N. Stanley Nahman

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

INTRODUCTIONnCardiac implantable electronic devices (CIED) are increasingly being used in end-stage renal disease (ESRD) patients. These patients have a high risk of device infection.nnnOBJECTIVESnTo study the optimal management of device infections in patients with ESRD.nnnMETHODnWe 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.nnnRESULTSnOf 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).nnnCONCLUSIONnPatients 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.

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.

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 321u2005mg (range 58–2000u2005mg). The most common daily doses were 200 (n=768, 37.5%) and 400u2005mg (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 45u2005years or older (compared to 20u2005years old and younger, aged 45–64u2005years, OR 0.66, 95% CI (0.54 to 0.79); aged 65–74u2005years, OR 0.58, 95% CI (0.44 to 0.76); aged 75u2005years 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.

A model of acute renal allograft rejection in outbred Yorkshire piglets.

Pigs represent a desirable animal model for the study of rejection in kidney transplantation with inbred Yucatan miniature swine (YMS) the most commonly studied strain due to well defined swine leukocyte antigen (SLA) genotypes. However, limitations to YMS may include cost and availability. Outbred Yorkshire pigs are widely available and significantly cheaper than YMS. Recent advances in SLA genotyping have allowed its application to outbred strains. On this basis, we theorized that Yorkshire pigs would be a viable alternative to YMS for the study of rejection in kidney transplantation. To address this question, we performed auto (Auto) and allotransplants (Allo) in 24 Yorkshire pigs, and assessed SLA genotypes and acute rejection after 72h. At sacrifice, and when compared to autotransplants, allotransplants had significant elevations in serum creatinine (8.4±1.3 vs 2.8±2.0mg/dL for Allo vs autotransplants, respectively) and BUN (61±9 vs 19.2±15mg/dL for Allo vs autotransplants, respectively). Warm ischemia times between the two groups did not differ (24±2.3 vs 26.4±1.4min for Auto vs Allo, respectively). There were 16 distinct SLA haplotypes identified from pigs undergoing allotransplantion, no matched donor-recipient pairs, and all allografts demonstrated rejection. Type IIA cellular rejection (Banff) was the most common. One allograft demonstrated hyperacute rejection due a blood group incompatibility. Histologically, the expression of regulatory Tcells and dendritic cells was increased in allografts. These data suggest that Yorkshire pigs may be a useful model for the study of acute rejection in experimental kidney transplantation.

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 15u2005months 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

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

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.

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

BACKGROUNDnIndoleamine 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.nnnMETHODSnWe 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.nnnRESULTSnThese 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.nnnCONCLUSIONnThese results suggest a biologic role for non-coding, IDO-dependent genes in regulating the early response to IRI.

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

Abstract 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 2u2009years, with a mean time to death of 8.1u2009months. 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 2u2009years 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.