Observations on the use of cidofovir for BK virus infection in renal transplantation.

BACKGROUND: In renal transplantation, BK virus infection can result in significant graft nephropathy and loss. While reduction in immunosuppression (IS) is considered standard therapy, adjunct agents may be warranted. Data are suggestive of a possible role of cidofovir for the management of BK. This study aims to describe the course of BK viremia (BKV) in a large cohort of renal transplant patients receiving adjunct cidofovir. METHODS: We evaluated kidney and kidney-pancreas recipients who received cidofovir combined with reduced IS for management of high-level BKV or BK virus nephropathy (BKVN). We examined the rate and timing of BKV clearance, and performed a multivariate analysis to identify risk factors associated with long-term (>6 months) viremia. RESULTS: In total, 75 patients received a median of 13 doses of cidofovir in conjunction with reduced IS; 32 patients (43%) had short-term BKV (≤6 months), and 43 (57%) had long-term BKV. Overall, 53 of 75 patients (71%) eventually cleared BKV at a median of 4.2 months (interquartile range 2.1-9.3 months). Independent factors associated with long-term BKV included older age (odds ratio [OR] 1.1, P = 0.02), delayed graft function (OR 31.4, P = 0.01), and higher peak BKV (OR 12.8, P = 0.02), while BKV reduction by at least 1 log(10) copies/mL at 1 month of treatment was associated with clearance within 6 months (OR 49.3, P < 0.01). Patients with earlier clearance maintained stable graft function and no graft losses, while long-term BKV was associated with a 15% decline in estimated glomerular filtration rate. CONCLUSIONS: Adjunct cidofovir resulted in preservation of renal function when viral clearance occurred within 6 months of initiation. This retrospective review defines factors predicting response to cidofovir in conjunction with reduced IS for BKVN or high-level BKV. Still, considering cost, frequency of administration, and treatment duration, a randomized trial is necessary to define the exact utility of cidofovir in the setting of BK virus infection.

Dynamic self-assembly of DNA minor groove-binding ligand DB921 into nanotubes triggered by an alkali halide.

We describe a novel self-assembling supramolecular nanotube system formed by a heterocyclic cationic molecule which was originally designed for its potential as an antiparasitic and DNA sequence recognition agent. Our structural characterisation work indicates that the nanotubes form via a hierarchical assembly mechanism that can be triggered and tuned by well-defined concentrations of simple alkali halide salts in water. The nanotubes assembled in NaCl have inner and outer diameters of ca. 22 nm and 26 nm respectively, with lengths that reach into several microns. Our results suggest the tubes consist of DB921 molecules stacked along the direction of the nanotube long axis. The tubes are stabilised by face-to-face π-π stacking and ionic interactions between the charged amidinium groups of the ligand and the negative halide ions. The assembly process of the nanotubes was followed using small-angle X-ray and neutron scattering, transmission electron microscopy and ultraviolet/visible spectroscopy. Our data demonstrate that assembly occurs through the formation of intermediate ribbon-like structures that in turn form helices that tighten and compact to form the final stable filament. This assembly process was tested using different alkali-metal salts, showing a strong preference for chloride or bromide anions and with little dependency on the type of cation. Our data further demonstrates the existence of a critical anion concentration above which the rate of self-assembly is greatly enhanced.

Outcomes of living donor renal transplants with a negative cross-match and pretransplant donor-specific antibody.

INTRODUCTION: Management of renal transplant recipients with a negative complement-dependent cytotoxicity-antihuman globulin (CDC-AHG) cross-match and pretransplant donor-specific antibody (DSA) is controversial. We sought to compare outcomes of immunologically high-risk living donor (LD) renal transplant recipients with and without DSA. METHODS: We conducted a single-center, retrospective review of all high immune-risk LD renal transplant recipients with a negative CDC-AHG cross-match performed between January 2008 and December 2010. Pretransplant desensitization for DSA was not utilized. Immunosuppression consisted of thymoglobulin induction, followed by tacrolimus, myeophenolate mofetil, and prednisone. DSA was assessed pretransplant and at 1, 3, 6, 9, and 12 months, and every 6 months thereafter. RESULTS: Between January 2008 and December 2010, 44 LD renal transplants were performed in high immune-risk recipients with a negative CDC-AHG cross-match. Outcomes of 14 recipients with pretransplant DSA were compared with 30 recipients with no DSA. After a median follow-up of 26 months (range, 12-40), overall death-censored graft survival was 100%, with no acute rejection episodes in the DSA group and 1 antibody-mediated rejection in the non-DSA cohort. Mean serum creatinines of the DSA and non-DSA groups at 1 year post-transplant were 1.0 ± 0.4 and 1.2 ± 0.6 mg/dL (P = NS), respectively. Among the pretransplant DSA cohort, 5 of the 14 (36%) developed persistent post-transplant DSA at a median of 9 months (range, 3-24) versus 2 of 30 (7%; P = .025) at a median of 12 months post-transplant in the non-DSA cohort. All recipients in the pretransplant DSA group underwent renal biopsy for persistent post-transplant DSA. Three of 5 biopsies showed C4D deposition in peritubular capillaries without glomerulopathy or arteriopathy. CONCLUSIONS: Early post-transplant outcomes for LD recipients with a negative cross-match and pretransplant DSA were excellent. In recipients with good and stable renal function, the significance of persistent post-transplant DSA in combination with C4D deposition on biopsy is unclear at this time.

De novo donor specific antibodies and patient outcomes in renal transplantation.

Single antigen identification of HLA antibodies is used to detect donor specific antibodies (DSAs). However, the impact of DSA elements such as class, relative strength, duration, and longitudinal effect on graft function and survival, remains unclear. Routine DSAs (LabScreen, One Lambda, Inc., Canoga Park, CA) and metabolic studies were performed at 1, 3, 6, 9, and 12 months post-transplant, and every 6 months for renal transplant recipients from 7/2007-7/2010 (n = 389). Biopsies were evaluated by updated Banff 2005 guidelines after two consecutive positive DSAs. Based on these tests, 25% of recipients developed de novo DSA. Those with DSA had increased acute rejection episodes (AR), higher creatinine (Scr), and worse graft survival. Three subgroups of these patients were identified based on duration: persistent DSA (> 1), isolated DSA, or no DSA. Persistent DSA patients were more likely to be African American, and have higher mean fluorescence intensity (MFI) and AR rates. Persistent DSA patients, with or without AR, had elevated Scr. Recipients with DQ-only DSA had higher rates of antibody mediated rejection (AMR). From this, we conclude that routine posttransplant DSA monitoring identifies recipients at risk for graft damage or loss. Persistent de novo DSAs correlated with inferior graft outcomes and AMR. With or without AR, DSA persistence was associated with worse outcomes, possibly warranting intervention. De novo DQ-DSA may be a biomarker for chronic damage and/or AMR, while an isolated DSA determination appears clinically insignificant.

Phase I clinical trial of combined therapy with vinblastine (NSC-49842), bleomycin (NSC-125066), and cisdichlorodiammineplatinum(II)( NSC-119875).

Seventeen patients with various histologic types of incurable malignant disease were treated with a combination of vinblastine, bleomycin, and cis-dichlorodiammineplatinum(II). Creatinine and blood urea nitrogen elevations were noted but were not of a severe degree. White blood cell and platelet count depressions were seen and appeared to be cumulative, though not life-threatening. Tinnitus and high-frequency hearing loss were noted. Tumor regression was seen in one patient with adenocarcinoma of the lung and in one patient with a testicular tumor. This appears to be a manageable drug combination with frequent monitoring of renal, hematopoietic, pulmonary, and auditory function. A phase II study establishing the therapeutic efficacy of this combination in advanced testicular neoplasms now appears to be indicated.

Java-based graphical user interface for the MRUI quantitation package.

This article describes the Java-based version of the magnetic resonance user interface (MRUI) quantitation package. This package allows MR spectroscopists to easily perform time-domain analysis of in vivo MR spectroscopy data. We show that the Java programming language is very well suited for developing highly interactive graphical software applications such as the MRUI software. We have also established that MR quantitation algorithms, programmed in other languages, can easily be embedded into the Java-based MRUI by using the Java native interface (JNI). This new graphical user interface (GUI) has been conceived for the processing of large data sets and uses prior knowledge data-bases to make interactive quantitation algorithms more userfriendly.