Morbidity and Mortality of Spinal Epidural Abscess in End-Stage Renal Disease Patients: A Case-Control Study.

BACKGROUND: Spinal epidural abscess (SEA) is an uncommon and highly morbid infection of the epidural space. End-stage renal disease (ESRD) patients are known to be at increased risk of developing SEA; however, there are no studies that have described the risk factors and outcomes of SEA in ESRD patients utilizing the United States Renal Data System (USRDS). METHODS: To determine risk factors, morbidity, and mortality associated with SEA in ESRD patients, a retrospective case-control study was conducted using the USRDS. ESRD patients diagnosed with SEA between 2005 and 2010 were identified, and logistic regression was performed to examine correlates of SEA, as well as risk factors associated with mortality in SEA-ESRD patients. RESULTS: The prevalence of SEA amongst ESRD patients was 0.39% (n = 1,697). Patients with SEA were more likely to be male [adjusted Odds Ratio (OR) = 1.22], black (OR = 1.19), diabetic (OR = 1.26), with catheter access (OR = 1.29), and less likely to be ≥65 years old (OR = 0.64). Osteomyelitis, bacteremia/septicemia, MRSA, and endocarditis were all significantly associated with increased risk of SEA (OR = 1.54-5.14). Age ≥65 years (HR = 1.45), urinary tract infections (HR = 1.26), decubitus ulcers (HR=1.37), and post-SEA paraplegia (HR = 1.25) were significantly associated with mortality among those with SEA. CONCLUSIONS: As described in previous literature, risk factors for SEA included infections, diabetes, and indwelling catheters. Additionally, clinicians should be aware of the risk factors for mortality in SEA-ESRD patients. As the largest study of SEA to date, our report identifies important risk factors for SEA in ESRD patients, and novel data regarding their mortality-associated risk factors.

Incidence, risk factors and distribution of syphilis in the end-stage renal disease population in the USA.

BACKGROUND: Syphilis is a sexually transmitted infection with an incidence of 14.9 cases per 100 000 persons in the USA in 2011. Untreated syphilis may remain quiescent for years but can also result in clinical sequelae, including neurosyphilis. End-stage renal disease (ESRD) patients may be at risk for syphilis due to a higher incidence of risk factors for the disease, including human immunodeficiency virus (HIV). Despite the presence of these risk factors, the incidence of syphilis in the ESRD population has not been reported. To address this issue, we investigated the incidence and risk factors for syphilis in the ESRD population using the United States Renal Data System (USRDS). METHODS: This study analyzed incident ESRD patients from 2004 to 2010. Based on International Classification of Diseases, Ninth Revision codes for syphilis, we determined the incidence and risk factors for syphilis following an inpatient diagnosis. Generalized linear modeling was used to examine the relative risk (RR) for the disease when controlling for demographic and other clinical risk factors. RESULTS: A total of 383 diagnoses of syphilis were identified after screening 759 066 patients. The 8-year incidence of any type of syphilis was 50.45 cases per 100 000 person-years. Other unspecified syphilis (29.77 cases per 100 000 person-years) and neurosyphilis (10.93 cases per 100 000 person-years) were the most common diagnoses. The greatest incidence was found on the East and West Coasts. Patients with the disease were younger and more likely to be black and non-Hispanic. In the final model, the adjusted RR for syphilis was significantly increased with HIV (7.61), hepatitis C (3.57), herpes simplex (2.06) and hepatitis B (1.75). CONCLUSIONS: The incidence of syphilis is >3-fold greater in ESRD patients when compared with the general population and is associated with sexually transmitted viral infections. Neurosyphilis is a common occurrence and is treatable, suggesting that all assessments of confusion in dialysis patients should include screening for the disease.

Efficacy of Implantable Cardioverter-defibrillators for Secondary Prevention of Sudden Cardiac Death in Patients with End-stage Renal Disease.

End-stage renal disease (ESRD) constitutes a major burden on the health-care system in the United States, with more than 300,000 patients nationwide being treated with renal replacement therapy. Very few studies to date have evaluated the benefit of implantable cardioverter-defibrillator (ICD) implantation for secondary prevention in patients with ESRD. In this study, we evaluated the efficacy of secondary-prevention ICDs in reducing all-cause mortality in patients on dialysis using the United States Renal Data System (USRDS) database. We queried the USRDS for relevant data between 2004 and 2010. Patients with diagnoses of ventricular fibrillation (VF), ventricular tachycardia (VT), or sudden cardiac arrest (SCA) were included in the study. Patients were excluded from the analysis if they were younger than 18 years; had missing age, sex, or race/ethnicity information; had experienced myocardial infarction; or had an ICD in situ at the time of VF, VT, or SCA diagnosis. The primary endpoint of this study was to determine the efficacy of secondary-prevention ICDs in reducing all-cause mortality in patients on dialysis. A total of 1,442 patients (3.4%) with ESRD had ICD insertion. Patients who received an ICD were predominantly younger, white males with lower Charlson Comorbidity Index and with fewer cardiovascular events. Survival at two years was 53% among those with an ICD relative to 27% among those without an ICD. In this study, we observed a substantial decrease in mortality in patients receiving an ICD for secondary prevention when compared with a cohort of similar patients with a history of VF, VT, or SCA.

Dietary Protein Source and Phosphate Levels in Patients on Hemodialysis.

OBJECTIVE: To determine the sources of protein and phosphorus levels from the food consumed by patients on dialysis. DESIGN AND METHODS: This is a retrospective, secondary data analysis of the Comprehensive Dialysis Survey study participants who had a baseline food frequency questionnaire and baseline lab data (N = 358). We examined intake of protein, phosphorus, and 7 other key nutrients from a subcohort of the Comprehensive Dialysis Survey based on the published National Kidney Foundation Kidney Dialysis Outcome Quality Initiative's nutrition recommendations. We studied the relationship of dietary protein source (plant or animal) with phosphorus intake using self-reported data from food frequency questionnaires. Variables included in final analysis are demographic, lab variables (albumin and prealbumin, alpha-1 acid glycoprotein, and C-reactive protein), and nutrition variables (calorie density, protein density, total fat, saturated fat, cholesterol, carbohydrates, phosphorus, calcium, sodium, potassium, plant-based protein, animal-based protein, and daily protein intake). RESULTS: Most of the patients had a lower than recommended consumption of calories, protein, phosphorus, and potassium while sodium, total, and saturated fats were overconsumed. Patients intake of dietary protein and calories was proportional to the amount of food consumed for both plant- and animal-based food. The levels of dietary protein and phosphorus were significantly (P < .05) lower in patients who primarily consumed a plant-based diet than in those who mainly consumed an animal-based diet. CONCLUSIONS: Consuming more plant-based protein as part of a varied diet could be nutritionally adequate while limiting intake of absorbable dietary phosphorus. More research in plant-based protein diets and their impact on patients with end-stage renal disease is needed.

Rheumatoid Arthritis and Mortality in End Stage Renal Disease.

OBJECTIVE: To determine whether rheumatoid arthritis (RA) is a risk factor for cardiovascular disease (CVD) events, all-cause mortality and cardiovascular mortality in End Stage Renal Disease (ESRD). METHODS: Cohort study of adult patients with ESRD in the United States Renal Data System (USRDS) with RA and a 5% random sample of those without RA. CVD events, all-cause mortality and cardiovascular mortality were determined in those with RA compared to those without RA using Cox Proportional Hazards modeling. RESULTS: 2,824 subjects, 407 with RA and 2,417 without RA, were included in the analyses. The duration of the study was up to 5 years, depending on mortality and initiation of dialysis. There were no significant differences in CVD events by RA status (n = 311 [76.4% RA] vs. n = 1936 [80.1% without RA], p = 0.09). Subjects with RA had a significantly shorter mean time in months from start of dialysis to an incident CVD event (20.1 ± 12.2 vs. 21.2 ± 14.1, p < 0.01) than those without RA. In multivariable adjusted models, RA was not associated with an increased risk for all-cause mortality (aHR = 1.09, 95%CI 0.94-1.27) or cardiovascular mortality (aHR = 0.95, 95% CI 0.74-1.22) within 5 years. Risk factors for all-cause mortality and cardiovascular mortality in RA included older age and a higher Charlson comorbidity index (CCI). CONCLUSIONS: Clinicians should be aware that persons with RA who develop ESRD incur cardiac events sooner than the general population. However, RA is not an independent risk factor for all-cause or cardiovascular mortality in ESRD.

Risk Factors Associated With Invasive Fungal Infections in Kidney Transplant Patients.

BACKGROUND: Kidney transplant recipients are at increased risk for developing invasive fungal infections (IFI). We queried the United States Renal Data System (USRDS) for risk factors for IFI in these patients. METHODS: Patients who underwent a kidney transplant between 2005 and 2008 were queried for an IFI diagnosis using ICD-9 codes. An IFI was defined as at least one documented diagnosis from one of the following: (1) Candida (candidemia); (2) Histoplasmosis; (3) Aspergillosis; (4) Cryptococcosis; (5) "Other" mycoses. Potential risk factors included demographics, certain comorbidities and immunosuppressive medications. To examine the relative risk (RR), simple bivariate models were used, followed by a comprehensive full model to estimate the adjusted RR (aRR). RESULTS: Of 57,188 kidney transplant patients, 1,218 had 1,343 IFI diagnoses, with a median time to infection of 495 days. "Other" mycoses accounted for the most IFI diagnoses (37%), followed by aspergillosis (22%). The risk for any IFI was increased with age ≥65 years. Diabetes (aRR = 1.71), bacterial pneumonia (aRR = 1.62) and UTI (aRR = 1.34) were the top 3 clinical risk factors for infection. Each of the IFI groups was also associated with individual risk factors. Therapy with mycophenolate mofetil was associated with a decreased risk of candidemia. CONCLUSIONS: Risk factors for IFI in renal transplant patients include demographic, medication-associated and clinical data, as well as organism-specific factors. These results offer an extensive clinical profile of risk for IFI, and may thus help inform the diagnosis and presumptive therapy of invasive fungal infections in renal transplant recipients.

Differential Expression of Prostaglandin E2 Receptors in Porcine Kidney Transplants.

BACKGROUND: Acute rejection of a kidney allograft results from adaptive immune responses and marked inflammation. The eicosanoid prostaglandin E2 (PGE2) modulates the inflammatory response, is generated by cyclooxygenase 2 (COX-2), and binds to 1 of the 4 G protein-coupled E prostanoid cell surface receptors (EP1-4). Receptor activation results in in proinflammatory (EP1 and EP3) or anti-inflammatory (EP2 and EP4) responses. We theorized that expression of the components of the COX-PGE2-EP signaling pathway correlates with acute rejection in a porcine model of allogeneic renal transplantation. METHOD: COX-2 enzyme and EP receptor protein expression were quantitated with western blotting and immunohistochemistry from allotransplants (n = 18) and autotransplants (n = 5). Linear regression analysis was used to correlate EP receptor expression with the Banff category of rejection. RESULTS: Pigs with advanced rejection demonstrated significant increases in serum PGE2 metabolites, while pigs with less rejection demonstrated higher tissue concentrations of PGE2 metabolites. A significant negative correlation between COX-2 expression and Banff category of rejection (R = -0.877) was shown. Rejection decreased expression of EP2 and EP4. For both receptors, there was a significant negative correlation with the extent of rejection (R = -0.760 and R = -0.891 for EP2 and EP4, respectively). Rejection had no effect on the proinflammatory receptors EP1 and EP3. CONCLUSION: Downregulation of COX-2 and the anti-inflammatory EP2 and EP4 receptors is associated with acute rejection in unmatched pig kidney transplants, suggesting that the COX-2-PGE2-EP pathway may modulate inflammation in this model. Enhancing EP2 and/or EP4 activity may offer novel therapeutic approaches to controlling the inflammation of acute allograft rejection.

Mortality risk after herpes zoster infection in end-stage renal disease patients.

BACKGROUND: End-stage renal disease (ESRD) patients have increased risk of developing herpes zoster (zoster) compared with the general population, but mortality risk is unknown. We assessed the risk of mortality in hospitalized ESRD patients with a diagnosis of zoster from the inpatient hospital files (as opposed to outpatient records) of the United States Renal Data System. METHODS: This study analyzed incident ESRD patients from 2006 to 2009. Based on an International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis code of zoster infection, we determined 2-year mortality following an inpatient diagnosis. Cox proportional hazards models were used to examine the association of mortality and zoster, when controlling for demographic and other clinical risk factors. RESULTS: Zoster was diagnosed in 2784 patients, 51% of whom died within 2 years, with a mean time to death of 8.1 months. Patients who died were more likely to be white and older, score higher on the Charlson Comorbidity Index (CCI) and have other clinical diagnoses besides CCI. Increased risk of death within 2 years was associated with older age (adjusted hazard ratio 1.03), malnutrition (1.31), bacteremia/septicemia (1.16) and increasing CCI (1.10). Zoster vaccine was administered to 27 patients, but the small number precluded analysis of its impact. CONCLUSIONS: Mortality in ESRD patients with an inpatient zoster diagnosis is increased with older age and higher severity of clinical comorbidities. The role of zoster vaccination on mortality in this population remains to be defined.

Is Dietary Protein Intake Predictive of 1-Year Mortality in Dialysis Patients?

BACKGROUND: High mortality in dialysis patients may be associated with protein-energy wasting (PEW) syndrome characterized by progressively depleted protein and energy stores. While early diagnosis and treatment of PEW can reduce mortality, clinically practical measures for its detection are lacking. Poor dietary protein intake (DPI) is associated with risk of malnutrition and PEW. However, the impact of DPI on mortality is unclear. The purpose of this study is to examine the ability of DPI to predict 1-year mortality in dialysis patients. METHODS: This prospective, secondary study using data from the Comprehensive Dialysis Study and United States Renal Data System examined risk factors associated with 1-year mortality in dialysis patients. RESULTS: Seventeen (7.5%) of the 227 subjects died within 1 year following baseline data collection. One year survivors were significantly younger (60 ± 13.6 versus 71 ± 12.8; P = 0.0043), had a lower Charlson Comorbidity Index score (1.6 ± 2.3 versus 4.0 ± 3.6; P = 0.0157), higher serum albumin level (3.5 ± 0.5 versus 3.3 ± 0.4; P = 0.0173) and had higher DPI (63 ± 33.7 versus 49.5 ± 21.5 g/day; P = 0.0386) than those who died. In multivariable Cox proportional hazards model analyses, only the Charlson Comorbidity Index adjusted hazard ratio for death (1.24) was significantly associated with increased mortality. The Comprehensive Dialysis Study data showed no association between DPI and 1-year mortality in dialysis patients. CONCLUSIONS: Future studies using more precise measures should further examine the impact of DPI on mortality given the known association of DPI with PEW syndrome and the definitive link between PEW syndrome and survival in dialysis patients.

Regulation of indoleamine 2,3 dioxygenase and its role in a porcine model of acute kidney allograft rejection.

In kidney transplantation acute allograft rejection is the most common cause of late allograft loss. Changes in indoleamine 2,3 dioxygenase (IDO) activity, which catabolizes the degradation of tryptophan to kynurenine, may predict rejection. However, exogenous IDO is immunosuppressive in rodent kidney transplantation. Thus, the increase in IDO activity observed in acute allograft rejection is insufficient to prevent rejection. To address this question, we assessed the regulation of IDO and its role in acute rejection in a porcine model of kidney transplant. In tissue samples from rejecting kidney allografts, we showed a 13-fold increase in IDO gene transcription and 20-fold increase in IDO enzyme activity when compared with autotransplanted kidneys. Allografts also demonstrated an over fourfold increase in tissue interferon (IFN)-γ, with marked increases in tumor necrosis factor (TNF)-α, TNF-ß and interleukin 1ß. Gene transcription and protein levels of kynurenine 3-monooxygenase (KMO) were decreased. KMO generates the immunosuppressive kynurenine, 3-hydroxykynurenine. The results of these studies demonstrate a clear association between rejection and increased allograft IDO expression, likely driven in part by IFN-γ and facilitated by other cytokines of the allogeneic response. Moreover, the loss of downstream enzymatic activity in the IDO metabolic pathway may suggest novel mechanisms for the perpetuation of rejection.

Autophagy is activated to protect against podocyte injury in adriamycin-induced nephropathy.

Podocytes are highly differentiated epithelial cells wrapping glomerular capillaries to form the filtration barrier in kidneys. As such, podocyte injury or dysfunction is a critical pathogenic event in glomerular disease. Autophagy plays an important role in the maintenance of the homeostasis and function of podocytes. However, it is less clear whether and how autophagy contributes to podocyte injury in glomerular disease. Here, we have examined the role of autophagy in adriamycin-induced nephropathy, a classic model of glomerular disease. We show that autophagy was induced by adriamycin in cultured podocytes in vitro and in podocytes in mice. In cultured podocytes, activation of autophagy with rapamycin led to the suppression of adriamycin-induced apoptosis, whereas inhibition of autophagy with chloroquine enhanced podocyte apoptosis during adriamycin treatment. To determine the role of autophagy in vivo, we established an inducible podocyte-specific autophagy-related gene 7 knockout mouse model (Podo-Atg7-KO). Compared with wild-type littermates, Podo-Atg7-KO mice showed higher levels of podocyte injury, glomerulopathy, and proteinuria during adriamycin treatment. Together, these observations support an important role of autophagy in protecting podocytes under the pathological conditions of glomerular disease, suggesting the therapeutic potential of autophagy induction.

Clostridium difficile infection in dialysis patients.

Clostridium difficile infection (CDI) is the most common cause of nosocomial diarrhea. Patients with end-stage renal disease (ESRD) may be at increased risk for CDI. Patients with ESRD with CDI have increased mortality, longer length of stay, and higher costs. The present studies extend these observations and address associated comorbidities, incidence of recurrence, and risk factors for mortality. We queried the United States Renal Data System (USRDS) for patients with ESRD diagnosed with CDI, and assessed for the incidence of infection, comorbidities, and mortality. The records of 419,875 incident dialysis patients from 2005 to 2008 were reviewed. 4.25% had a diagnosis of a first CDI. In the majority of patients with CDI positive, a hospitalization or ICU stay was documented within 90 days prior to the diagnosis of CDI. The greatest adjusted relative risk (aRR) of CDI was present in patients with HIV (aRR 2.68), age ≥65 years (aRR 1.76), and bacteremia (aRR 1.74). The adjusted HR (aHR) for death was 1.80 in patients with CDI. The comorbidities demonstrating the greatest risk for death in dialysis patients with CDI included age ≥65 years and cirrhosis (aHR 2.28 and 1.76, respectively). Recurrent CDI occurred in 23.6%, was more common in Caucasians, and in those who were older. CDI is a common occurrence in patients with ESRD, with elderly patients, patients with HIV positive, and bacteremic patients at highest risk for infection. Patients with CDI had nearly a twofold increased risk of death.

A departmental initiative for clinical and translational research.

To encourage departmental research activities, the Department of Medicine of the Medical College of Georgia (MCG) introduced an internally funded Translational Research Program (TRP) in 2014. Patterned after the Vanderbilt Institute for Clinical and Translational Research, the program offers research studios for project guidance, research mentoring and the availability of limited financial support through research vouchers. Additional academic services include abstract reviewing, conducting research conferences, organizing departmental research programs for students, and offering courses in biostatistics. During the first 15 months of its existence, the TRP working group addressed 132 distinct activities. Research mentoring, publications, and the conduct of research studios or voucher approvals encompassed 49% of working group activities. Other academic services constituted the remaining 51%. Twenty-four per cent of TRP committee activities involved research mentoring of 32 investigators (25% faculty and 75% trainees). Mentored projects generated 17 abstracts, 2 manuscripts and $87,000 in funds. The TRP conducted 13 research studios; trainees presented 54%. The TRP reviewed 36 abstracts for local and state organizations. Monthly research conferences and statistical courses were conducted and well attended. Our experience thus far indicates that a departmental TRP may serve to facilitate the growth of patient-oriented research with minimal financial support. It requires active engagement of volunteer faculty and departmental leadership willing to balance research with the other demands of the academic mission.

Hydroxychloroquine in patients with systemic lupus erythematosus with end-stage renal disease.

OBJECTIVES: To determine dosing patterns and examine predictors of filled hydroxychloroquine (HCQ) prescriptions in patients with systemic lupus erythematosus (SLE) with end-stage renal disease (ESRD). METHODS: This was a retrospective cohort study of patients with SLE in the US Renal Data System (USRDS) database in fiscal year 2011. All patients were Medicare Part D beneficiaries. Patients with a diagnosis of SLE were identified by the International Classification of Diseases, 9th revision code 710. The prevalence, dosing, and predictors of filled HCQ prescriptions (demographic factors, dialysis type, and provider subspecialty) were determined. RESULTS: There were 10,276 patients with SLE identified; 2048 (19.9%) had a prescription for HCQ filled. The mean daily dose of HCQ was 321 mg (range 58-2000 mg). The most common daily doses were 200 (n=768, 37.5%) and 400 mg (n=1161, 56.7%). In multivariable logistic regression analysis, significant predictors of filled HCQ prescriptions included black/African-American race (OR 1.34, 95% CI (1.17 to 1.46)), hemodialysis (1.50, 95% CI (1.29 to 1.74)), and care from a rheumatologist (5.06, 95% CI (4.56 to 5.62)). Negative predictors of filled HCQ prescriptions included male gender (OR 0.72, 95% CI (0.63 to 0.83)) and those aged 45 years or older (compared to 20 years old and younger, aged 45-64 years, OR 0.66, 95% CI (0.54 to 0.79); aged 65-74 years, OR 0.58, 95% CI (0.44 to 0.76); aged 75 years and older, OR 0.56, 95% CI (0.39 to 0.82)). CONCLUSIONS: In patients with SLE with ESRD, the dosing strategies for HCQ with regard to potential toxicity and disparities in prescribing patterns need further study.

Cardiac implantable electronic device infection in patients with end-stage renal disease.

INTRODUCTION: Cardiac implantable electronic devices (CIED) are increasingly being used in end-stage renal disease (ESRD) patients. These patients have a high risk of device infection. OBJECTIVES: To study the optimal management of device infections in patients with ESRD. METHOD: We used the United States Renal Data System (USRDS) to assess the presence of a CIED and associated comorbidities, risk factors for infection, and mortality following device extraction or medical management in ESRD patients with CIED infection. Univariable, multivariable, and survival analyses were performed using USRDS data from 2005 to 2009. RESULTS: Of 546,769 patients, 6.4% had CIED and 8.0% of those developed CIED infection. The major risk factors for device infection were black race, temporary dialysis catheter, and body mass index >25. Patients with artificial valves were excluded from the analysis. Only 28.4% of infected CIED were removed. CIED removal was more common in those with congestive heart failure. The median time to death following diagnosis of a CIED infection was 15.7 months versus 9.2 months for those treated via device extraction versus medical-only therapy (hazard ratio: 0.75; 95% confidence interval: 0.68-0.82). CONCLUSION: Patients with ESRD and infected CIEDs have a poor prognosis. Rates of device extraction are low, but this strategy appears to be associated with modest improvement in survival.

Bacteremia in hemodialysis patients with hepatitis C.

BACKGROUND: Hepatitis C virus (HCV) infection and bacteremia are common comorbidities in hemodialysis patients. A specific relationship between HCV infection and bacteremia has not been defined; however, there is evidence of immune compromise in both HCV-infected and uremic patients, suggesting that this group may be at higher risk for infection. METHODS: We investigated risk factors and mortality associated with bacteremia in HCV-infected hemodialysis patients from the United States Renal Data System. RESULTS: During the 4-year study period, HCV was present in 2.1% of 355,084 patients initiating hemodialysis. When compared with the total population, the rate of bacteremia was significantly higher in patients with HCV (38.3% versus 21.8%). The adjusted relative risk (RR) for bacteremia was higher in HCV versus all patients (relative risk, 95% confidence interval [CI]) in the presence of methicillin-resistant Staphylococcus aureus infection (2.64, CI: 2.58-2.70 versus 2.32, CI: 2.27-2.38), HIV (1.93, CI: 1.85-2.02 versus 1.86, CI: 1.77-1.95) urinary tract infection (1.79, CI: 1.77, 1.82 versus 1.64, CI: 1.61-1.67) and cirrhosis (1.49, CI: 1.45-1.54 versus 1.29, CI: 1.25-1.34). The hazard ratio (95% CI) for death was higher in HCV versus all patients at 1.69 (CI: 1.58-1.81) versus 1.54 (CI: 1.53-1.56). CONCLUSIONS: These data indicate that several clinical covariates increase the risk of bacteremia in hemodialysis patients, with the magnitude of that risk being further increased by HCV infection. Improving outcomes in HCV-infected hemodialysis patients will likely be dependent on aggressive diagnosis and treatment of both HCV and bacteremia.

Indoleamine 2,3-dioxygenase inhibition alters the non-coding RNA transcriptome following renal ischemia-reperfusion injury.

BACKGROUND: Indoleamine 2,3 dioxygenase (IDO) degrades the essential amino acid tryptophan and has been shown to minimize rejection in animal models of renal transplantation. Ischemia-reperfusion injury (IRI) is unavoidable in renal transplantation and correlates with shorter graft survival times. Despite its favorable effects on rejection, there is evidence that IDO may facilitate renal IRI. Differentiating the negative impact of IDO on IRI from its pro-tolerant effects in allograft rejection is of clinical relevance. In these studies we hypothesized that constitutive IDO activity may influence renal genes associated with recovery from IRI, and that IDO inhibition may unmask these effects. METHODS: We examined the renal transcriptome in a rat model of IRI with and without IDO inhibition with 1-methyl-d-tryptophan (1-MT), and assessed for alterations in the gene expression signature. RESULTS: These studies demonstrated that during recovery from renal IRI, pre-treatment with 1-MT alleviated alterations in 105 coding sequences associated with IRI, and in turn triggered new changes in 66 non-coding transcripts, the majority of which were represented by small nucleolar RNA. CONCLUSION: These results suggest a biologic role for non-coding, IDO-dependent genes in regulating the early response to IRI.

GLUT1 regulation of the pro-sclerotic mediators of diabetic nephropathy.

Diabetic glomerulosclerosis is characterized by accumulation of extracellular matrix proteins, mesangial expansion, and tubulointerstitial fibrosis. Hyperglycemia accelerates development of the disease, a direct result of increased intracellular glucose availability. The facilitative glucose transporter GLUT1 mediates mesangial cell glucose flux which leads to activation of signaling cascades favoring glomerulosclerosis, including pathways mediated by angiotensin II (Ang II), transforming growth factor ß (TGF-ß), connective tissue growth factor (CTGF), and vascular endothelial growth factor (VEGF). Ang II has both hemodynamic and metabolic effects directly inducing GLUT1 and/or matrix protein synthesis through diacyl glycerol (DAG) or protein kinase C (PKC) induction, mesangial cell stretch, and/or through transactivation of the epidermal growth factor receptor, the platelet-derived growth factor receptor, and the insulin-like growth factor-1 receptor, all of which may stimulate GLUT1 synthesis via an ERK-mediated pathway. Conversely, inhibition of Ang II effects suppresses GLUT1 and cellular glucose uptake. GLUT1-mediated glucose flux leads to metabolism of glucose via glycolysis, with induction of DAG, PKC, TGF-ß1, CTGF and VEGF. VEGF in turn triggers both GLUT1 and matrix synthesis. New roles for GLUT1-mTOR and GLUT1-mechano-growth factor interactions in diabetic glomerulosclerosis have also recently been suggested. Recent mouse models confirmed roles for GLUT1 in vivo in stimulating glomerular growth factor expression, growth factor receptors and development of glomerulosclerosis. GLUT1 may therefore act in concert with cytokines and growth factors to induce diabetic glomerulosclerosis. Further clarification of the pathways involved may prove useful for the therapy of diabetic nephropathy. New directions for investigation are discussed.

Hepatitis C infection and the risk of bacteremia in hemodialysis patients with tunneled vascular access catheters.

BACKGROUND: The major complication of tunneled vascular catheters in dialysis patients is infection. In preliminary work, an association was noted between hepatitis C virus (HCV) infection and bacteremia in these patients. On this basis, we theorized that HCV infection may be associated with bacteremia in dialysis patients with tunneled catheters. METHODS: We conducted a two-phase clinical study to define the association between HCV infection and bacteremia in hemodialysis patients with catheters. Phase 1 was a cross-sectional study designed to assess the association between HCV serologic status and bacteremia. Phase 2 was a prospective study that examined the relationship between HCV viral load and bacteremia. RESULTS: In Phase 1, HCV (+) patients had a significantly greater prevalence of bacteremia than HCV (-) patients (61 vs 7.7% respectively, P < 0.05). In Phase 2, the presence of detectable virus was associated with a numerical trend toward an increase in the incidence of bacteremia (40 vs 0% for patients with and without detectable virus, respectively, P = 0.09). CONCLUSION: These studies suggest that HCV infection may be associated with the development of bacteremia in hemodialysis patients with tunneled catheters.