Ganciclovir-resistant cytomegalovirus infection in solid organ transplant recipients: a single-center retrospective cohort study.

BACKGROUND: Ganciclovir-resistant cytomegalovirus (GCV-R CMV) is an emerging challenge among solid organ transplant (SOT) recipients. The literature suggests that about 1% of abdominal transplant recipients develop GCV-R CMV infection. The epidemiology and outcome of GCV-R CMV in SOT recipients who have received alemtuzumab induction is not well described. METHODS: After Institutional Review Board approval, a single-center, retrospective review of 2148 abdominal SOT recipients between January 2006 and July 2011 at our institution (n = 2148) was conducted to identify patients with proven or empirically treated GCV-R CMV. Descriptive statistics on collected demographics, clinical course, and therapeutic outcomes were performed. RESULTS: Of 116 SOT recipient treated for CMV, 14 patients (12.1% of cases; 0.65% of all SOT patients) had proven or suspected GCV-R CMV. Eight (50%) developed GCV-R CMV while receiving valganciclovir (valGCV) prophylaxis. The remainder developed late-onset disease, after having completed an average 212 days (range 83-353) of prophylaxis. Resistance was clinically suspected an average of 103 days (range 10-455) after CMV infection was initially identified; 10 patients had confirmed genotypic resistance. Foscarnet therapy was associated with resolution of CMV in 13. CONCLUSION: Suboptimal dosing of valGCV is associated with development of GCV-R CMV. Our observed rate of GCV-R CMV in alemtuzumab-induced patients is similar to rates seen to historical data for other induction agents.

BK virus replication and nephropathy after alemtuzumab-induced kidney transplantation.

BK virus nephropathy (BKVN) is a recognized cause of graft failure in kidney transplant recipients. There are limited data on the epidemiology of BK virus (BKV) infection after alemtuzumab induction. By clinical protocol, the kidney transplant recipients at our center were screened with BKV plasma PCR monthly for the first 4 months posttransplant then every 2-3 months for 2 years. A single center retrospective cohort study of all kidney transplant recipients from January 2008 to August 2010 was conducted to determine incidence and outcomes of BKV infection. Descriptive statistics and Kaplan-Meier analysis was performed. Of 666 recipients, 250 (37.5%) developed viruria, 80 (12%) developed viremia and 31 (4.7%) developed BKVN at a median of 17, 21 and 30 weeks, respectively. Induction with alemtuzumab did not significantly affect incidence of BKVN. Increased recipient age, African American race, acute graft rejection and CMV infection were significantly associated with the development of BKVN in multivariate analysis. The incidence of BK viruria, viremia and nephropathy was not significantly different among kidney transplant recipients who received alemtuzumab induction compared to patients receiving less potent induction.

Cytokine phenotype, genotype, and renal outcomes at cardiac surgery.

BACKGROUND: Cardiac surgery modulates pro- and anti-inflammatory cytokine balance involving plasma tumour necrosis factor alpha (TNFα) and interleukin-10 (IL-10) together with urinary transforming growth factor beta-1 (TGFß1), interleukin-1 receptor antagonist (IL1ra) and tumour necrosis factor soluble receptor-2 (TNFsr2). Effects on post-operative renal function are unclear. We investigated if following cardiac surgery there is a relationship between cytokine (a) phenotype and renal outcome; (b) genotype and phenotype and (c) genotype and renal outcome. Since angiotensin-2 (AG2), modulates TGFß1 production, we determined whether angiotensin converting enzyme insertion/deletion (ACE I/D) genotype affects urinary TGFß1 phenotype as well as renal outcome. METHODS: In 408 elective cardiac surgery patients we measured pre- and 24 h post-operative urinary TGFß-1, IL1ra and TNFsr2 and pre- and 2 h post-operative plasma TNFα and IL-10. Post-operative responses were compared for each cytokine in patients grouped according to presence or absence of renal dysfunction defined as a drop from baseline eGFR of greater than 25% (as calculated by the method of modification of diet in renal disease (MDRD)) occurring (1) within the first 24 and (2) 48 postoperative hours (early renal dysfunction), (3) on the fifth postoperative day (late renal dysfunction) or (4) at any time throughout the 5 day postoperative period (early and late combined). Patient genotype was determined for TNF/G-308A, TGFß1-509 C/T, IL10/G-1082A and ACE I/D. RESULTS: Post-operative plasma IL-10 and urinary TGFß1 responses were significantly higher in patients who developed early renal dysfunction. IL1ra and TNFsr2 responses were significantly lower 24h post-operatively in patients who developed late renal dysfunction. Genotype did not alter cytokine phenotype or outcome. CONCLUSIONS/INFERENCES: Cytokine profiling may help predict early and late renal dysfunction. Genotypes studied did not alter phenotype or outcome.

Cell salvage alters the systemic inflammatory response after off-pump coronary artery bypass grafting surgery.

BACKGROUND: Retransfused cardiotomy suction blood contains elevated inflammatory markers and is a bypass independent source of inflammatory mediators. We hypothesized that, during off-pump coronary artery bypass (OPCAB) grafting surgery, avoiding retransfusion of unwashed cardiotomy suction blood would beneficially alter both urinary and plasma cytokine concentrations and be renoprotective. METHODS: Thirty-seven OPCAB surgery patients were randomly allocated to control (retransfusion of unwashed shed blood) and treatment (retransfusion of washed shed blood or discarding of unwashed blood) groups. Over 72 hours we measured plasma (tumor necrosis factor-alpha [TNF-alpha], interleukin-8, interleukin-6, interleukin-10, TNF soluble receptor-2, and interleukin-1 receptor antagonist) and urinary TNF soluble receptor-2 and interleukin-1 receptor antagonist and markers of renal injury and dysfunction (N-acetyl beta D glucosaminidase and alpha1-microglobulin). RESULTS: We demonstrated elevated proinflammatory cytokines in cardiotomy suction blood, which were effectively eliminated by cell salvage. After retransfusion, in comparison with controls, the treatment group had reduced plasma TNF soluble receptor-2. As compared with controls, treatment group patients also demonstrated significantly reduced levels of the urinary anti-inflammatory cytokine TNF soluble receptor-2. There were no between group differences in markers of renal injury or dysfunction. CONCLUSIONS: We have demonstrated that the management of shed mediastinal blood alters perioperative, systemic, plasma and urinary cytokine homeostasis at OPCAB surgery but does not impact on subclinical renal injury or dysfunction in this low risk group of patients.

A clinical, renal and immunological assessment of surface modifying additive treated (SMART) cardiopulmonary bypass circuits.

Biocompatible cardiopulmonary bypass (CPB) circuits aim to reduce contact activation and its physiological consequences. We investigated the hypothesis that use of Surface Modifying Additive (SMA)-treated circuits (Sorin Group Ltd) compared with non-SMA circuits would be associated with preservation of blood pressure during CPB and modulation of perioperative subclinical renal function (urinary alpha-1-microglobulin (alpha-1-m)) and plasma and urinary cytokine changes. In a study of low-risk CABG patients (n=40), randomized to SMA (n=20) versus non-SMA circuits (n=20), we found better preserved blood pressure at CPB initiation in SMA patients (p <0.05), particularly in ACE-inhibited SMA patients (n =11) versus ACE-inhibited non-SMA patients (n =10) (p <0.05). Plasma anti-inflammatory IL-10, as well as urinary alpha-1-m, were elevated 48 hours postoperatively (p <0.05). SMA patients also had lower blood loss (p <0.05). SMA circuits have some clinical benefit, especially in ACE-inhibited patients.

A case of peroneal neuropathy-induced footdrop. Correlated and compensatory lower-extremity function.

This article reports on the case of a man with peroneal neuropathy-induced footdrop who was seen at the authors' institution 3 years after open reduction and internal fixation of a proximal fibular fracture and a distal, spiral, oblique tibial fracture of the right leg. A comprehensive gait analysis was conducted. A significant footdrop in gait resulted in a "reverse check mark" center-of-pressure pattern, an increased transverse-plane rotation of the foot, and excessive knee and hip flexion in the sagittal plane. These objective findings documented significant dysfunction within the involved lower extremity; in addition, aberrant biomechanics were observed in structures other than the site of initial injury within both limbs.

Proteoglycan composition in the human sclera during growth and aging.

PURPOSE: Scleral proteoglycans were characterized from human donor eyes aged 2 months to 94 years to identify age-related changes in the synthesis and/or accumulation of these extracellular matrix components. METHODS: Newly synthesized proteoglycans (previously radiolabeled with 35SO4) and total accumulated scleral proteoglycans were extracted with 4 M guanidine hydrochloride and separated by molecular sieve chromatography on a Sepharose CL-4B column. The elution positions of newly synthesized and total accumulated proteoglycans were determined by assaying each fraction for radioactivity and glycosaminoglycans, respectively. Regression analyses were performed on the three major proteoglycan peaks to identify age-related changes in scleral proteoglycan composition. Scleral proteoglycans were further purified by anion-exchange chromatography and characterized by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blot analyses. RESULTS: Human scleral proteoglycans were apparent as three major peaks after chromatography on Sepharose CL-4B. The two faster eluting peaks contained alternative forms of the cartilage proteoglycan, aggrecan, whereas the third peak contained the small proteoglycans biglycan and decorin. The relative percentage of newly synthesized and total accumulated aggrecan increased approximately two- to sixfold from infancy to 94 years. In contrast, the relative percentage of newly synthesized and total accumulated biglycan and decorin decreased by approximately 25%. Chromatography and Western blot results indicated that the absolute amounts of all three proteoglycans significantly increased in concentration within the sclera from birth to the fourth decade. Beyond the fourth decade, decorin and biglycan decreased in all scleral regions and were present in lowest concentrations by the ninth decade. In contrast, aggrecan, which was present in highest concentration in the posterior sclera, was not significantly reduced with increasing age. CONCLUSIONS: The age-related changes in scleral proteoglycan composition observed in the present study are likely to contribute to the regional alterations in biomechanical properties of the sclera associated with growth and aging.