15-Lipoxygenase worsens renal fibrosis, inflammation, and metabolism in a murine model of ureteral obstruction.

15-Lipoxygenase (15-LO) is a nonheme iron-containing dioxygenase that has both pro- and anti-inflammatory roles in many tissues and disease states. 15-LO is thought to influence macrophage phenotype, and silencing 15-LO reduces fibrosis after acute inflammatory triggers. The goal of the present study was to determine whether altering 15-LO expression influences inflammation and fibrogenesis in a murine model of unilateral ureteral obstruction (UUO). C57BL/6J mice, 15-LO knockout (Alox15-/-) mice, and 15-LO transgenic overexpressing (15LOTG) mice were subjected UUO, and kidneys were analyzed at 3, 10, and 14 days postinjury. Histology for fibrosis, inflammation, cytokine quantification, flow cytometry, and metabolomics were performed on injured tissues and controls. PD146176, a specific 15-LO inhibitor, was used to complement experiments involving knockout animals. Compared with wild-type animals undergoing UUO, Alox15-/- mouse kidneys had less proinflammatory, profibrotic message along with less fibrosis and macrophage infiltration. PD146176 inhibited 15-LO and resulted in reduced fibrosis and macrophage infiltration similar to Alox15-/- mice. Flow cytometry revealed that Alox15-/- UUO-injured kidneys had a dynamic change in macrophage phenotype, with an early blunting of CD11bHiLy6CHi "M1" macrophages and an increase in anti-inflammatory CD11bHiLy6CInt "M2c" macrophages and reduced expression of the fractalkine receptor chemokine (C-X3-C motif) receptor 1. Many of these findings were reversed when UUO was performed on 15LOTG mice. Metabolomics analysis revealed that wild-type kidneys developed a glycolytic shift postinjury, while Alox15-/- kidneys exhibited increased oxidative phosphorylation. In conclusion, 15-LO manipulation by genetic or pharmacological means induces dynamic changes in the inflammatory microenvironment in the UUO model and appears to be critical in the progression of UUO-induced fibrosis.NEW & NOTEWORTHY 15-Lipoxygenase (15-LO) has both pro- and anti-inflammatory functions in leukocytes, and its role in kidney injury and repair is unexplored. Our study showed that 15-LO worsens inflammation and fibrosis in a rodent model of chronic kidney disease using genetic and pharmacological manipulation. Silencing 15-LO promotes an increase in M2c-like wound-healing macrophages in the kidney and alters kidney metabolism globally, protecting against anaerobic glycolysis after injury.

PTEN (Phosphatase and Tensin Homolog) Protects Against Ang II (Angiotensin II)-Induced Pathological Vascular Fibrosis and Remodeling-Brief Report.

OBJECTIVE: Pathological vascular remodeling and excessive perivascular fibrosis are major contributors to reduced vessel compliance that exacerbates cardiovascular diseases, for instance, promoting clinically relevant myocardial remodeling. Inflammation plays a significant role in both pathological vascular remodeling and fibrosis. We previously demonstrated that smooth muscle cell-specific PTEN depletion promotes significant vascular fibrosis and accumulation of inflammatory cells. In the current study, we aimed to determine the beneficial role of systemic PTEN elevation on Ang II (angiotensin II)-induced vascular fibrosis and remodeling. Approach and Results: Transgenic mice carrying additional copies of the wild-type Pten gene (super PTEN [sPTEN]) and WT littermates were subjected to Ang II or saline infusion for 14 or 28 days. Compared with WT, Ang II-induced vascular fibrosis was significantly blunted in sPTEN mice, as shown by histochemical stainings and label-free second harmonic generation imaging. The protection against Ang II was recapitulated in sPTEN mice bearing WT bone marrow but not in WT mice reconstituted with sPTEN bone marrow. Ang II-induced elevation of profibrotic and proinflammatory gene expression observed in WT mice was blocked in aortic tissue of sPTEN mice. Immunofluorescent staining and flow cytometry both indicated that perivascular infiltration of T cells and macrophages was significantly inhibited in sPTEN mice. In vitro induction of PTEN expression suppressed Ang II-induced Ccl2 expression in vascular smooth muscle cells. CONCLUSIONS: Systemic PTEN elevation mediates protection against Ang II-induced vascular inflammation and fibrosis predominantly through effects in resident vascular cells. Our data highly support that pharmacological upregulation of PTEN could be a novel and viable approach for the treatment of pathological vascular fibrosis.

Inhibition of 5-lipoxygenase decreases renal fibrosis and progression of chronic kidney disease.

In inflammatory diseases, the 5-lipoxygenase (5-LO) pathway contributes to epithelial damage and fibrosis by catalyzing the production of leukotrienes (LTs). Antagonists of the 5-LO pathway are currently approved for use in patients and are well tolerated. We found that expression of 5-LO is strongly induced in three models of chronic kidney disease: unilateral ureteral obstruction (UUO), folate nephropathy, and an orthologous mouse model of polycystic kidney disease. Immunohistochemistry showed that macrophages are the dominant source of 5-LO. Zileuton, a US Food and Drug Administration-approved antagonist of 5-LO, significantly reduced fibrosis at 7 and 14 days after UUO; these findings were confirmed using a genetically modified [5-LO-associated protein-knockout ( Alox5ap-/-)] mouse strain. Inhibition of 5-LO did not appear to change infiltration of leukocytes after UUO as measured by flow cytometry. However, fluorescence-lifetime imaging microscopy showed that 5-LO inhibitors reversed the glycolytic switch in renal tubular epithelial cells after UUO. Two downstream enzymes of 5-LO, LTA4 hydrolase (LTA4H) and LTC4 synthase (LTC4S), are responsible for the synthesis of LTB4 and cysteinyl LTs, respectively. Fibrosis was reduced after UUO in Ltc4s-/-, but not Lta4h-/-, mice. In contrast, using the folate nephropathy model, we found reduced fibrosis and improved renal function in both Ltc4s-/- and Lta4h-/- mice. In summary, our studies suggest that manipulation of the 5-LO pathway may represent a novel treatment approach for chronic kidney disease.

Bone marrow-derived cPLA2α contributes to renal fibrosis progression.

The group IVA calcium-dependent cytosolic phospholipase A2 (cPLA2α) enzyme directs a complex "eicosanoid storm" that accompanies the tissue response to injury. cPLA2α and its downstream eicosanoid mediators are also implicated in the pathogenesis of fibrosis in many organs, including the kidney. We aimed to determine the role of cPLA2α in bone marrow-derived cells in a murine model of renal fibrosis, unilateral ureteral obstruction (UUO). WT C57BL/6J mice were irradiated and engrafted with donor bone marrow from either WT mice [WT-bone marrow transplant (BMT)] or mice deficient in cPLA2α (KO-BMT). After full engraftment, mice underwent UUO and kidneys were collected 3, 7, and 14 days after injury. Using picrosirius red, collagen-3, and smooth muscle α actin staining, we determined that renal fibrosis was significantly attenuated in KO-BMT animals as compared with WT-BMT animals. Lipidomic analysis of homogenized kidneys demonstrated a time-dependent upregulation of pro-inflammatory eicosanoids after UUO; KO-BMT animals had lower levels of many of these eicosanoids. KO-BMT animals also had fewer infiltrating pro-inflammatory CD45+CD11b+Ly6Chi macrophages and reduced message levels of pro-inflammatory cytokines. Our results indicate that cPLA2α and/or its downstream mediators, produced by bone marrow-derived cells, play a major role in eicosanoid production after renal injury and in renal fibrinogenesis.

CD8+ T cells modulate autosomal dominant polycystic kidney disease progression.

Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent inherited nephropathy. To date, therapies alleviating the disease have largely focused on targeting abnormalities in renal epithelial cell signaling. ADPKD has many hallmarks of cancer, where targeting T cells has brought novel therapeutic interventions. However, little is known about the role and therapeutic potential of T cells in ADPKD. Here, we used an orthologous ADPKD model, Pkd1 p.R3277C (RC), to begin to define the role of T cells in disease progression. Using flow cytometry, we found progressive increases in renal CD8+ and CD4+ T cells, correlative with disease severity, but with selective activation of CD8+ T cells. By immunofluorescence, T cells specifically localized to cystic lesions and increased levels of T-cell recruiting chemokines (CXCL9/CXCL10) were detected by qPCR/in situ hybridization in the kidneys of mice, patients, and ADPKD epithelial cell lines. Importantly, immunodepletion of CD8+ T cells from one to three months in C57Bl/6 Pkd1RC/RC mice resulted in worsening of ADPKD pathology, decreased apoptosis, and increased proliferation compared to IgG-control, consistent with a reno-protective role of CD8+ T cells. Thus, our studies suggest a functional role for T cells, specifically CD8+ T cells, in ADPKD progression. Hence, targeting this pathway using immune-oncology agents may represent a novel therapeutic approach for ADPKD.

A new CTGF target in renal fibrosis.

Lymphangiogenesis appears to accompany renal fibrosis, but signals that regulate the lymphangiogenic growth factor vascular endothelial growth factor C are not well understood. Kinashi et al. have shown that conditionally deleting connective tissue growth factor reduces renal fibrosis, vascular endothelial growth factor C, and lymphangiogenesis. Connective tissue growth factor has pleiotropic effects in the setting of renal fibrosis; this study adds a potentially new mechanism for the profibrotic effects of connective tissue growth factor.

Cytosolic phospholipase A2α increases proliferation and de-differentiation of human renal tubular epithelial cells.

The group IVA calcium-dependent cytosolic phospholipase A2 (cPLA2α) enzyme controls the release of arachidonic acid from membrane bound phospholipids and is the rate-limiting step in production of eicosanoids. A variety of different kidney injuries activate cPLA2α, therefore we hypothesized that cPLA2α activity would regulate pathologic processes in HK-2 cells, a human renal tubular epithelial cell line, by regulating cell phenotype and proliferation. In two lentiviral cPLA2α-silenced knockdowns, we observed decreased proliferation and increased apoptosis compared to control HK-2 cells. cPLA2α-silenced cells also demonstrated an altered morphology, had increased expression E-cadherin, and decreased expression of Ncadherin. Increased levels of E-cadherin were associated with increased promoter activity and decreased levels of SNAIL1, SNAIL2, and ZEB1, transcriptional repressors of E-cadherin expression. Addition of exogenous arachidonic acid, but not PGE2, reversed the phenotypic changes in cPLA2α-silenced cells. These data suggest that cPLA2α may play a key role in renal repair after injury through a PGE2-independent mechanism.

Activation of the retinoid X receptor modulates angiotensin II-induced smooth muscle gene expression and inflammation in vascular smooth muscle cells.

The retinoid X receptor (RXR) partners with numerous nuclear receptors, such as the peroxisome proliferator activated receptor (PPAR) family, liver X receptors (LXRs), and farnesoid X receptor (FXR). Although each heterodimer can be activated by specific ligands, a subset of these receptors, defined as permissive nuclear receptors, can also be activated by RXR agonists known as rexinoids. Many individual RXR heterodimers have beneficial effects in vascular smooth muscle cells (SMCs). Because rexinoids can potently activate multiple RXR pathways, we hypothesized that treating SMCs with rexinoids would more effectively reverse the pathophysiologic effects of angiotensin II than an individual heterodimer agonist. Cultured rat aortic SMCs were pretreated with either an RXR agonist (bexarotene or 9-cis retinoic acid) or vehicle (dimethylsulfoxide) for 24 hours before stimulation with angiotensin II. Compared with dimethylsulfoxide, bexarotene blocked angiotensin II-induced SM contractile gene induction (calponin and smooth muscle-α-actin) and protein synthesis ([(3)H]leucine incorporation). Bexarotene also decreased angiotensin II-mediated inflammation, as measured by decreased expression of monocyte chemoattractant protein-1 (MCP-1). Activation of p38 mitogen-activated protein (MAP) kinase but not extracellular signal-related kinase (ERK) or protein kinase B (Akt) was also blunted by bexarotene. We compared bexarotene to five agonists of nuclear receptors (PPARα, PPARγ, PPARδ, LXR, and FXR). Bexarotene had a greater effect on calponin reduction, MCP-1 inhibition, and p38 MAP kinase inhibition than any individual agonist. PPARγ knockout cells demonstrated blunted responses to bexarotene, indicating that PPARγ is necessary for the effects of bexarotene. These data demonstrate that RXR is a potent modulator of angiotensin II-mediated responses in the vasculature, partially through inhibition of p38.

Immune checkpoint activity regulates polycystic kidney disease progression.

Innate and adaptive immune cells modulate the severity of autosomal dominant polycystic kidney disease (ADPKD), a common kidney disease with inadequate treatment options. ADPKD has parallels with cancer, in which immune checkpoint inhibitors have been shown to reactivate CD8+ T cells and slow tumor growth. We have previously shown that in PKD, CD8+ T cell loss worsens disease. This study used orthologous early-onset and adult-onset ADPKD models (Pkd1 p.R3277C) to evaluate the role of immune checkpoints in PKD. Flow cytometry of kidney cells showed increased levels of programmed cell death protein 1 (PD-1)/cytotoxic T lymphocyte associated protein 4 (CTLA-4) on T cells and programmed cell death ligand 1 (PD-L1)/CD80 on macrophages and epithelial cells in Pkd1RC/RC mice versus WT, paralleling disease severity. PD-L1/CD80 was also upregulated in ADPKD human cells and patient kidney tissue versus controls. Genetic PD-L1 loss or treatment with an anti-PD-1 antibody did not impact PKD severity in early-onset or adult-onset ADPKD models. However, treatment with anti-PD-1 plus anti-CTLA-4, blocking 2 immune checkpoints, improved PKD outcomes in adult-onset ADPKD mice; neither monotherapy altered PKD severity. Combination therapy resulted in increased kidney CD8+ T cell numbers/activation and decreased kidney regulatory T cell numbers correlative with PKD severity. Together, our data suggest that immune checkpoint activation is an important feature of and potential novel therapeutic target in ADPKD.

SDF-1α induction in mature smooth muscle cells by inactivation of PTEN is a critical mediator of exacerbated injury-induced neointima formation.

OBJECTIVE: PTEN inactivation selectively in smooth muscle cells (SMC) initiates multiple downstream events driving neointima formation, including SMC cytokine/chemokine production, in particular stromal cell-derived factor-1α (SDF-1α). We investigated the effects of SDF-1α on resident SMC and bone marrow-derived cells and in mediating neointima formation. METHODS AND RESULTS: Inducible, SMC-specific PTEN knockout mice (PTEN iKO) were bred to floxed-stop ROSA26-ß-galactosidase (ßGal) mice to fate-map mature SMC in response to injury; mice received wild-type green fluorescent protein-labeled bone marrow to track recruitment. Following wire-induced femoral artery injury, ßGal(+) SMC accumulated in the intima and adventitia. Compared with wild-type, PTEN iKO mice exhibited massive neointima formation, increased replicating intimal and medial ßGal(+)SMC, and enhanced vascular recruitment of bone marrow cells following injury. Inhibiting SDF-1α blocked these events and reversed enhanced neointima formation observed in PTEN iKO mice. Most recruited green fluorescent protein(+) cells stained positive for macrophage markers but not SMC markers. SMC-macrophage interactions resulted in a persistent SMC inflammatory phenotype that was dependent on SMC PTEN and SDF-1α expression. CONCLUSION: Resident SMC play a multifaceted role in neointima formation by contributing the majority of neointimal cells, regulating recruitment of inflammatory cells, and contributing to adventitial remodeling. The SMC PTEN-SDF-1α axis is a critical regulator of these events.

Mechanisms of type I and type II pseudohypoaldosteronism.

Pseudohypoaldosteronism (PHA) types I and II are curious genetic disorders that share hyperkalemia as a predominant finding. Together they have become windows to understanding new molecular physiology in the kidney. Autosomal recessive PHAI results from mutations in the epithelial sodium channel (ENaC), whereas autosomal dominant PHAI is characterized by mutations in the mineralocorticoid receptor. PHAII is the result of mutations in a family of serine-threonine kinases called with-no-lysine kinases (WNK)1 and WNK4. WNK4 negatively regulates the NaCl cotransporter (NCC), and PHAII mutations in WNK4 abrogate this affect. WNK4 also regulates the expression or function of renal outer medullary potassium (ROMK) channels, ENaCs, and Cl transporters. WNK1 also regulates NCC and ROMK. Aldosterone inactivates WNK1 and WNK4 activity. Whether angiotensin II can fine tune the actions of aldosterone is still unclear.

Targeted deletion of PTEN in smooth muscle cells results in vascular remodeling and recruitment of progenitor cells through induction of stromal cell-derived factor-1alpha.

We previously showed that changes in vascular smooth muscle cell (SMC) PTEN/Akt signaling following vascular injury are associated with increased SMC proliferation and neointima formation. In this report, we used a genetic model to deplete PTEN specifically in SMCs by crossing PTEN(LoxP/LoxP) mice to mice expressing Cre recombinase under the control of the SM22alpha promoter. PTEN was downregulated with increases in phosphorylated Akt in major vessels, hearts, and lungs of mutant mice. SMC PTEN depletion promoted widespread medial SMC hyperplasia, vascular remodeling, and histopathology consistent with pulmonary hypertension. Increased vascular deposition of the chemokine stromal cell-derived factor (SDF)-1alpha and medial and intimal cells coexpressing SM-alpha-actin and CXCR4, the SDF-1alpha receptor, was detected in SMC PTEN-depleted mice. PTEN deficiency in cultured aortic SMCs induced autocrine growth through increased production of SDF-1alpha. Blocking SDF-1alpha attenuated autocrine growth and blocked growth of control SMCs induced by conditioned media from PTEN-deficient SMCs. In addition, SMC PTEN deficiency enhanced progenitor cell migration toward SMCs through increased SDF-1alpha production. SDF-1alpha production by other cell types is regulated by the transcription factor hypoxia-inducible factor (HIF)-1alpha. We found SMC nuclear HIF-1alpha expression in PTEN-depleted mice and increased nuclear HIF-1alpha in PTEN-deficient SMCs. Small interfering RNA-mediated downregulation of HIF-1alpha reversed SDF-1alpha induction by PTEN depletion and inhibition of phosphatidylinositol 3-kinase signaling blocked HIF-1alpha and SDF-1alpha upregulation induced by PTEN depletion. Our data show that SMC PTEN inactivation establishes an autocrine growth loop and increases progenitor cell recruitment through a HIF-1alpha-mediated SDF-1alpha/CXCR4 axis, thus identifying PTEN as a target for the inhibition of pathological vascular remodeling.

PTEN deficiency promotes pathological vascular remodeling of human coronary arteries.

Phosphatase and tensin homolog (PTEN) is an essential regulator of the differentiated vascular smooth muscle cell (SMC) phenotype. Our goal was to establish that PTEN loss promotes SMC dedifferentiation and pathological vascular remodeling in human atherosclerotic coronary arteries and nonatherosclerotic coronary arteries exposed to continuous-flow left ventricular assist devices (CF-LVADs). Arteries were categorized as nonatherosclerotic hyperplasia (NAH), atherosclerotic hyperplasia (AH), or complex plaque (CP). NAH coronary arteries from CF-LVAD patients were compared to NAH coronaries from non-LVAD patients. Intimal PTEN and SMC contractile protein expression was reduced compared with the media in arteries with NAH, AH, or CP. Compared with NAH, PTEN and SMC contractile protein expression was reduced in the media and intima of arteries with AH and CP. NAH arteries from CF-LVAD patients showed marked vascular remodeling and reduced PTEN and α-smooth muscle actin (αSMA) in medial SMCs compared with arteries from non-LVAD patients; this correlated with increased medial collagen deposition. Mechanistically, compared with ApoE-/- mice, SMC-specific PTEN-null/ApoE-/- double-knockout mice exhibited accelerated atherosclerosis progression and increased vascular fibrosis. By microarray and validated quantitative RT-PCR analysis, SMC PTEN deficiency promotes a global upregulation of proinflammatory and profibrotic genes. We propose that PTEN is an antiinflammatory, antifibrotic target that functions to maintain SMC differentiation. SMC loss of PTEN results in pathological vascular remodeling of human arteries.

Selective inactivation of PTEN in smooth muscle cells synergizes with hypoxia to induce severe pulmonary hypertension.

BACKGROUND: Pulmonary vascular remodeling in pulmonary hypertension (PH) is characterized by increased vascular smooth muscle cell (SMC) and adventitial fibroblast proliferation, small vessel occlusion, and inflammatory cell accumulation. The underlying molecular mechanisms driving progression remain poorly defined. We have focused on loss of the phosphatase PTEN in SMCs as a major driver of pathological vascular remodeling. Our goal was to define the role of PTEN in human PH and in hypoxia-induced PH using a mouse model with inducible deletion of PTEN in SMCs. METHODS AND RESULTS: Staining of human biopsies demonstrated enhanced inactive PTEN selectively in the media from hypertensive patients compared to controls. Mice with induced deletion of PTEN in SMCs were exposed to normoxia or hypoxia for up to 4 weeks. Under normoxia, SMC PTEN depletion was sufficient to induce features of PH similar to those observed in wild-type mice exposed to chronic hypoxia. Under hypoxia, PTEN depletion promoted an irreversible progression of PH characterized by increased pressure, extensive pulmonary vascular remodeling, formation of complex vascular lesions, and increased macrophage accumulation associated with synergistic increases in proinflammatory cytokines and proliferation of both SMCs and nonSMCs. CONCLUSIONS: Chronic inactivation of PTEN selectively in SMC represents a critical mediator of PH progression, leading to cell autonomous events and increased production of factors correlated to proliferation and recruitment of adventitial and inflammatory cells, resulting in irreversible progression of the disease.

Inactivation of the tumour suppressor, PTEN, in smooth muscle promotes a pro-inflammatory phenotype and enhances neointima formation.

AIMS: Phosphatase and tensin homolog (PTEN) is implicated as a negative regulator of vascular smooth muscle cell (SMC) proliferation and injury-induced vascular remodelling. We tested if selective depletion of PTEN only in SMC is sufficient to promote SMC phenotypic modulation, cytokine production, and enhanced neointima formation. METHODS AND RESULTS: Smooth muscle marker expression and induction of pro-inflammatory cytokines were compared in cultured SMC expressing control or PTEN-specific shRNA. Compared with controls, PTEN-deficient SMC exhibited increased phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signalling and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) activity, reduced expression of SM markers (SM-alpha-actin and calponin), and increased production of stromal cell-derived factor-1alpha (SDF-1alpha), monocyte chemotactic protein-1 (MCP-1), interleukin-6 (IL-6), and chemokine (C-X-C motif) ligand 1 (KC/CXCL1) under basal conditions. PI3K/Akt or mTOR inhibition reversed repression of SM marker expression, whereas PI3K/Akt or NF-kappaB inhibition blocked cytokine induction mediated by PTEN depletion. Carotid ligation in mice with genetic reduction of PTEN specifically in SMC (SMC-specific PTEN heterozygotes) resulted in enhanced neointima formation, increased SMC hyperplasia, reduced SM-alpha-actin and calponin expression, and increased NF-kappaB and cytokine expression compared with wild-types. Lesion formation in SMC-specific heterozygotes was similar to lesion formation in global PTEN heterozygotes, indicating that inactivation of PTEN exclusively in SMC is sufficient to induce considerable increases in neointima formation. CONCLUSION: PTEN activation specifically in SMC is a common upstream regulator of multiple downstream events involved in pathological vascular remodelling, including proliferation, de-differentiation, and production of multiple cytokines.

New treatment options and protocols for peritoneal dialysis-related peritonitis.

Peritonitis remains a major complication in patients undergoing peritoneal dialysis. The most recent ISPD guidelines for the empiric initial treatment of peritonitis recommend the use of antibiotics that provide coverage against Gram-positive organisms (vancomycin or cefazolin) and Gram-negative organisms (a third-generation cephalosporin or an aminoglycoside). However, there are some situations in which this regimen may not be desirable. Concerns of resistant organisms, changing microbiology, drug toxicity, or difficulties administering therapy may lead a provider to modify the initial regimen. Drug resistant Staphylococcus aureus strains and Enterococcus strains may require administration of newer agents such as linezolid, quinipristin/dalfopristin, or daptomycin. Many centers have reported that, over time, the microbiology at those institutions has been changing. Some centers have reported a significant decrease in gram positive organisms and increase in extended spectrum beta-lactamase (ESBL) organisms. It is important for each center to examine its microbiology to document such trends. Although the currently recommended therapies have low toxicities, it is possible that concerns for untoward side effects in an individual patient may dictate changing the regimen. Finally, there is evidence from many prospective studies that monotherapy with different agents (oral quinolones or cefepime) is efficacious; if ease of therapy is a consideration, these may also be appropriate agents.

Beta-blockade in chronic dialysis patients.

Approximately 50% of the mortality in chronic dialysis patients is due to cardiovascular diseases (CVD). Cardiomyopathy, coronary artery disease, and arrhythmia are all common conditions and predispose to sudden death, which accounts for 60% of all cardiac deaths in this population. Despite advances in dialysis therapy, the mortality from CVD remains substantially unchanged, partly due to the lack of evidence-based strategies for improving the outcome of cardiac diseases in this population. Activation of the sympathetic adrenergic system is well documented in chronic dialysis patients and is likely involved in the pathogenesis of myocardial hypertrophy, coronary artery disease, heart failure, and arrhythmia. Given the proven benefit of beta-blockers in patients with normal kidney function with similar cardiac comorbidities, beta-blockers would seem to be attractive agents to reduce cardiovascular morbidity and mortality in the patient population with advanced chronic kidney disease. However, the value of beta-blockade in patients on chronic dialysis remains unclear. This uncertainty surrounding the efficacy is compounded by the risk of side effects to these patients, such as hypotension, bradycardia, and hyperkalemia. In addition, numerous studies have suggested suboptimal usage of beta-blockers in the dialysis population; this is seen even in high risk patients, such as those with established coronary artery disease. In this review, we will focus on sympathetic nervous system activation in kidney disease and highlight the benefit and risks of beta-blockers usage in the chronic dialysis patient population.