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A correction to the article "Irs1 and Irs2 signaling is essential for hepatic glucose homeostasis and systemic growth" that was published in an earlier issue is presented.

A correction to the article "Identification of thrombospondin 1 (TSP-1) as a novel mediator of cell injury in kidney ischemia" that was published in an earlier issue is presented.

Carbonic anhydrase (CAII) binds to the electrogenic basolateral Na + -[Formula: see text] cotransporter (NBCe1) and facilitates [Formula: see text] reabsorption across the proximal tubule. However, whether the inhibition of CAII with acetazolamide (ACTZ) alters NBCe1 activity and interferes with the ammoniagenesis pathway remains elusive. To address this issue, we compared the renal adaptation of rats treated with ACTZ to NH 4 Cl loading for up to 2 wk. The results indicated that ACTZ-treated rats exhibited a sustained metabolic acidosis for up to 2 wk, whereas in NH 4 Cl-loaded rats, metabolic acidosis was corrected within 2 wk of treatment. [Formula: see text] excretion increased by 10-fold in NH 4 Cl-loaded rats but only slightly (1.7-fold) in ACTZ-treated rats during the first week despite a similar degree of acidosis. Immunoblot experiments showed that the protein abundance of glutaminase (4-fold), glutamate dehydrogenase (6-fold), and SN1 (8-fold) increased significantly in NH 4 Cl-loaded rats but remained unchanged in ACTZ-treated rats. Na + /H + exchanger 3 and NBCe1 proteins were upregulated in response to NH 4 Cl loading but not ACTZ treatment and were rather sharply downregulated after 2 wk of ACTZ treatment. ACTZ causes renal [Formula: see text] wasting and induces metabolic acidosis but inhibits the upregulation of glutamine transporter and ammoniagenic enzymes and thus suppresses ammonia synthesis and secretion in the proximal tubule, which prevented the correction of acidosis. This effect is likely mediated through the inhibition of the CA-NBCe1 metabolon complex, which results in cell alkalinization. During chronic ACTZ treatment, the downregulation of both NBCe1 and Na + /H + exchanger 3, along with the inhibition of ammoniagenesis and [Formula: see text] generation, contributes to the maintenance of metabolic acidosis.

Chronic adenine feeding is extensively used to develop animal models of chronic renal failure with metabolic features resembling those observed in humans. However, the mechanism by which adenine induces renal failure is poorly understood. In this study, we examined the early effects of adenine on water metabolism and salt balance in rats placed in metabolic cages and fed control or adenine-containing diets for 7 days. Molecular and functional studies demonstrated that adenine-fed rats exhibited a significant reduction in food intake, polyuria, polydipsia, decreased urine osmolality, and increased salt wasting. These effects are independent of changes in food intake and result from a coordinated downregulation of water channel aquaporin-2 (AQP2) and salt transporter (Na + -K + -Cl - cotransporter 2; NKCC2) in the collecting duct and medullary thick ascending limb, respectively. As a result, adenine-fed rats exhibited massive volume depletion, as indicated by a significant body weight loss, increased blood urea nitrogen, and increased hematocrit and hemoglobin levels, all of which were significantly corrected with NaCl replacement. Adenine-induced urinary concentrating defect was not corrected by exogenous arginine vasopressin (AVP), and it correlated with reduced cAMP production in vivo and in vitro. In conclusion, adenine acts on renal tubules as a signaling molecule and causes nephrogenic diabetes insipidus with salt wasting, at least, by directly interfering with AVP V2 receptor signaling with subsequent downregulation of NKCC2 and AQP2 in the kidney. The combination of renal fluid loss and decreased food intake with subsequent massive volume depletion likely plays an important role in the development of early prerenal failure that progresses to chronic kidney disease in long-term adenine feeding.

Background: Arteriovenous (AV) access confers survival benefits over central venous catheters (CVC) in hemodialysis patients. Although chronic kidney disease disproportionately affects women and racial minorities, disparities in the -utilization of hemodialysis access across Asians, Native Americans, Hispanics, blacks, and whites among males and females after accounting for pre-dialysis health are not well studied., Methods: We evaluated 885,699 patients with end-stage renal disease who initiated hemodialysis between January 1, 2004 and December 31, 2014 using the US Renal Data System. Multivariable logistic regression models -adjusted for pre-dialysis health were used to test the associations between gender and race on type of vascular access (AV access vs. CVC, and AV fistula vs. AV graft) at hemodialysis initiation as primary outcome, and on 1-year mortality as a secondary outcome., Results: Mean age was 65 ± 14 years. Females were less likely to use AV access for hemodialysis initiation than were males (OR 0.85; 95% CI 0.84-0.86). Compared to whites, adjusted odds of AV access for hemodialysis initiation were higher in blacks (OR 1.08; 95% CI 1.07-1.70), Asians (OR 1.11; 95% CI 1.07-1.14); and lower in Hispanics (OR 0.89; 95% CI 0.87-0.90). There was no -significant difference in mortality between males and females. Compared to whites, 1-year adjusted mortality was lower in Asians (OR 0.55; 95% CI 0.53-0.56), blacks (OR 0.67; 95% CI 0.66-0.68), Hispanics (OR 0.62; 95% CI 0.61-0.63), and Native Americans (OR 0.62; 95% CI 0.58-0.66)., Conclusion: Females had lower odds of using AV access than do males for hemodialysis initiation. As compared to whites, blacks and Asians were more likely, and Hispanics were less likely to use AV access for first outpatient hemodialysis. Further investigation of biological and process of care factors may help in developing ways to reduce these disparities., (The Author(s). Published by S. Karger AG, Basel.)

Over the past decade, there has been a marked increase in the number of primary and revision total hip and knee arthroplasties performed in the United States. Acute kidney injury (AKI) is a common complication of these procedures; however, little is known about its epidemiology in the elective arthroplasty population. We conducted a study to determine the incidence, risk factors, and outcomes of AKI after elective joint arthroplasty. Drawing on the Nationwide Inpatient Sample database, we found that the proportion of hospitalizations complicated by AKI increased rapidly from 0.5% in 2002 to 1.8% to 1.9% in 2012. Multivariate analysis revealed that the key risk factors for AKI were chronic kidney disease and the postoperative events of sepsis, acute myocardial infarction, and blood transfusion. Moreover, codiagnosis with chronic kidney disease increased the risk for AKI associated with all 3 postoperative events. After adjusting for confounders, we found an association between AKI and a significantly increased risk for in-hospital mortality and discharge to long-term facilities. AKI serves as an important quality indicator in elective hip and knee surgeries. With elective arthroplasties expected to rise, carefully planned approach to interdisciplinary perioperative care is essential to reduce both the risk and consequences of AKI.

Background and Purpose: The epidemiology of dialysis requiring acute kidney injury (AKI-D) in acute ischemic stroke (AIS) and intracerebral hemorrhage (ICH) admissions is poorly understood with previous studies being from a single center or year., Methods: We used the Nationwide Inpatient Sample to evaluate the yearly incidence trends of AKI-D in hospitalizations with AIS and ICH from 2002 to 2011. We also evaluated the trend of impact of AKI-D on in-hospital mortality and adverse discharge using adjusted odds ratios (aOR) after adjusting for demographics and comorbidity indices., Results: We extracted a total of 3,937,928 and 696,754 hospitalizations with AIS and ICH, respectively. AKI-D occurred in 1.5 and 3.5 per 1000 in AIS and ICH admissions, respectively. Incidence of admissions complicated by AKI-D doubled from 0.9/1000 to 1.7/1000 in AIS and from 2.1/1000 to 4.3/1000 in ICH admissions. In AIS admissions, AKI-D was associated with 30% higher odds of mortality (aOR, 1.30; 95% confidence interval, 1.12-1.48; P<0.001) and 18% higher odds of adverse discharge (aOR, 1.18; 95% confidence interval, 1.02-1.37; P<0.001). Similarly, in ICH admissions, AKI-D was associated with twice the odds of mortality (aOR, 1.95; 95% confidence interval, 1.61-2.36; P<0.01) and 74% higher odds of adverse discharge (aOR, 1.74; 95% confidence interval, 1.34-2.24; P<0.01). Attributable risk percent of mortality was high with AKI-D (98%-99%) and did not change significantly over the study period., Conclusions: Incidence of AKI-D complicating hospitalizations with cerebrovascular accident continues to grow and is associated with increased mortality and adverse discharge. This highlights the need for early diagnosis, better risk stratification, and preparedness for need for complex long-term care in this vulnerable population., (© 2015 American Heart Association, Inc.)

In response to the recently released 2012 KDIGO (Kidney Disease: Improving Global Outcomes) clinical practice guideline for acute kidney injury (AKI), the National Kidney Foundation organized a group of US experts in adult and pediatric AKI and critical care nephrology to review the recommendations and comment on their relevancy in the context of current US clinical practice and concerns. The first portion of the KDIGO guideline attempts to harmonize earlier consensus definitions and staging criteria for AKI. While the expert panel thought that the KDIGO definition and staging criteria are appropriate for defining the epidemiology of AKI and in the design of clinical trials, the panel concluded that there is insufficient evidence to support their widespread application to clinical care in the United States. The panel generally concurred with the remainder of the KDIGO guidelines that are focused on the prevention and pharmacologic and dialytic management of AKI, although noting the dearth of clinical trial evidence to provide strong evidence-based recommendations and the continued absence of effective therapies beyond hemodynamic optimization and avoidance of nephrotoxins for the prevention and treatment of AKI., (Published by Elsevier Inc.)

The incidence of acute kidney injury (AKI) is generally 5-7.5% in all acute care hospitalizations and accounts for up to 20% of admissions to intensive care units (ICUs). Of all of the cases of AKI during hospitalization, approximately 30-40% are observed in operative settings. AKI is a serious morbidity that is associated with greater length of hospital stay, high risk of hospital mortality, and increased risk of incident and progressive chronic kidney disease. The incidence of AKI is variable depending on the specific surgical setting under consideration. Much of our knowledge regarding the epidemiology of AKI is derived from studies related to cardiac or vascular surgery. With limited treatment options, prevention of AKI and amelioration of its severity remain important cornerstones of improving patient outcomes. The magnitude of the problem and the unique set of patient characteristics calls for a multidisciplinary approach for the perioperative management of renal complications. The purpose of the review presented here is to discuss the current knowledge regarding the epidemiology and risk factors, outcomes, diagnoses, and prevention and treatment of AKI during the perioperative period in cardiovascular and noncardiovascular surgical settings., (Published by Elsevier Inc.)

Heart failure (HF) contributes to a high rate of hospitalizations. Acute kidney injury (AKI), with or without chronic kidney disease (CKD), is a common complication in patients with HF. The link between AKI and the risk for readmission for repeat episodes of HF is not well studied. In this study, 6,535 patients discharged with primary diagnoses of HF derived from a statewide inpatient database were examined. The association between AKI, with and without CKD, and risk for 30-day readmission with HF was assessed. Logistic regression was used to test the relations between predictor variables and outcomes. The mean age was 73.8 ± 14.6 years, and 51% of patients (n = 3,351) were women. AKI occurred in 6.5% of patients during the index hospitalization, whereas 16% had CKD. Nine hundred seventy-seven patients (15%) required readmission within 30 days for HF. Index hospital mortality was 1.7% in those without AKI or CKD compared to 11% and 13% in those with AKI without and with CKD, respectively (p <0.0001). Patients with AKI had a 30-day readmission rate of 21%, compared to 14% in those without AKI (p <0.0001). On multivariate analysis, AKI without CKD was associated with the highest risk for readmission (odds ratio 1.81, 95% confidence interval 1.35 to 2.39) compared to those with neither of the 2 diagnoses. In conclusion, patients with HF who have AKI experience a high rate of 30-day readmission for repeat episodes of HF. Reducing the risk for AKI, and follow-up monitoring after AKI, may improve care and reduce health care costs in patients with HF., (Published by Elsevier Inc.)

Background: Vitamin D is a steroid hormone with pleiotropic effects including immune system modulation, lung tissue remodeling, and bone health. Vitamin D deficiency has been implicated in the development of autoimmune diseases. We sought to evaluate the prevalence of vitamin D deficiency in a cohort of patients with interstitial lung disease (ILD) and hypothesized that vitamin D deficiency would be associated with an underlying connective tissue disease (CTD) and reduced lung function., Methods: Patients in the University of Cincinnati ILD Center database were evaluated for serum 25-hydroxyvitamin D levels as part of a standardized protocol. Regression analysis evaluated associations between 25-hydroxyvitamin D levels and other variables., Results: One hundred eighteen subjects were included (67 with CTD-ILD, 51 with other forms of ILD). The overall prevalence of vitamin D deficiency and insufficiency in the study population was 38% and 59%, respectively. Those with CTD-ILD were more likely to have vitamin D deficiency (52% vs 20%, P < .0001) and insufficiency (79% vs 31%, P < .0001) than other forms of ILD. Diminished FVC was associated with lower 25-hydroxyvitamin D(3) levels (P = .01). The association between vitamin D insufficiency and CTD-ILD persisted (OR, 11.8; P < .0001) after adjustment for potential confounders. Among subjects with CTD-ILD, reduced 25-hydroxyvitamin D(3) levels were strongly associated with reduced lung function (FVC, P = .015; diffusing capacity for carbon monoxide, P = .004)., Conclusions: There is a high prevalence of vitamin D deficiency in patients with ILD, particularly those with CTD-ILD, and it is associated with reduced lung function. Vitamin D may have a role in the pathogenesis of CTD-ILD.

Background: Long-term care hospitals (LTCHs) provide intermediary care after an acute-care hospitalization and usually furnish care to patients with complex medical problems. Outcomes of hemodialysis patients admitted to LTCHs, which includes patients with either end-stage renal disease (ESRD) or acute kidney injury (AKI) requiring dialysis therapy, are not known., Study Design: Observational study., Setting & Participants: All consecutive hemodialysis patients admitted to an LTCH., Predictors: Demographic characteristics, comorbid and laboratory variables, ESRD, and AKI status during LTCH stay., Outcomes: Disposition from LTCHs was classified as discharge to home, nursing home, death in LTCH or hospice care, and re-admission to the hospital. In patients with AKI, renal recovery was defined as discontinuation of dialysis therapy before meeting disposition outcomes., Results: 96 of 206 (46.6%) patients had ESRD, whereas 110 of 206 (53.3%) developed AKI requiring dialysis therapy during the acute-care hospitalization. 63 of 206 (31%) were discharged to home, 11 of 206 (5.4%) died or transferred to hospice, 81 of 206 (40%) went to a nursing home, and 49 of 206 (24%) were re-admitted to a hospital; mortality after re-admission was 32%. Older age (OR, 0.96; 95% CI, 0.93-0.98), diabetes mellitus (OR, 0.45; 95% CI, 0.23-0.94), number of re-admissions to the hospital (OR, 0.38; 95% CI, 0.18-0.78), aminoglycoside use (OR, 0.16; 95% CI, 0.04-0.64), and duration of hospitalization before LTCH admission (OR, 0.96; 95% CI, 0.94-0.99) were associated with lower odds of discharge to home. Of 110 patients with AKI requiring dialysis therapy, 30% (33 patients) discontinued dialysis therapy, whereas 70% were deemed to have ESRD on discharge., Limitations: Retrospective observational study., Conclusions: Most dialysis patients at LTCHs are either re-admitted to acute-care hospitals or require nursing home placement. Only 30% of patients with AKI recover sufficiently to discontinue dialysis therapy, whereas 70% are deemed to have ESRD., (Published by Elsevier Inc.)

Background: Acute kidney injury (AKI) after coronary artery bypass grafting (CABG) is associated with significant morbidity and mortality. Controversy exists regarding whether an off-pump technique can reduce post-CABG renal injury., Study Design: Systematic review and meta-analysis., Setting & Population: Adult patients undergoing CABG., Selection Criteria for Studies: MEDLINE, EMBASE, Cochrane Renal Library, and Google Scholar were searched in May 2008 for randomized controlled trials (RCTs) and observational studies comparing off-pump CABG (OPCAB) with conventional CABG (CAB) for renal outcomes. Studies involving patients on long-term renal replacement therapy (RRT) were excluded., Intervention: OPCAB., Outcomes: Primary outcomes were overall AKI and AKI requiring RRT., Results: 22 studies (6 RCTs and 16 observational studies) comprising 27,806 patients met the inclusion criteria. The pooled effect from both study cohorts showed a significant reduction in overall AKI (odds ratio [OR], 0.57; 95% confidence interval [CI], 0.43 to 0.76; P for effect < 0.001; I(2) = 67%; P for heterogeneity < 0.001) and AKI requiring RRT (OR, 0.55; 95% CI, 0.43 to 0.71; P for effect < 0.001; I(2) = 0%; P for heterogeneity = 0.5) in the OPCAB group compared with the CAB group. In RCTs, overall AKI was significantly reduced in the OPCAB group (OR, 0.27; 95% CI, 0.13 to 0.54); however, no statistically significant difference was noted in AKI requiring RRT (OR, 0.31; 95% CI, 0.06 to 1.59). In the observational cohort, both overall AKI (OR, 0.61; 95% CI, 0.45 to 0.81) and AKI requiring RRT (OR, 0.54; 95% CI, 0.40 to 0.73) were significantly less in the OPCAB group. RCTs were noted to be underpowered and biased toward recruiting low-risk patients. Sensitivity analysis restricted to good-quality studies showed a significant reduction in AKI., Limitations: Lack of uniform AKI definition in the included studies, heterogeneity for overall AKI outcome., Conclusions: Analysis of the current evidence suggests a reduction in AKI using the OPCAB technique; however, studies lack consistency in defining AKI. Available RCTs are underpowered to detect a difference in AKI requiring RRT; evidence from observational studies suggests a reduction in RRT requirement. Future studies should apply a standard definition of AKI and target a high-risk population.

The risk of mortality associated with acute renal failure (ARF) after open-heart surgery continues to be distressingly high. Accurate prediction of ARF provides an opportunity to develop strategies for early diagnosis and treatment. The aim of this study was to develop a clinical score to predict postoperative ARF by incorporating the effect of all of its major risk factors. A total of 33,217 patients underwent open-heart surgery at the Cleveland Clinic Foundation (1993 to 2002). The primary outcome was ARF that required dialysis. The scoring model was developed in a randomly selected test set (n = 15,838) and was validated on the remaining patients. Its predictive accuracy was compared by area under the receiver operating characteristic curve. The score ranges between 0 and 17 points. The ARF frequency at each score level in the validation set fell within the 95% confidence intervals (CI) of the corresponding frequency in the test set. Four risk categories of increasing severity (scores 0 to 2, 3 to 5, 6 to 8, and 9 to 13) were formed arbitrarily. The frequency of ARF across these categories in the test set ranged between 0.5 and 22.1%. The score was also valid in predicting ARF across all risk categories. The area under the receiver operating characteristic curve for the score in the test set was 0.81 (95% CI 0.78 to 0.83) and was similar to that in the validation set (0.82; 95% CI 0.80 to 0.85; P = 0.39). In conclusion, a score is valid and accurate in predicting ARF after open-heart surgery; along with increasing its clinical utility, the score can help in planning future clinical trials of ARF.