critically ill children (6,13).Using a large cohort of critically ill adults participating in the National Institutes of Health (NIH)-sponsored Validation of Biomarkers for Acute Lung Injury Diagnosis (VALID) study; we examined the ability of uIL-18 to predict both the development of AKI and clinically relevant outcomes including mortality and dialysis in a heterogeneous intensive care unit (ICU) population. Results were also compared independently and in combination with the previously reported performance of urine NGAL (uNGAL) (14).     

Phase 1 Study of Anti-CTGF Monoclonal Antibody in Patients with Diabetes and Microalbuminuria

Background and objectives: This report summarizes the first phase 1 trial treating patients with microalbuminuric diabetic kidney disease (DKD) using FG-3019, a human monoclonal antibody to connective tissue growth factor (CTGF). CTGF is critically involved in processes of progressive fibrosis, including DKD. This phase 1, open-label, dose-escalation trial evaluated safety, pharmacokinetics, and possible therapeutic effects of FG-3019 on albuminuria, proteinuria, and tubular proteins.Design, setting, participants, and measurements: Microalbuminuric subjects (n = 24) with type 2 (79%) or type 1 (21%) diabetes received 3 or 10 mg/kg FG-3019 dosed intravenously every 14 days for four doses. Albuminuria and safety follow-up were to days 62 and 365, respectively.Results: No infusion was interrupted for symptoms, although 5 of 24 subjects had mild infusion-day adverse events thought to be possibly drug-related. No subject developed anti-FG-3019 antibodies. FG-3019 clearance was lower at 10 mg/kg than at 3 mg/kg, suggesting a saturable elimination pathway. Although this study was not designed for efficacy testing, it was notable that urinary albumin/creatinine ratio (ACR) decreased significantly from mean pretreatment ACR of 48 mg/g to mean post-treatment (day 56) ACR of 20 mg/g (P = 0.027) without evidence for a dose-response relationship.Conclusions: Treatment of microalbuminuric DKD subjects using FG-3019 was well tolerated and associated with a decrease in albuminuria. The data demonstrate a saturable pathway for drug elimination, minimal infusion adverse events, and no significant drug-attributable adverse effects over the year of follow-up. Changes in albuminuria were promising but require validation in a prospective, randomized, blinded study.Patients with diabetic kidney disease (DKD) are at increased risk for cardiovascular complications and early mortality. Those who survive long enough tend to progress to ESRD requiring dialysis or transplantation. Although advances in therapy with angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor type II blockers (ARBs) have attenuated the incident rate of ESRD (1), disease progression remains common (2–4) and diabetes continues to be the leading cause for initiation of dialysis in the United States (1).Connective tissue growth factor (CTGF) is a 349-amino-acid secreted pleiotropic protein belonging to the cysteine-rich CCN (CTGF/Cyr61/Cef10/NOVH) family. Numerous glomerular, tubulointerstitial, and vascular cells types can produce CTGF, and many factors associated with the diabetic condition can stimulate CTGF expression, including hypertension, hyperglycemia, and hyperlipidemia (5–24).CTGF is a critical mediator of extracellular matrix accumulation and coordinates a final common pathway of fibrosis (5,25,26). CTGF has been shown to amplify the fibrogenic activity of TGFβ (27) and IGF-1 (17) and to inhibit the action of antifibrotic and regenerative factors bone morphogenic protein-7 (27,28) and vascular endothelial growth factor (29,30).In type 1 diabetes, plasma and urine CTGF levels correlate with the level of albuminuria and the stage of progressive renal insufficiency (31–34), and the plasma CTGF level is an independent predictor of vascular disease as assessed by intimal medial thickness (35) and of mortality and progression to ESRD (36). In renal biopsy specimens from patients with diabetes, elevated levels of CTGF mRNA are associated with chronic tubulointerstitial damage, albuminuria, and progression of renal insufficiency (37–39).FG-3019 is a recombinant human anti-CTGF monoclonal IgG₁ antibody that has shown activity in rodent models of kidney dysfunction associated with type 1 and 2 diabetes (40–42). Here, we report results of an open-label dose-escalation trial of FG-3019 infusions administered biweekly over 56 days in patients with DKD, the first study designed to evaluate safety and potential therapeutic effect of FG-3019 in this patient population.     

Back-Calculating Baseline Creatinine with MDRD Misclassifies Acute Kidney Injury in the Intensive Care Unit

Background and objectives: The purpose of this study was to assess the viability of back-calculation with the Modification of Diet in Renal Disease (MDRD) formula to determine baseline creatinine on the basis of acute kidney injury (AKI) metrics, RIFLE criteria, and Acute Kidney Injury Network (AKIN) criteria for the purpose of clinical trial outcomes or epidemiology.Design, setting, participants, & measurements: This study was a retrospective analysis of prospectively collected data from patients with measured baseline creatinines before entry to the intensive care unit (ICU). The AKI status was determined using five different baseline creatinines: the measured creatinine (the standard) and an estimated creatinine determined by back-calculation using MDRD assuming a GFR of 75 ml/min (epCr₇₅), 100 ml/min (epCr₁₀₀), randomly generating a value on a lognormal curve (epCr_Rnd), and choosing the lowest creatinine value within the first week in the ICU (epCr_low). A subgroup of patients without chronic kidney disease (CKD) was similarly analyzed.Results: Of 224 patients, 70 (31%) had AKI according to RIFLE and 93 (42%) according to AKIN. The epCr₇₅ and epCr₁₀₀ distributions greatly overestimated the proportion with AKI. The epCr_low overestimated AKI according to AKIN but correctly estimated AKI according to RIFLE. The mean of 1000 epCr_Rnd distributions correctly estimated AKI according to RIFLE and AKIN. Each estimated distribution performed better in the non-CKD population with the exception of epCr_Rnd. However, only the epCr_low distribution accurately determined the proportion with AKI.Conclusions: A measured rather than estimated value should be used for baseline creatinine in trials or epidemiologic studies of AKI.The consensus definitions of acute kidney injury (AKI), first by the Acute Dialysis Quality Initiative (ADQI) and later by the Acute Kidney Injury Network (AKIN), were a necessary and important step in harmonizing epidemiologic studies and clinical trials of AKI (1,2). The RIFLE (R = risk, I = injury, F = failure, L = loss, E = end-stage) and AKIN definitions stage AKI according to changes in urine output or changes in plasma creatinine from baseline. RIFLE also utilized changes in GFR as equivalent to changes in creatinine, although there was a mathematical error for R and F in this equivalence (3). The validation of these criteria has been principally through use of the plasma creatinine criteria of the first three stages of RIFLE (R, I, F) or AKIN (stages I, II, III) (4–8). The use of each classification in clinical trials and many of their strengths and limitations have been reviewed recently (9,10).

Table 1.

Acute kidney injury status

Temporary Perioperative Decline of Renal Function Is an Independent Predictor for Chronic Kidney Disease

Background and objectives: Acute kidney injury is an independent predictor of short- and long-term survival; however, data on the relationship between reversible transitory decline of kidney function and chronic kidney disease (CKD) are lacking. We assessed the prognostic value of temporary renal function decline on the development of long-term CKD.Design, setting, participants, & measurements: The study included 1308 patients who were undergoing major vascular surgery (aortic aneurysm repair, lower extremity revascularization, or carotid surgery), divided into three groups on the basis of changes in Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) estimated GFR (eGFR) on days 1, 2, and 3 after surgery, compared with baseline: Group 1, improved or unchanged (change in CKD-EPI eGFR ±10%); group 2, temporary decline (decline >10% at day 1 or 2, followed by complete recovery within 10% to baseline at day 3); and group 3, persistent decline (>10% decrease). Primary end point was the development of incident CKD during a median follow-up of 5 years.Results: Perioperative renal function was classified as unchanged, temporary decline, and persistent decline in 739 (57%), 294 (22%), and 275 (21%) patients, respectively. During follow-up, 272 (21%) patients developed CKD. In multivariate logistic regression analyses, temporary and persistent declines in renal function both were independent predictors of long-term CKD, compared with unchanged renal function.Conclusion: Vascular surgery patients have a high incidence of temporary and persistent perioperative renal function declines, both of which were independent predictors for development of long-term incident CKD.Acute kidney injury (AKI) is a common and serious complication in hospitalized patients and is associated with a high rate of in-hospital morbidity and mortality and prolonged length of stay (1). The incidence of AKI ranges between 2 and 45% and depends on the type of population, underlying comorbidities, and the definition used to define AKI (2–4). During the past decade, the incidence of AKI has increased to approximately 500 events per 100,000 in the general population (1).Although episodes of AKI seem to be reversible, there is a silent, ongoing inflammatory and fibrotic process that leads to progressive structural kidney damage (5,6). This process predisposes to worsening BP control, proteinuria, and more rapid decreases in GFR, which are widely known risk factors for incident chronic kidney disease (CKD) and cardiovascular disease (CVD) (7). Meta-analyses have demonstrated an increased risk for short- and long-term mortality after an episode of AKI (6,8). In these analyses, several definitions of AKI were used, including small temporary kidney function decline. In fact, a meta-analysis by Coca et al. (8) demonstrated that even a 10 to 24% increase in serum creatinine (Scr) levels was strongly associated with an in increased mortality risk; therefore, small changes in Scr levels seem to provide a sensitive definition of AKI and could promote early prevention or treatment strategies. Although numerous studies (4,6,9,10) have investigated the predictive value of AKI for long-term CVD and mortality, data regarding the relationship between a temporary decline of renal function during the perioperative period with incident CKD are lacking; therefore, we performed this study to assess the relationship between temporary decline of renal function and the development of CKD during long-term follow-up.     

Outcomes Associated with Serum Calcium Level in Men with Non-Dialysis-Dependent Chronic Kidney Disease

Background and objectives: Elevated serum calcium has been associated with increased mortality in dialysis patients, but it is unclear whether the same is true in non-dialysis-dependent (NDD) chronic kidney disease (CKD). Outcomes associated with low serum calcium are also not well-characterized.Design, setting, participants, & measurements: We examined associations of baseline, time-varying, and time-averaged serum calcium with all-cause mortality in a historic prospective cohort of 1243 men with moderate and advanced NDD CKD by using Cox models.Results: The association of serum calcium with mortality varied according to the applied statistical models. Higher baseline calcium and time-averaged calcium were associated with higher mortality (multivariable adjusted hazard ratio (95% confidence interval): 1.31 (1.13, 1.53); P < 0.001 for a baseline calcium 1 mg/dl higher). However, in time-varying analyses, lower calcium levels were associated with increased mortality.Conclusions: Higher serum calcium is associated with increased long-term mortality (as reflected by the baseline and time-averaged models), and lower serum calcium is associated with increased short-term mortality (as reflected by the time-varying models) in patients with NDD CKD. Clinical trials are warranted to determine whether maintaining normal serum calcium can improve outcomes in these patients.Mineral and bone disorders in chronic kidney disease (CKD) (1) have emerged as novel mortality risk factors in dialysis patients (2–8). Some of these abnormalities (such as serum phosphorus and parathyroid hormone (PTH) levels) have also been implicated in similar ways in patients with non-dialysis-dependent (NDD) CKD (9–12). Serum calcium''s effect on outcomes has been the focus of attention mainly in dialysis patients, where calcium metabolism is significantly distorted (13–19). The use of calcium-containing phosphate binders further complicates the picture because these medications could be involved in the etiology of vascular calcification (20,21), and their roles as therapeutic agents have been intensely debated (22). Supporting the potential role for calcium in cardiovascular disease were epidemiologic studies showing an association between higher calcium and increased mortality (2–8). Some of the same studies have also suggested that extremely low calcium levels may themselves be deleterious (2,3), which has ultimately resulted in recommendations to attain a low-normal serum calcium level in dialysis patients (23). Studies examining the role of calcium in NDD CKD patients are fewer and failed to unequivocally show an association between abnormal calcium levels and vascular calcification (24–27). No study has yet examined the association of calcium levels with mortality in NDD CKD.We examined the association of serum calcium levels with all-cause mortality in a large number of male US veterans with moderate and advanced NDD CKD at a single medical institution.     

Activation of TRPC1 by STIM1 in ER-PM microdomains involves release of the channel from its scaffold caveolin-1

Store-operated Ca²⁺ entry (SOCE) is activated by redistribution of STIM1 into puncta in discrete ER-plasma membrane junctional regions where it interacts with and activates store-operated channels (SOCs). The factors involved in precise targeting of the channels and their retention at these specific microdomains are not yet defined. Here we report that caveolin-1 (Cav1) is a critical plasma membrane scaffold that retains TRPC1 within the regions where STIM1 puncta are localized following store depletion. This enables the interaction of TRPC1 with STIM1 that is required for the activation of TRPC1-SOCE. Silencing Cav1 in human submandibular gland (HSG) cells decreased plasma membrane retention of TRPC1, TRPC1-STIM1 clustering, and consequently reduced TRPC1-SOCE, without altering STIM1 puncta. Importantly, activation of TRPC1-SOCE was associated with an increase in TRPC1-STIM1 and a decrease in TRPC1-Cav1 clustering. Consistent with this, overexpression of Cav1 decreased TRPC1-STIM1 clustering and SOCE, both of which were recovered when STIM1 was expressed at higher levels relative to Cav1. Silencing STIM1 or expression of ΔERM-STIM1 or STIM1(⁶⁸⁴EE⁶⁸⁵) mutant prevented dissociation of TRPC1-Cav1 and activation of TRPC1-SOCE. However expression of TRPC1-(⁶³⁹KK⁶⁴⁰) with STIM1(⁶⁸⁴EE⁶⁸⁵) restored function and the dissociation of TRPC1 from Cav1 in response to store depletion. Further, conditions that promoted TRPC1-STIM1 clustering and TRPC1-SOCE elicited corresponding changes in SOCE-dependent NFkB activation and cell proliferation. Together these data demonstrate that Cav1 is a critical plasma membrane scaffold for inactive TRPC1. We suggest that activation of TRPC1-SOC by STIM1 mediates release of the channel from Cav1.Store-operated calcium entry (SOCE) is activated by depletion of endoplasmic reticulum (ER) Ca²⁺ stores and regulates a variety of critical cellular functions (1). Ca²⁺ depletion in the ER lumen is detected by the Ca²⁺-binding protein STIM1, which oligomerizes into puncta and relocates to discrete ER-plasma membrane (ER-PM) junctional regions (2, 3) where it associates with and activates store-operated channels including Orai1 and TRPC1, which are components of CRAC and SOC channels, respectively (4–13). Therefore, the location of these channels in the plasma membrane is likely to be critical for their interaction with peripheral STIM1 and activation. However, mechanisms involved in the precise targeting and retention of the channels at the domains where STIM1 puncta are located are not well-understood.Distinct regions of STIM1 determine aggregation and targeting of the protein to ER-PM junctional domains as well as its clustering with and gating of Orai1 and TRPC1 at these sites. The SAM and coiled-coiled domains are involved in STIM1 aggregation while the polybasic C-terminal region of STIM1 is suggested to target STIM1 to ER-PM junctional regions, which is the likely site for SOCE in native cells (3, 9–11, 14). Thus, it can be predicted that SOCs are either localized in this region or in close proximity to it so that they can be readily recruited following store depletion. Clustering of STIM1 in ER-PM junctional regions results in relatively high local concentrations of STIM1 at these sites, which appears to be sufficient to drive the diffusion of Orai1 into this region where it binds to STIM1, resulting in CRAC channel activation (11, 12).STIM1 also associates with and regulates store-operated TRPC channels, including TRPC1-SOC (6–8, 13, 15–19). Several studies show that association between TRPC1 and STIM1 increases following store depletion (6, 16, 19, 20), although a recent study was unable to demonstrate this (21). While the ezrin/radixin/moesin (ERM) domain of STIM1 appears to bind to TRPC1, the C-terminal ⁶⁸⁴KK⁶⁸⁵ residues are involved in gating the channel via electrostatic interaction with TRPC1(⁶³⁹DD⁶⁴⁰) (8, 13). We have reported earlier that lipid raft domains (LRD) provide a platform for regulation of TRPC1-SOCE (22). Further, we demonstrated that peripheral STIM1 puncta are anchored in LRD which facilitates TRPC1-STIM1 association required for activation of TRPC1-SOCE (6). This has now been suggested in several other studies (10, 18, 23). The role of LRD in the regulation of TRPC1-SOC suggested by these recent findings are consistent with previous reports which showed that plasma membrane localization of TRPC1 depends on its association with the cholesterol-binding protein caveolin-1 (Cav1), which promotes retention of TRPC1 within the LRD (6, 18, 22–25). Together, these findings suggest a critical role for Cav1 and LRD in the association of TRPC1 with STIM1 within ER-PM junctional regions that is required for SOCE (10, 26–28). However, the precise molecular interactions involving Cav1, STIM1, and TRPC1 that are triggered by store depletion and are critical for TRPC1-SOCE have not yet been defined.Here we have examined the contribution of Cav1 and STIM1 in the regulation of TRPC1-SOCE that occurs within the ER-PM junctional region in response ER-Ca²⁺ store depletion. We report that Cav1 is a critical plasma membrane scaffold that retains TRPC1-SOC within the ER-PM region where STIM1 puncta are localized following store depletion. Retention of TRPC1 in this region facilitates the interaction of STIM1 with the channel that is required for activation of SOCE. Activation of TRPC1 by STIM1 also releases the channel from Cav1.     

Treatment with IFN-α, -β, or -γ Is Associated with Collapsing Focal Segmental Glomerulosclerosis

Background and objectives: Treatment with IFN is rarely associated with nephrotic syndrome and renal biopsy findings of minimal-change disease or FSGS.Design, setting, participants, & measurements: We report 11 cases of collapsing FSGS that developed during treatment with IFN and improved after discontinuation of therapy.Results: The cohort consists of seven women and four men with a mean age of 48.2 yr. Ten of the 11 patients were black. Six patients were receiving IFN-α for hepatitis C virus infection (n = 5) or malignant melanoma (n = 1), three were receiving IFN-β for multiple sclerosis, and two were treated with IFN-γ for idiopathic pulmonary fibrosis. After a mean and median duration of therapy of 4.0 and 12.6 months, respectively, patients presented with acute renal failure (mean creatinine 3.5 mg/dl) and nephrotic-range proteinuria (mean 24-hour urine protein 9.7 g). Renal biopsy revealed collapsing FSGS with extensive foot process effacement and many endothelial tubuloreticular inclusions. Follow-up was available for 10 patients, all of whom discontinued IFN. At a mean of 23.6 months, nine of 10 patients had improvement in renal function, including one with complete remission and two with partial remission. Among the seven patients with available data, mean proteinuria declined from 9.9 to 3.0 g/d. Four of the seven patients were treated with immunosuppression, and there was no detectable benefit.Conclusions: Collapsing FSGS may occur after treatment with IFN-α, -β, or -γ and is typically accompanied by the ultrastructural finding of endothelial tubuloreticular inclusions. Optimal therapy includes discontinuation of IFN.FSGS is the most common cause of idiopathic nephrotic syndrome in black patients and may be the most frequent cause of nephrotic syndrome in the general population (1–6). The spectrum of FSGS includes primary forms mediated by a putative circulating or permeability factor and a number of secondary forms caused by such diverse insults as hereditable mutations in podocyte genes, drugs, viral infections, and adaptive responses to reduced renal mass or other hemodynamic stress (1). A variety of histologic variants of FSGS have been identified and can be applied to both primary and secondary forms (7–9). Many secondary forms tend to manifest as particular morphologic subtypes (1).The collapsing variant of FSGS is defined by implosive wrinkling and “collapse” of the glomerular basement membrane associated with hypertrophy and hyperplasia of overlying podocytes (10–12). Collapsing FSGS was mainly described in patients with HIV-associated nephropathy (HIVAN) (13) but also was recognized as a variant of idiopathic FSGS (11,12). Both idiopathic collapsing FSGS and HIVAN are most commonly seen in young black patients (8–12,14). Compared with the usual, most common form of FSGS with discrete segmental scars (FSGS not otherwise specified [FSGS NOS]), collapsing FSGS is distinguished by more severe nephrotic syndrome and renal insufficiency at presentation and a more rapid course to renal failure (8–12,14). Central to the morphogenesis of the collapsing variant is podocyte injury that leads to podocyte dedifferentiation, apoptosis, and proliferation, in part through dysregulation of cell cycle–related proteins (15–19). Podocyte precursor cells from the parietal cell layer may contribute to the glomerular epithelial cell proliferation (20).HIVAN is not the only established secondary cause of collapsing FSGS. Collapsing FSGS has been reported in the setting of Parvovirus B19 infection (21) and in patients with hemophagocytic syndrome (with or without underlying lymphoma) (22). Collapsing FSGS also may follow treatment with pamidronate (23), with 15 cases reported in the medical literature (23,24). In contrast, FSGS NOS has been reported to result from treatment with lithium (25), sirolimus (26), and more recently anabolic steroids (27). Although rare cases of collapsing FSGS also have been reported after treatment with IFN-α (28–30), this therapeutic agent is more commonly associated with minimal-change disease (MCD) (31–38) and FSGS NOS (39–47). We report 11 additional cases of collapsing FSGS that developed during treatment with IFN, including six IFN-α (for hepatitis C virus [HCV] infection or melanoma), three IFN-β (for multiple sclerosis [MS]), and two IFN-γ (for idiopathic pulmonary fibrosis).     

Nephrogenic Systemic Fibrosis: A Survey of Nephrologists' Perceptions and Practices

Background and objectives: Nephrogenic systemic fibrosis (NSF) is a disorder that can affect patients with renal dysfunction exposed to a gadolinium-based contrast agent (GBCA). Given the unique role nephrologists play in caring for patients at risk to develop NSF, this study surveyed their perceptions and practices regarding NSF.Design, setting, participants, & measurements: An internet-based, cross-sectional survey of clinical nephrologists in the United States was performed. Perceptions and self-reported practices regarding NSF and local facility policies were assessed concerning GBCA use in renal dysfunction.Results: Of the 2310 eligible nephrologists e-mailed to participate in the survey, 171 (7.4%) responded. Respondents spent 85% of their time in direct patient care and 83% worked in private practice; 59% had cared for a patient with NSF. Although over 90% were aware of the morbidity and mortality associated with NSF, 31% were unaware of an association with specific GBCA brand and 50% believed chronic kidney disease stage 3 patients were at risk to develop NSF. Changes in facility policies concerning GBCA use in renal dysfunction were widespread (>90%). Most nephrologists (56%) felt that enacted policies were appropriate, yet 58% were uncertain if the changes had benefited patients.Conclusions: These results indicate that nephrologists are generally familiar with the risk factors and consequences of NSF, but their perceptions do not always align with current evidence. Local policy changes in GBCA use are pervasive. Most nephrologists are comfortable with these policy changes but have mixed feelings regarding their effectiveness.In 1997, several patients at a southern California hemodialysis center developed symptoms of a previously unknown fibrosing skin disorder (1). Skin biopsies revealed lesions similar to scleromyxedema. Subsequently, further cases were recognized and renal dysfunction was conspicuously present in all affected patients. Although no clear etiology could be identified, researchers later noted that this new disease (nephrogenic fibrosing dermopathy) could affect multiple systems, with documented fibrosis in the heart, liver, lungs, skeletal muscle, and other organs (2–5). In light of these observations, the disease was redesignated nephrogenic systemic fibrosis (NSF) (2–7).In 2006, Grobner suggested a link between gadolinium-based contrast agents (GBCAs) and NSF (8). A second report that same year further supported a causative role for GBCAs in the development of NSF (9). Shortly thereafter, the U.S. Food and Drug Administration (FDA) issued a warning to healthcare professionals and the public regarding the potential risks of NSF after GBCA exposure in patients with renal dysfunction. Since then, numerous studies have corroborated an association between GBCA and NSF (10–16), and in 2007 the FDA required the addition of a black box warning for all GBCAs (17).This warning notified healthcare providers about the risk of developing NSF after GBCA exposure in patients with acute or chronic kidney disease with a GFR < 30ml/min/1.73m² or acute kidney injury (AKI) of any degree due to the hepatorenal syndrome or in the setting of a liver transplant (17). In addition to screening for renal dysfunction and avoiding GBCA use in high-risk scenarios unless essential, the FDA also recommended avoiding repeated or high doses of GBCAs in patients with renal dysfunction. In patients receiving hemodialysis (HD) that are administered a GBCA, the FDA recommended considering prompt HD postexposure while acknowledging that this prophylactic approach was unproven (17).Despite the discovery of gadolinium as a key factor in the development of NSF in patients with renal dysfunction, relatively little else is firmly known regarding other contributing factors, the natural history of the disease, or effective treatments (16,18–21). Nearly all patients with documented NSF had chronic kidney disease (CKD) with an estimated GFR (eGFR) < 30 ml/min/1.73 m² or AKI. In addition to renal dysfunction, potential associations with liver transplant, vascular injury, inflammatory processes, and high doses of erythropoietin stimulating agents have been theorized (16,18,20,22).Frequently, clinical nephrologists and their patients confront difficult risk-benefit considerations when choosing whether to use imaging studies with GBCAs. Since 2007, multiple publications have reported on local changes in radiology and/or hospital policies regarding the use of GBCAs in patients with renal dysfunction (23–26). Some of these reports document potentially improved outcomes, including a lower incidence of NSF, after the introduction of new, restrictive departmental or institutional guidelines (24). Conversely, others have anecdotally reported on the potential detrimental effects of delayed or missed diagnoses (e.g., a malignancy) because of these changes (23). Given the relative rarity of NSF [approximately 315 cases of NSF have been identified as of June, 2009 (27)], many nephrologists are unlikely to possess an abundance of clinical experience with the disease to help make these challenging risk-benefit decisions. Limitations in clinical experience and our inadequate knowledge of NSF are likely to influence nephrologists'' beliefs and practices regarding the disease and the policies established to reduce the risk of developing it. Because nephrologists'' play a vital role in caring for and advising the patients most affected by the risks and benefits of undergoing a study with GBCA exposure, it is useful to understand their perceptions and practices concerning NSF and GBCAs. We surveyed clinical nephrologists on their perceptions and practices regarding NSF and GBCAs. We also explored whether clinical experience with this rare disease was associated with differences in responses.     

Phosphoinositides and SNARE chaperones synergistically assemble and remodel SNARE complexes for membrane fusion

Yeast vacuole fusion requires 4 SNAREs, 2 SNARE chaperone systems (Sec17p/Sec18p/ATP and the HOPS complex), and 2 phosphoinositides, phosphatidylinositol 3-phosphate [PI(3)P] and phosphatidylinositol 4,5-bisphosphate [PI(4,5)P₂]. By reconstituting proteoliposomal fusion with purified components, we now show that phosphoinositides have 4 distinct roles: PI(3)P is recognized by the PX domain of the SNARE Vam7p; PI(3)P enhances the capacity of membrane-bound SNAREs to drive fusion in the absence of SNARE chaperones; either PI(3)P or PI(4,5)P₂ can activate SNARE chaperones for the recruitment of Vam7p into fusion-competent SNARE complexes; and either PI(3)P or PI(4,5)P₂ strikingly promotes synergistic SNARE complex remodeling by Sec17p/Sec18p/ATP and HOPS. This ternary synergy of phosphoinositides and 2 SNARE chaperone systems is required for rapid fusion.Intracellular membrane fusion is a conserved reaction, vital for vesicle trafficking, hormone secretion, and neurotransmission. Fusion is regulated by NSF (N-ethylmaleimide-sensitive factor)/Sec18p, αSNAP (soluble NSF attachment protein)/Sec17p, SNAREs (SNAP receptors), Sec1p/Munc18–1p family (SM) proteins, Rab GTPases, and Rab:GTP-binding proteins, termed “Rab effectors” (1–3). Lipids, including phosphoinositides, sterols, diacylglycerol (DAG), and phosphatidic acid (PA), have specific roles in fusion (4–14). Proteins and lipids cooperate for their enrichment in membrane fusion microdomains (6, 8, 15, 16).SNARE proteins are integral or peripheral membrane proteins required for membrane fusion. SNAREs have either a Q or R residue at the center of their SNARE domain and associate in 4-helical QabcR complexes in cis (anchored to one membrane) or in trans (anchored to apposed membranes), where a, b, and c are families of related Q-SNAREs (2, 17, 18). Reconstituted proteoliposomes (RPLs) bearing Q-SNAREs fuse with RPLs bearing an R-SNARE through trans-SNARE-complex assembly (19, 20). This fusion has slow kinetics, requires nonphysiologically high SNARE densities, and causes substantial leakage of luminal contents of the RPLs (21–24).We study membrane fusion with yeast vacuoles (lysosomes). Vacuole fusion (25) requires 3 Q-SNAREs (Vam3p, Vti1p, and Vam7p) and 1R-SNARE (Nyv1p) (26, 27), two SNARE chaperone systems, Sec17p/Sec18p/ATP (28), and the HOPS (homotypic fusion and vacuole protein sorting)/Vps Class C complex (29, 30), the Rab-GTPase Ypt7p (31), and chemically minor but functionally vital “regulatory lipids”: ergosterol (ERG), DAG, PI(3)P, and PI(4,5)P₂ (8). Inactive 4SNARE cis-complexes on isolated organelles are disassembled by Sec17p/Sec18p/ATP (27). The heterohexameric HOPS complex, containing the SM protein Vps33p as a subunit, promotes and proofreads SNARE-complex assembly (32–34). HOPS can physically interact with the Q-SNAREs [Vam7p (35) and Vam3p (36, 37)], 4SNARE cis-complexes (32), GTP-bound Ypt7p (29), and phosphoinositides (35). PI(3)P supports the membrane association of the Qc-SNARE Vam7p, which has no transmembrane domain, through binding its PX domain (38). SNAREs, HOPS, Ypt7p, and regulatory lipids assemble in an interdependent fashion to form a fusion-competent membrane microdomain, the “vertex ring” (8, 16, 39). Trans-SNARE complexes are essential for fusion (26), yet fusion can be accelerated by SNARE-associating factors such as HOPS (14, 35) and by cycles of SNARE complex disassembly and reassembly, termed “remodeling” (40).Membrane fusion has been reconstituted with all purified yeast vacuolar components, including 4SNAREs, vacuolar lipids, 2 SNARE chaperone systems, and phosphoinositides (14). We now show distinct functions of phosphoinositides in RPL fusion: the PX-domain of the SNARE Vam7p recognizes PI(3)P, as reported (38); PI(3)P activates the 3Q-SNAREs to be more fusogenic in the absence of SNARE chaperones; either PI(3)P or PI(4,5)P₂ accelerates fusion by promoting the synergy between Sec17p/Sec18p and HOPS, although this synergy is not a function of the membrane recruitments of these SNARE chaperones. This ternary synergy between phosphoinositides and SNARE chaperones is essential for the assembly and remodeling of SNARE complexes.     

Hypophosphatemic Effect of Niacin in Patients without Renal Failure: A Randomized Trial

Background and objectives: Niacin administration lowers the marked hyperphosphatemia that is characteristic of renal failure. We examined whether niacin administration also reduces serum phosphorus concentrations in patients who have dyslipidemia and are free of advanced renal disease.Design, setting, participants, & measurements: We performed a post hoc data analysis of serum phosphorus concentrations that had been determined serially (at baseline and weeks 4, 8, 12, 18, and 24) among 1547 patients who had dyslipidemia and were randomly assigned in a 3:2:1 ratio to treatment with extended release niacin (ERN; 1 g/d for 4 weeks and dose advanced to 2 g/d for 20 weeks) combined with the selective prostaglandin D2 receptor subtype 1 inhibitor laropiprant (L; n = 761), ERN alone (n = 518), or placebo (n = 268).Results: Repeated measures analysis revealed that ERN-L treatment resulted in a net mean (95% confidence interval) serum phosphorus change comparing ERN-L with placebo treatment of −0.13 mmol/L (−0.15 to −0.13 mmol/L; −0.41 mg/dl [−0.46 to −0.37 mg/dl]). These results were consistent across the subgroups defined by estimated GFR of <60 or ≥60 ml/min per 1.73 m², a serum phosphorus of >1.13 mmol/L (3.5 mg/dl) versus ≤1.13 mmol/L (3.5 mg/dl), the presence of clinical diabetes, or concomitant statin use.Conclusions: We have provided definitive evidence that once-daily ERN-L treatment causes a sustained 0.13-mmol/L (0.4-mg/dl) reduction in serum phosphorus concentrations, approximately 10% from baseline, which is unaffected by estimated GFR ranging from 30 to ≥90 ml/min per 1.73 m² (i.e., stages 1 through 3 chronic kidney disease).Abnormalities in calcium-phosphorus homeostasis, including significant elevations in serum phosphorus concentrations, are thought to contribute to arterial stiffening, hypertension, and cardiovascular disease (CVD) risk in patients with advanced chronic kidney disease and ESRD that requires maintenance dialysis (1–6). Observational data from population-based studies suggested that even serum phosphorus concentrations within the normative range are linearly associated with measures of subclinical arteriosclerosis and the development of incident CVD outcomes (7–12). Two cross-sectional studies from patients who underwent cardiac catheterization have further indicated that serum phosphorus concentrations, primarily within the normative range, were directly associated with both the presence and the severity of angiographic coronary artery disease (13,14). Moreover, a graded, independent association between serum phosphorus concentrations (again, within the normative range) and recurrent CVD events was reported among a large clinical trial cohort of patients with a previous myocardial infarction (15).Supplementation of calcium salts, despite their efficacy and tolerability as a phosphorus-lowering treatment in ESRD, may enhance coronary artery and aortic valve calcification (16,17). This observation highlights the need for hyperphosphatemia treatment protocols to balance potential benefits and adverse effects (18–22). Phosphorus-lowering drugs that target other cardiovascular risk factors in chronic kidney disease (CKD), simultaneously, including, for example, dyslipidemia (23), might have additive or synergistic benefits. These findings may also be relevant to populations with less advanced CKD or normal renal function.Preliminary studies suggested that niacin administration (as niacinamide, niceritrol, or nicotinic acid) could be a useful primary or adjunctive treatment for the marked hyperphosphatemia that is characteristic of ESRD (24–30). Several reports from clinical trials of extended-release niacin (ERN) that was given to patients who had dyslipidemia and were free of clinical renal disease and hyperphosphatemia have contained limited additional data noting up to 10% reductions in the serum phosphorus concentrations of actively treated patients (31–34). These repeated clinical observations (24–34) are most plausibly explained by the direct inhibitory effect of niacin compounds on active transport-mediated phosphorus absorption in the mammalian small intestine (35–39).Published studies of patient populations who had dyslipidemia and were receiving ERN that included phosphorus data may have failed to provide information on baseline phosphorus values (33,34), and none (31–34) performed repeated measures analyses to examine the potential effects of niacin treatment on serum phosphorus and calcium concentrations, as well as the calcium-phosphorus products.Focused reexamination of the large, placebo-controlled clinical trial data set assembled by Maccubbin et al. (34) afforded us a unique opportunity to elucidate these and other unresolved issues regarding the impact of niacin given as the fixed-dose combination of ERN and laropiprant (ERN-L), a selective prostaglandin D2 receptor subtype 1 inhibitor that reduces niacin-induced flushing (34) or ERN alone on serum phosphorus and calcium concentrations and calcium-phosphorus products. We further evaluated whether there was evidence for significant effect modification by estimated GFR (eGFR), baseline serum phosphorus concentration, the presence of diabetes, or concurrent hepatic hydroxymethyl glutaryl–CoA reductase inhibitor (statin) use when assessing the potential impact of niacin on these routine clinical measures of calcium-phosphorus homeostasis.     

Training of Surgeons in Peritoneal Dialysis Catheter Placement in the United States: A National Survey

Background and objectives: Peritoneal dialysis (PD) depends on timely and skilled placement of a PD catheter (PDC). Most PDCs are placed surgically, but little is known about the residency training of surgeons in this procedure. Inadequate residency training could limit surgical expertise in PDCs, resulting in high complication rates that discourage PD use. This study assessed surgical PDC training in the United States to explore this issue.Design, setting, participants, & measurements: A survey was sent to program directors of 248 U.S. surgery residency programs regarding the amount of PDC training, attitudes toward PDCs, and barriers to PDC training. Results were compared between academic and private centers.Results: Ninety-three surgery programs (38%) responded: 82% provided training in PDC and 69% were academic centers. Most surgeons placed 2 to ≤5 catheters during residency. Forty-eight percent of program directors felt that PDC training was important, 61% felt PDC training affected outcomes and increased the likelihood surgeons would place PDCs in practice, and 62% of programs expressed willingness to provide more PDC training. Lack of referrals from nephrology was the most frequently cited barrier to PDC training.Conclusions: Although many U.S. surgery residency programs provide PDC training, this training appears inadequate. Low PD use and lack of referrals limits surgical training at most centers. Nephrologists need to develop initiatives with surgeons to improve PDC training and outcomes.The use of peritoneal dialysis (PD) in the United States is declining. Despite comparable efficacy, improving outcomes, and cost savings compared with hemodialysis (HD), only 6% of incident and 7.2% of prevalent dialysis patients are treated with PD (1–4). Although many factors determine success on PD, a well functioning PD catheter (PDC) is absolutely necessary. Placement of a PDC by an experienced operator is strongly recommended to reduce complications (5–9). Little attention has been given to the potential effect of surgical PDC training on PD use and outcomes (1–2,10). Conversely, considerable focus has been placed on improving surgical training and outcomes for HD access (11–15).Problems with PDC placement and malfunction can disrupt efforts to grow and develop a PD program (5,9,16–18). PDC problems frustrate patients, nurses, and nephrologists alike, leading to dissatisfaction with PD and an early switch to HD (18). PDC malfunction is second only to infection as the cause of technique failure in PD (19,20). Surgeons insert most PD catheters in the United States because most nephrologists are not trained in PDC placement (5,21–23). Unfortunately, there is a shortage of surgeons interested and skilled in performing this procedure (5).Surgical outcomes correlate strongly with training during residency (24). Reluctance by surgeons to place PDCs and suboptimal PDC outcomes might stem from inadequate residency training. Unfortunately, little is known about the training surgeons undergo in this outwardly simple, yet critical procedure. We sought to investigate PDC training in U.S. surgery residency programs and explore surgical program directors'' attitudes toward this procedure.