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In patients with respiratory failure, loop diuretics remain the cornerstone of the treatment to maintain fluid balance, but resistance is common.To determine the efficacy and safety of common diuretic combinations in critically ill patients with respiratory failure.We searched MEDLINE, Embase, Cochrane Library and PROSPERO for studies reporting the effects of a combination of a loop diuretic with another class of diuretic. A meta-analysis using mean differences (MD) with 95% confidence interval (CI) was performed for the 24-h fluid balance (primary outcome) and the 24-h urine output, while descriptive statistics were used for safety events.Nine studies totalling 440 patients from a total of 6510 citations were included. When compared to loop diuretics alone, the addition of a second diuretic is associated with an improved negative fluid balance at 24 h [MD: -1.06 L (95%CI: -1.46; -0.65)], driven by the combination of a thiazide plus furosemide [MD: -1.25 L (95%CI: -1.68; -0.82)], while no difference was observed with the combination of a loop-diuretic plus acetazolamide [MD: -0.40 L (95%CI: -0.96; 0.16)] or spironolactone [MD: -0.65 L (95%CI: -1.66; 0.36)]. Heterogeneity was high and the report of clinical and safety endpoints varied across studies.Based on limited evidence, the addition of a second diuretic to a loop diuretic may promote diuresis and negative fluid balance in patients with respiratory failure, but only when using a thiazide. Further larger trials to evaluate the safety and efficacy of such interventions in patients with respiratory failure are required.

Introduction: Thrombocytopenia (TCP) is a common finding in patients receiving continuous renal replacement therapy (CRRT). Objective: The purpose of this study was to assess the nature of TCP in patients receiving CRRT. Methods: This is a single-center case-control observational study of 795 patients involving over 166,950 h of delivered CRRT at Johns Hopkins Hospital. Concurrent TCP in patients receiving CRRT was defined as a decrease in platelet count of ≥50% any time within 72 h of initiation of CRRT with strict exclusion criteria. Results: There was a higher incidence of TCP in the cardiac intensive care unit (CICU) (22.5%) compared to medical ICU (MICU) (13.1%). Using logistic regression, the odds of developing concurrent TCP in patients receiving CRRT was 2.46 (95% CI 1.32–3.57, p < 0.05) times higher in the CICU compared with the MICU. There was no difference in the incidence of severe or profound TCP or timing of acute TCP between the CICU and MICU. Conclusion: Safe delivery of dialysis care in the ICU is paramount and creating awareness of potential risks such as concurrent TCP in patients receiving CRRT should be part of this care.

Loop diuretics are among the most widely used drugs worldwide and are commonly employed in the management of complications associated with acute kidney injury (AKI), namely volume overload and electrolyte management. The use of loop diuretics in critically ill patients with AKI is paramount to preventing or treating pulmonary edema. The naturetic response to a loop diuretic is based on its unique renal pharmacology. Our review article summarizes the pharmacology of furosemide in the intact nephron and discusses how this response might be altered by the presence of AKI. We discuss the increasing body of literature on the latest clinical utility of furosemide namely, it’s challenge test, known as the furosemide stress test which has highlighted a new and novel role for furosemide over the past number of years. This test assists with the identification of AKI subjects at higher risk of AKI progression and the need for renal replacement therapy. The stress test can also predict cessation of continuous renal replacement therapy in patients with established AKI. On the basis of the evidence presented in this review, we propose future potential studies of furosemide in AKI.

Acceptance of organs from acute chemical intoxicated donors remains controversial and outcomes are insufficiently explored. This is a single-center retrospective cohort analysis of 484 patients undergoing deceased donor kidney transplantation (DDKT). We assessed the association of positive urine drug screen before transplantation with cohort statistics, delayed graft function (DGF), and graft outcomes at 2 years. Multiple logistical regression (MLR) analysis was used to assess the odds ratio for DGF. Of 484 random DDKTs performed at our institution between January 2010 and October 2015, 280 deceased kidney donors were current drug users. Mean age was 35.4 (15) years, 39% male, 61% were African Americans, and 38.2% had more than one test positive. The main chemical toxins detectable in donor urine were alcohol, heroin, opioid/methadone, cocaine, marijuana, benzodiazepines, methamphetamine, ecstasy, and LSD. Single and multiple urine chemical toxicology of kidney donors did not have a significant effect on KT outcomes of DGF and graft failure during a median follow-up (P for odds ratios > 0.05). The use of deceased donor kidney grafts from donors with positive urine chemical toxicology may be a worthwhile method of increasing the availability of scarce donor kidney organs as such exposure to illicit drug(s) is not associated with major adverse transplant outcomes.

Chemotherapeutic agents require precise dosing to ensure optimal efficacy and minimize complications. For those agents which are removed from the body by the kidney, accurate knowledge of glomerular filtration rate (GFR) is critical. In addition, GFR needs to be determined rapidly, easily and, if possible, with little additional cost. The ability to easily measure GFR also allows for rapid detection of nephrotoxicity. Current methodologies include direct clearance measurement of an indicator substance or estimation of creatinine clearance or GFR through regression equations that use a serum marker such as creatinine or cystatin C. These methodologies all have shortfalls and limitations some of which are specific to the cancer patient. Newer methodologies that directly measure GFR are in clinical trials and offer the ability to rapidly and non-invasively provide accurate estimates of drug clearance as well as detection of nephrotoxicity. These methods offer the opportunity to refine drug dosing and improve outcomes.

Background: As the use and indications of anti-angiogenic therapies such as vascular endothelial growth factor (VEGF) and tyrosine kinases inhibitors (TKI’s) continues to expand, clinicians will be faced with an increase in adverse kidney events associated with these therapies. Focal segmental glomerulosclerosis (FSGS) and thrombotic microangiopathies (TMA) are well recognized kidney pathologies identified in patients receiving anti-angiogenic therapy. Options to treat the nephrotoxicity induced by these agents include discontinuation or dose reduction of the anti-angiogenic therapy or change to alternative agent within the same class of drug. Case presentation: We describe the case of a 74-year-old Caucasian man with metastatic papillary thyroid carcinoma who developed proteinuria and peripheral edema following treatment with Lenvatinib, 20 mg. Kidney biopsy revealed FSGS. Partial resolution of proteinuria (>1.0 g/g) was achieved via temporary discontinuation of Lenvatinib and treatment with oral prednisone. Subsequently, tumor burden increased off Lenvatinib and a collective decision was made to resume this medication at a lower dose. Proteinuria then increased to nephrotic range (>4.0 g/g) following resumption of Lenvatinib, 14 mg. Over the next 3 months the patient went into a complete clinical remission of his nephrotic syndrome following administration of the calcineurin-inhibitor, tacrolimus and permitted ongoing concurrent use of Lenvatinib. Conclusions: Our case demonstrates that low-dose calcineurin inhibitors may have efficacy as a second-line treatment in instances of TKI-induced FSGS. Further studies must be conducted to determine the protective mechanisms of tacrolimus on podocytes from TKIs, however, we hypothesize that calcineurin inhibitors may protect podocytes via downregulation of c-mip, which is overexpressed in the presence of VEGF inhibition and contributes to podocyte cytoskeleton remodeling and subsequent proteinuria.

Background Acute kidney injury (AKI) is common in hospitalized patients and is associated with high morbidity and mortality. The Dublin Acute Biomarker Group Evaluation study is a prospective cohort study of critically ill patients (n = 717). We hypothesized that novel urinary biomarkers would predict progression of AKI and associated outcomes. Methods The primary (diagnostic) analysis assessed the ability of biomarkers levels at the time of early Stage 1 or 2 AKI to predict progression to higher AKI stage, renal replacement therapy (RRT) or death within 7 days of intensive care unit admission. In the secondary (prognostic) analysis, we investigated the association between biomarker levels and RRT or death within 30 days. Results In total, 186 patients had an AKI within 7 days of admission. In the primary (diagnostic) analysis, 8 of the 14 biomarkers were independently associated with progression. The best predictors were cystatin C [adjusted odds ratio (aOR) 5.2; 95% confidence interval (CI) 1.3–23.6], interleukin-18 (IL-18; aOR 5.1; 95% CI 1.8–15.7), albumin (aOR 4.9; 95% CI 1.5–18.3) and neutrophil gelatinase-associated lipocalin (NGAL; aOR 4.6; 95% CI 1.4–17.9). Receiver-operating characteristics and net reclassification index analyses similarly demonstrated improved prediction by these biomarkers. In the secondary (prognostic) analysis of Stages 1–3 AKI cases, IL-18, NGAL, albumin and monocyte chemotactic protein-1 were also independently associated with RRT or death within 30 days. Conclusions Among 14 novel urinary biomarkers assessed, cystatin C, IL-18, albumin and NGAL were the best predictors of Stages 1–2 AKI progression. These biomarkers, after further validation, may have utility to inform diagnostic and prognostic assessment and guide management of AKI in critically ill patients.

Background: The Dublin Acute Biomarker Group Evaluation (DAMAGE) Study is a prospective 2-center observational study investigating the utility of urinary biomarker combinations for the diagnostic and prognostic assessment of acute kidney injury (AKI) in a heterogeneous adult intensive care unit (ICU) population. The objective of this study is to evaluate whether serial urinary biomarker measurements, in combination with a simple clinical model, could improve biomarker performance in the diagnostic prediction of severe AKI and clinical outcomes such as death and need for renal replacement therapy (RRT). Methods: Urine was collected daily from patients admitted to the ICU, for a total of 7 post-admission days. Urine biomarker concentrations (neutrophil gelatinase-associated lipocalin [NGAL], α-glutathione S-transferase [GST], π-GST, kidney injury molecule-1 [KIM-1], liver-type fatty acid-binding protein [L-FABP], Cystatin C, creatinine, and albumin) were measured. Urine biomarkers were combined with a clinical prediction of AKI model, to determine ability to predict AKI (any stage, within 2 days or 7 days of ICU admission), or a ­30-day composite clinical outcome (RRT – or death). Results: A total of 257 (38%) patients developed AKI within 7 days of ICU admission. Of those who developed AKI, 106 (41%) patients met stage 3 AKI within 7 days of ICU admission and 208 patients of the entire study cohort (31%) met the composite clinical endpoint of in-hospital mortality or RRT within 30 days of ICU admission. The addition of urinary NGAL/albumin to the clinical model modestly improved the prediction of AKI, in particular severe stage 3 AKI (area under the curve [AUC] of 0.9 from 0.87, p = 0.369) and the prediction of 30-day RRT or death (AUC 0.83 from 0.79, p = 0.139). Conclusion: A clinical model incorporating severity of illness, patient demographics, and chronic illness with currently available clinical biomarkers of renal function was strongly predictive of development of AKI and associated clinical outcomes in a heterogeneous adult ICU population. The addition of urinary NGAL/albumin to this simple clinical model improved the prediction of severe AKI, need for RRT and death, but not at a statistically or clinically significant level, when compared to the clinical model alone.

Onconephrology is a new subspecialty of nephrology that recognizes the important intersections of kidney disease with cancer. This intersection takes many forms and includes drug-induced nephrotoxicity, electrolyte disorders, paraneoplastic glomerulonephritis, and the interactions of chronic kidney disease with cancer. Data clearly demonstrate that, when patients with cancer develop acute or chronic kidney disease, outcomes are inferior, and the promise of curative therapeutic regimens is lessened. This highlights the imperative for collaborative care between oncologists and nephrologists in recognizing and treating kidney disease in patients with cancer. In response to this need, specific training programs in onconephrology as well as dedicated onconephrology clinics have appeared. This comprehensive review covers many of the critical topics in onconephrology, with a focus on acute kidney injury, chronic kidney disease, drug-induced nephrotoxicity, kidney disease in stem cell transplantation, and electrolyte disorders in patients with cancer.

BackgroundIn the era of combined antiretroviral therapy, classic focal segmental glomerulosclerosis (FSGS) is the most common histopathological finding in African American HIV-positive patients with kidney disease. We sought to determine whether HIV suppression is associated with lower risk of progression to end-stage renal disease (ESRD) among HIV-positive African Americans with biopsy-confirmed classic FSGS.MethodsHIV-positive African Americans who underwent kidney biopsies at a single tertiary hospital between January 1996 and June 2011 were confirmed as having classic FSGS by the presence of segmental glomerulosclerosis without features of HIV-associated nephropathy. Multivariable Cox proportional hazards models were used to examine the independent association of viral suppression (HIV-RNA < 400 copies per milliliter at biopsy) with time to progression to ESRD.ResultsOf the 55 HIV-positive African Americans with classic FSGS, 26 had suppressed viral loads at the time of biopsy. Compared to viremic patients, those who were virally suppressed had a significantly higher mean CD4 cell count (452 vs. 260 cell/mm, respectively; P = 0.02) and median estimated glomerular filtration rate (53.5 vs 35.5 mL/min/1.73 m, respectively; P = 0.002). Adjusting for sex and baseline CD4 cell count, estimated glomerular filtration rate, and proteinuria, those with HIV-RNA levels

Despite the decreased incidence of human immunodeficiency virus (HIV)-associated nephropathy due to the widespread use of combined active antiretroviral therapy, it remains one of the leading causes of end-stage renal disease (ESRD) in HIV-1 seropositive patients. Patients usually present with low CD4 count, high viral load and heavy proteinuria, with the pathologic findings of collapsing focal segmental glomerulosclerosis. Increased susceptibility exists in individuals with African descent, largely due to polymorphism in APOL1 gene. Other clinical risk factors include high viral load and low CD4 count. Advanced kidney disease and nephrotic range proteinuria have been associated with progression to ESRD. Improvement in kidney function has been observed after initiation of combined active antiretroviral therapy. Other treatment options, when clinically indicated, are inhibition of the renin-angiotensin system and corticosteroids. Further routine management approaches for patients with chronic kidney disease should be implemented. In patients with progression to ESRD, kidney transplant should be pursued, provided that viral load control is adequate. Screening for the presence of kidney disease upon detection of HIV-1 seropositivity in high-risk populations is recommended.

OBJECTIVES AND METHODS: The Furosemide Stress Test (FST) is a novel dynamic assessment of tubular function that has been shown in preliminary studies to predict patients who will progress to advanced stage acute kidney injury, including those who receive renal replacement therapy (RRT). The aim of this study is to investigate if the urinary response to a single intraoperative dose of intravenous furosemide predicts delayed graft function (DGF) in patients undergoing deceased donor kidney transplant. RESULTS: On an adjusted multiple logistic regression, a single 100 mg dose of intraoperative furosemide after the anastomosis of the renal vessels (FST) predicted the need for RRT at 2 and 6 h post kidney transplantation (KT). Recipient urinary output was measured at 2 and 6 h post furosemide administration. In receiver-operating characteristic (ROC) analysis, the FST predicted DGF with an area-under-the curve of 0.85 at an optimal urinary output cut-off of

The concept of osmotic stability during renal replacement therapy has received limited attention thus far. We report an illustrative case of a previously healthy 22 year old male presenting after prolonged ventricular fibrillation with 75 minutes of resuscitative efforts before regaining spontaneous perfusing rhythm. Central nervous system protecting hypothermia protocol and veno-arterious (VA) extracorporeal membrane oxygenator (ECMO) therapy were initiated at hospital admission due to refractory hypoxemia. Cardiovascular imaging procedures described global hypokinesis. Due to the combination of anuria, mixed acidosis and hemodynamic instability, we started continuous renal replacement therapy (CRRT) in continuous veno-venous hemodiafiltration functionality with added hypertonic saline solution (HTS) protocol, calculated to stabilize his serum sodium between 148 and 150 mEq/L. Serum osmolality also ranged between 321 and 317 mOsm/kg thereafter. Course was complicated by an acute right leg ischemia distal to VA ECMO cannula placement, requiring salvage therapy with cryoamputation. Vasoactive medication requirement and hemodynamics improved after the addition of intravenous (IV) hydrocortisone. Brain magnetic resonance imaging (MRI) 22 days post-arrest showed signals of limited hypoxic injury. He left the hospital in stable condition with limited neurologic sequelae. Therefore, the use of HTS during CRRT is a viable way to address potential or manifest cerebral edema and reduce the degree of cerebral injury.

Acceptance of organs from acute chemical intoxicated donors remains controversial and outcomes are insufficiently explored.This is a single-center retrospective cohort analysis of 484 patients undergoing deceased donor kidney transplantation (DDKT). We assessed the association of positive urine drug screen before transplantation with cohort statistics, delayed graft function (DGF), and graft outcomes at 2 years. Multiple logistical regression (MLR) analysis was used to assess the odds ratio for DGF.Of 484 random DDKTs performed at our institution between January 2010 and October 2015, 280 deceased kidney donors were current drug users. Mean age was 35.4 (15) years, 39% male, 61% were African Americans, and 38.2% had more than one test positive. The main chemical toxins detectable in donor urine were alcohol, heroin, opioid/methadone, cocaine, marijuana, benzodiazepines, methamphetamine, ecstasy, and LSD. Single and multiple urine chemical toxicology of kidney donors did not have a significant effect on KT outcomes of DGF and graft failure during a median follow-up (P for odds ratios 0.05).The use of deceased donor kidney grafts from donors with positive urine chemical toxicology may be a worthwhile method of increasing the availability of scarce donor kidney organs as such exposure to illicit drug(s) is not associated with major adverse transplant outcomes.

PURPOSE: To validate the furosemide stress test (FST) for predicting the progression of acute kidney injury (AKI). MATERIALS AND METHODS: We performed a multicenter, prospective, observational study in patients with stage I or II AKI. The FST (1mg/kg for loop diuretic naïve patients and 1.5mg/kg in patients previously exposed to loop diuretics) was administered. Subsequent urinary flow rate (UFR) recorded and predictive ability of urinary output was measured by the area under the curve receiver operatic characteristics AuROC). Primary outcome was progression to Stage III AKI. Secondary outcomes included in-hospital mortality and adverse events. RESULTS: We studied 92 critically ill patients. 23 patients progressed to stage III AKI and had significantly lower UFR (p

Acute kidney injury (AKI) is a common and serious complication that is associated with several adverse outcomes in hospitalized patients. AKI significantly increases the risk of mortality, need for renal replacement therapy, and intensive care admission, and it also has serious economic ramifications. Effective risk stratification to identify patients at risk for severe AKI is essential for targeting our health care and research resources to tackle this important public health issue. The overwhelming majority of research in earlier diagnosis and risk stratification of AKI over the past 10 years has focused on novel biomarker development. The purpose of this review is to provide an update on other novel risk stratification tools than can be used in the prognostication of AKI. We discuss the utility of the furosemide stress test in predicting the severity of AKI and the renal angina index in predicting the occurrence of AKI. We also discuss NephroCheck, a prognostic test that measures tissue inhibitor of metalloproteinase-2 and insulin-like growth factor binding protein 7 for the early detection of severe AKI.

This chapter discusses the clinical implications of using different dialysate sodium concentrations when performing intermittent hemodialysis. How to safely manage patients with different degrees of hyponatremia and hypernatremia using intermittent hemodialysis is described. The factors that influence potassium removal during intermittent hemodialysis are reviewed. The effects of different dialysate calcium concentrations on patients' electrolyte abnormalities and hemodynamics are examined. The procedure for adjusting dialysate bicarbonate concentration to manage acid-base abnormalities and to understand its effects on serum calcium and potassium concentrations is detailed.

Background Linkage to the US Renal Data System (USRDS) registry commonly is used to identify end-stage renal disease (ESRD) cases, or kidney failure treated with dialysis or transplantation, but it underestimates the total burden of kidney failure. This study validates a kidney failure definition that includes both kidney failure treated and not treated by dialysis or transplantation. It compares kidney failure risk factors and outcomes using this broader definition with USRDS-identified ESRD risk factors and outcomes. Study Design Diagnostic test study with stratified random sampling of hospitalizations for chart review. Setting & Participants Atherosclerosis Risk in Communities Study (n=11,530; chart review, n=546). Index Test USRDS-identified ESRD; treated or untreated kidney failure defined by USRDS-identified ESRD or International Classification of Diseases, Ninth or Tenth Revision, Clinical Modification (ICD-9-CM/ICD-10-CM) code for hospitalization or death. Reference Test For ESRD, determination of permanent dialysis therapy or transplantation; for kidney failure, determination of permanent dialysis therapy, transplantation, or estimated glomerular filtration rate Results During 13 years' median follow-up, 508 kidney failure cases were identified, including 173 (34.1%) from the USRDS registry. ESRD and kidney failure incidence were 1.23 and 3.66 cases per 1,000 person-years in the overall population and 1.35 and 6.59 cases per 1,000 person-years among participants older than 70 years, respectively. Other risk-factor associations were similar between ESRD and kidney failure, except diabetes and albuminuria, which were stronger for ESRD. Survivals at 1 and 5 years were 74.0% and 24.0% for ESRD and 59.8% and 31.6% for kidney failure, respectively. Sensitivity and specificity were 88.0% and 97.3% comparing the kidney failure ICD-9-CM/ICD-10-CM code algorithm to chart review; for USRDS-identified ESRD, sensitivity and specificity were 94.9% and 100.0%. Limitations Some medical charts were incomplete. Conclusions A kidney failure definition including treated and untreated disease identifies more cases than linkage to the USRDS registry alone, particularly among older adults. Future studies might consider reporting both USRDS-identified ESRD and a more inclusive kidney failure definition.

INTRODUCTION: Human immunodeficiency virus (HIV) remains a worldwide disease with significant mortality and morbidity. There are a multitude of HIV-related kidney diseases including HIV-associated nephropathy (HIVAN) most prominently. The risk of developing HIVAN increases with decreasing CD4 count, higher viral load, and based on genetic factors. The mortality rate for those with HIVAN-end stage renal disease (ESRD) remains 2.5–3 times higher than ESRD patient without HIVAN. AREAS COVERED: The epidemiology of HIVAN, particularly risk assessment will be explored in this review. Further, the pathogenesis of HIVAN, from viral-specific renal expression to the role of genetics as well as characteristic renal pathology will be described. Diagnosis and treatment of HIVAN focusing on ESRD progression, will be addressed with an emphasis on various treatment strategies, including medication, dialysis, and kidney transplantation. EXPERT OPINION: HIVAN is associated with a high risk for progression to ESRD and increased mortality. The backbone of HIVAN therapy remains cART, while adjunctive therapies including RAAS blockade and prednisone, should be considered. In those who progress to ESRD, dialysis remains the mainstay of management, though increasing evidence has demonstrated that kidney transplantation can be effective in those with controlled HIV disease.

Rationale: Tenofovir alafenamide (TAF) is novel prodrug of Tenofovir, a nucleotide reverse transcriptase inhibitor. TAF is less nephrotoxic than its predecessor prodrug, tenofovir disoproxil fumarate (TDF). Tenofovir causes mitochondrial dysfunction and tubular injury when there is elevated accumulation in proximal tubule cells. TAF's unique pharmacokinetic profile enables provision of lower required doses for antiviral efficacy. Lower concentrations reach renal tubules minimizing intracellular accumulation and mitochondrial damage. TAF has not been associated with the histologic markers of tenofovir-associated nephrotoxicity that are seen with TDF, such as dysmorphic mitochondria in proximal tubule cells. Here, we report a patient with dysmorphic mitochondria on kidney biopsy after initiating therapy with TAF. Lessons: This case suggests that at risk individuals may experience tubular mitochondrial injury from lower concentrations of tenofovir with TAF.

Lipoxins (LX) are endogenously produced eicosanoids with a spectrum of bioactions that suggest anti-inflammatory, pro-resolution roles for these agents. Mesangial cell (MC) proliferation plays a pivotal role in the pathophysiology of glomerular inflammation and is coupled to sclerosis and tubulointerstitial fibrosis. We have previously reported that LXA4 acts through a specific G-protein-coupled-receptor (GPCR) to modulate MC proliferation in response to the proinflammatory mediators LTD4 and platelet-derived growth factor (PDGF). Further investigations revealed that these effects were mediated by modulation of receptor tyrosine kinase activity. Here we have explored the underlying mechanisms and report inhibition of growth factor (PDGF; epithelial growth factor) activation of Akt/PKB by LXA4. LXA4 (10 nmol/L) modulates PDGF-induced (10 ng/ml, 24 hours) decrements in the levels of cyclin kinase inhibitors p21Cip1 and p27Kip1. PDGF-induced increases in CDK2-cyclin E complex formation are also inhibited by LXA4. The potential of LXA4 as an anti-inflammatory therapeutic is compromised by its degradation; this has been circumvented by synthesis of stable analogs. We report that 15-(R/S)-methyl-LXA4 and 16-phenoxy-LXA4 mimic the native compound with respect to modulation of cell proliferation and PDGF-induced changes in cell cycle proteins. In vivo, MC proliferation in response to PDGF is associated with TGFbeta1 production and the subsequent development of renal fibrosis. Here we demonstrate that prolonged (24 to 48 hours) exposure to PDGF is associated with autocrine TGFbeta1 production, which is significantly reduced by LXA4. In aggregate these data demonstrate that LX inhibit PDGF stimulated proliferation via modulation of the PI-3-kinase pathway preventing mitogen-elicited G1-S phase progression and suggest the therapeutic potential of LX as anti-fibrotic agents.

Over the past decade, compelling in vivo and in vitro studies have highlighted lipoxins (LXs) and aspirin-triggered LXs (ATLs) as endogenously produced anti-inflammatory eicosanoids. LXs and ATLs elicit distinct anti-inflammatory and proresolution bioactions that include inhibition of leukocyte-mediated injury, stimulation of macrophage clearance of apoptotic neutrophils, repression of proinflammatory cytokine production, modulation of cytokine-stimulated metalloproteinase activity, and inhibition of cell proliferation and migration. An overview of recent advances in LX physiology is provided, with particular emphasis on the cellular and molecular processes involved. These data coupled with in vivo models of inflammatory diseases suggest that LX bioactions may be amenable to pharmacological mimicry for therapeutic gain.

The optimal management of cancer in patients with severe heart failure is not defined. This issue is particularly challenging when a diagnosis of limited-stage small cell lung cancer (SCLC) is made incidentally in the context of evaluating patient for candidacy for cardiac transplantation. Limited-stage SCLC is typically managed on a curative therapeutic paradigm with combined modality approach involving chemotherapy and radiation. Even with excellent performance status and good organ function, the presence of severe cardiomyopathy poses significant challenges to the delivery of even single modality approach with chemotherapy or radiotherapy, let alone the typical curative combined modality approach. With mechanical left ventricular devices to provide cardiac support, treatment options for cancer in the setting of advanced heart failure may be improved. Here we discuss the therapeutic dilemma involving a patient with severe cardiomyopathy and left ventricular assistant device (LVAD) who was found to have limited-stage SCLC during the evaluation process for cardiac transplantation.

Liver fatty acid-binding protein (L-FABP) binds selectively to intracellular free unsaturated fatty acids and lipid peroxidation products during hypoxic tissue injury. Urinary L-FABP is a potential biomarker for the detection and assessment of acute kidney injury (AKI). Ferguson et al. have demonstrated in a cross-sectional study that urinary L-FABP is an excellent biomarker of AKI and may be useful in predicting dialysis-free survival. This study did not assess utility for early diagnosis of AKI.

The lipoxygenase-derived eicosanoids leukotrienes and lipoxins are well defined regulators of hemeodynamics and leukocyte recruitment in inflammatory conditions. Here, we describe a novel bioaction of lipoxin A4(LXA4), namely inhibition of leukotriene D4 (LTD4)-induced human renal mesangial cell proliferation, and investigate the signal transduction mechanisms involved. LXA4 blocked LTD4-stimulated phosphatidylinositol 3-kinase (PI 3-kinase) activity in parallel to inhibition of LTD4-induced mesangial cell proliferation. Screening of a human mesangial cell cDNA library revealed expression of the recently described cys-leukotriene1/LTD4 receptor. LTD4-induced mesangial cell proliferation required both extracellular-related signal regulated kinase (erk) and PI 3-kinase activation and may involve platelet-derived growth factor receptor transactivation. LTD4-stimulated the MAP kinases erk and p38 via a pertussis toxin (PTX)-sensitive pathway dependent on PI 3-kinase and protein kinase C activation. On screening a cDNA library, mesangial cells were found to express the previously described LXA4 receptor. In contrast to LTD4, LXA4 showed differential activation of erk and p38. LXA4 activation of erk was insensitive to PTX and PI 3-kinase inhibition, whereas LXA4 activation of p38 was sensitive to PTX and could be blocked by the LTD4 receptor antagonist SKF 104353. These data suggest that LXA4stimulation of the MAP kinase superfamily involves two distinct receptors: one shared with LTD4 and coupled to a PTX-sensitive G protein (Gi) and a second coupled via an alternative G protein, such as Gq or G12, to erk activation. These data expand on the spectrum of LXA4bioactions within an inflammatory milieu.

Background In epidemiologic research, incident chronic kidney disease (CKD) commonly is determined by laboratory tests performed at planned study visits. Given the morbidity and mortality associated with CKD, persons with incident disease may be less likely to attend scheduled visits, affecting observed associations. The objective of this study was to quantify loss to follow-up by CKD status and determine whether supplementation with diagnostic code data improves capture of incident CKD. Study Design Prospective cohort study. Setting & Participants 11,560 participants in the Atherosclerosis Risk in Communities (ARIC) Study underwent continuous surveillance for hospitalizations and death from baseline visit (1996-1999) to follow-up visit (2011-2013). A subset of hospitalizations in Washington County, MD, was used in diagnostic code validation (n=2,540). Predictor Baseline demographics and comorbid conditions. Outcomes Incident CKD stage 3 ascertained by follow-up visit (visit-based definition) or hospitalization surveillance (hospitalization-based definition). Measurements Visit-based definition: ≥25% decline from baseline estimated glomerular filtration rate to 2 at follow-up visit; hospitalization-based definition: hospitalization CKD diagnostic code. Results Of 11,560 participants, 5,951 attended the follow-up visit and 9,264 were hospitalized. Never-hospitalized participants were younger, more often female, and had fewer comorbid conditions; 73.5% attended the follow-up visit. Incident CKD stage 3 occurred in 1,172 participants by the visit-based definition (251 were never hospitalized) and 1,078 participants by the hospitalization-based definition (237 attended the follow-up study visit). Sensitivity of the hospitalization-based CKD definition was 35.5% (95%CI, 31.6%-39.7%); specificity was 95.7% (95%CI, 94.2%-96.8%). Sensitivity was higher with later time period, older participant age, and baseline prevalent diabetes and CKD. Limitations A subset of hospitalizations was used for validation; 15-year gap between study visits. Conclusions The sensitivity of diagnostic code−identified CKD is low and varies by certain factors; however, supplementing a visit-based definition with hospitalization information can increase disease identification during periods of follow-up without study visits.

Renal dysfunction in association with congestive heart failure (CHF) is common, both chronically (chronic kidney disease, CKD) and in the setting of acute decompensated heart failure. Acute kidney injury (AKI) occurs in up to 20–45 % of admissions for acute heart failure [1, 2], and is associated with increased short- and long-term mortality and morbidity. Thus, there is a need to develop improved biomarkers of early renal injury and function to guide the management of patients with CHF, reduce adverse renal events, and improve outcomes.

A focused review of the nature, source, physiological role and rapidly expanding evidence for glutathione S-transferase (GST) subtypes π and α as biomarkers of acute kidney injury (AKI) in patients undergoing cardiac surgery. Expanded insights into the site-specific expression of the GSTs in defined parts of the nephron during renal damage are presented, with particular emphasis on the pathogenesis of cardiac surgery and cardiopulmonary bypass (CPB)-associated AKI and the role of GSTs in oxygen radical disposal.Recent developments have highlighted a potential role of urinary α-GST and π-GST in the diagnostic evaluation of cardiac surgery-associated AKI. Both urinary α-GST and π-GST are detected in the postoperative period. π-GST performed best at predicting AKI severity at the time of the initial diagnosis of AKI. α-GST was able to predict the future development of both stage 1 and stage 3 AKI.The current data from a small number of patients suggest a potential role of urinary GSTs in the clinical diagnostic evaluation of AKI following cardiac surgery. The performance of the GSTs for the early diagnosis of AKI needs to be validated in larger multicentre studies and in other patient populations at increased risk of AKI (e.g. patients with acute transplant rejection, septic patients). Comparison with other emerging AKI biomarkers is required to continue the development of π-GST and α-GST. Finally, additional studies examining the pathophysiological role of the GSTs in minimizing oxygen free radical exposure in the renal tubules during CPB may shed further light into their role as promising biomarkers of cardiac surgery-associated AKI.

Immunoglobulin type gamma 4 (IgG4)-related disease is a relatively newly described clinical entity characterized by a distinctive histopathological appearance, increased numbers of IgG4 positive plasma cells and often, but not always, elevated serum IgG4 concentrations. The most common renal manifestation of IgG4-related disease is tubulointerstitial nephritis marked with proteinuria, hematuria, decreased kidney function, hypocomplementemia, and radiologic abnormalities. Renal biopsy characteristics include dense lymphoplasmacytic tubulointerstitial nephritis that stains for IgG4, storiform fibrosis, and immune complex deposition in the interstitium and along tubule basement membranes. Treatment traditionally consists of prolonged glucocorticoids but cases refractory to glucocorticoids have been reported. We report a case of a 58-year-old Caucasian man who presented with fatigue, 50 pound weight loss, dyspnea, lymphadenopathy, and nephromegaly. The patient was first misdiagnosed as chronic interstitial nephritis secondary to renal sarcoid and was treated with repeated doses of prednisone. On his third relapse, he underwent a repeat renal biopsy and a diagnosis of IgG4-tubulointerstitial nephritis was confirmed. He was refractory to treatment with prednisone. The patient received Rituximab and had prompt sustained improvement in renal function. At 1 year post Rituximab treatment, his serum creatinine remains at baseline and imaging study revealed reduction in his kidney size. This is the first case report using Rituximab as a steroid sparing option for refractory IgG4-tubulointerstitial nephritis. More information is needed on the long-term effects of using of B-cell depleting agents for glucocorticoid resistant IgG4-tubulointerstitial nephritis.

Microarray and bioinformatic detection of novel and established genes expressed in experimental anti-Thy1 nephritis. Background Microarray technology is a powerful tool that can probe the molecular pathogenesis of renal injury. In this present study microarray analysis was used to monitor serial changes in the renal transcriptome of a rat model of mesangial proliferative glomerulonephritis. Administration of anti-Thy1 antibody results in phases of acute mesangial injury (day 2), cell proliferation (day 5), matrix expansion (days 5 and 7), and subsequent healing (day 14). Methods Using Affymetrix (RAE230A) microarrays coupled with sequential primary biologic function-focused and secondary "baited" global cluster analysis, a cohort of established and putative novel modulators of mesangial cell turnover was identified. Results Cluster analysis of proliferative genes identified a number of gene expression profiles. The most striking pattern was increased gene expression at day 5, a cluster that included platelet-derived growth factor (PDGF), cyclins and transforming growth factor-β (TGF-β). The gene expression patterns identified by primary focused cluster analysis were used as bioinformatic bait and resulted in the identification of novel families of genes such as the S100 family. The expression of established and novel genes was confirmed using reverse transcription-polymerase chain reaction (RT-PCR). Next, in vivo gene expression was compared to PDGF-stimulated mesangial cells in vitro revealing similar patterns of dysregulation. Conclusion Transcriptomic analysis defined both known and novel molecules involved in mesangial cell proliferation in vitro and in vivo and defined a panel of molecules that are potential contributors to mesangial cell dysfunction in glomerular disease.

Lipoxins (LXs), endogenously produced eicosanoids, possess potent anti-inflammatory, pro-resolution bioactivities. We investigated the potential of LXA(4) (1 to 10 nmol/L) to modify the effects of platelet-derived growth factor (PDGF)-induced gene expression in human renal mesangial cells (hMCs). Using oligonucleotide microarray analysis we profiled pro-fibrotic cytokines and matrix-associated genes induced in response to PDGF. LXA(4) modulated the expression of many PDGF-induced genes, including transforming growth factor-beta1, fibronectin, thrombospondin, matrix metalloproteinase 1, and several collagens. Analysis of both transcript and protein levels confirmed these findings. Because the activated glomerulus is frequently a source of injurious mediators that contribute to tubulointerstitial damage, we investigated the effect of hMC-secreted products on the integrity of renal proximal tubular epithelial cells using an in vitro model of progressive renal disease. Cell supernatant from PDGF-stimulated hMCs caused morphological and genetic changes in proximal tubular epithelial cells, consistent with a pro-fibrotic phenotype. Interestingly, supernatant from cells pre-exposed to LXA(4) and PDGF did not induce these effects. These results suggest a novel role for LXA(4) as a potent modulator of matrix accumulation and pro-fibrotic change and suggest a potential protective role in progressive renal disease.

The lipoxygenase-derived leukotrienes (LTs) are important proinflammatory lipid mediators. Lipoxins (LXs), more recently described lipoxygenase products, modulate many proinflammatory actions of LTs and have impressive proresolution properties. Mesangial cell (MC) proliferation is a central event in the pathogenesis of glomerulonephritis. LTD4-induced proliferation of mesangial cells is modulated by LXA4. Here, we demonstrate that LXA4 inhibits PDGF- and LTD4-stimulated proliferation through modulation of platelet-derived growth factor receptor beta (PDGFRbeta) activation. Specifically, we demonstrate that LTD4 transactivates the PDGFRbeta, a process associated with c-src recruitment and ras activation. We demonstrate expression of cysLT1 and cysLT2 receptors in MCs. LTD4-induced c-src activation was insensitive to pertussis toxin and the cysLT1 receptor antagonist Zafirlukast but was blocked by the nonselective antagonist Pobilukast. We show that LXA4 inhibits LTD4-stimulated activation of the PDGFRbeta and that LXA4 modulates PDGF-BB-stimulated tyrosine phosphorylation of the PDGFRb and subsequent mitogenic events. Furthermore, expression of recombinant LXA4 receptor (ALXR) in CHOK1 cells was associated with an attenuation of serum-stimulated proliferation. These data demonstrate that LXA4 receptor (ALXR) activation is accompanied by antimitogenic effects coupled with inactivation of growth factor receptors, highlighting the complex cross-talk between G protein-coupled receptors and receptor tyrosine kinases in an inflammatory milieu. These data elaborate on the profile of cell signaling events that underpin the anti-inflammatory and proresolution bioactions of LX.

Lipoxins (LXs) are endogenously produced eicosanoids typically generated during cell–cell interactions. In this article, the compelling evidence from in vitro and in vivo model systems that LXs actively promote the resolution of inflammation is reviewed. Of particular interest are indications that stable synthetic analogues of LXs and aspirin-triggered 15-epi-LXs can mimic many of the desirable anti-inflammatory, ‘pro-resolution' actions of native LXs. Given the enhanced stability and efficacy of these compounds a role as novel anti-inflammatory therapeutics is proposed.