Mycophenolate mofetil and sirolimus as calcineurin inhibitor-free immunosuppression for late cardiac-transplant recipients with chronic renal failure

BACKGROUND: Calcineurin-inhibitor (CNI)-related renal failure is a common problem after cardiac transplantation (HTx). The aim of this study was to introduce a CNI-free immunosuppressive regimen to HTx recipients with late posttransplant renal impairment and to evaluate the impact of conversion to this new immunosuppression (mycophenolate mofetil [MMF] and sirolimus [Sir]) treatment on renal function. METHODS AND RESULTS: Thirty-one HTx patients (25 men, 6 women; 0.2-14.2 years after transplantation) with CNI-based immunosuppression and a serum creatinine greater than 1.9 mg/dL were included in the study. Creatinine and cystatin levels were monitored to detect renal function. Mean patient age was 50+/-14 (range 19-74) years. Conversion was started with 6 mg Sir, continued with 2 mg, and the dose was adjusted to achieve target trough levels between 8 and 14 ng/mL. MMF was continued with trough level adjusted (1.5-4 microg/mL). Subsequently, the CNIs were tapered down and stopped. Clinical follow-up (first and every 3 months after conversion) included endomyocardial biopsies, echocardiography, and laboratory studies. Survival was 90% after a mean follow-up of 13+/-95 months. No acute rejection episode was detected during the study period. Renal function improved significantly after conversion: creatinine preconversion vs. postconversion: 3.14+/-0.76 mg/dL vs. 2.14+/-0.83 mg/dL, P =0.001. Cystatin preconversion vs. postconversion: 2.95+/-1.06 mg/L vs. 2.02+/-1.1 mg/L, P =0.01. In three patients, hemodialysis therapy was stopped completely after conversion. Graft function remained stable. Fractional shortening preconversion vs. postconversion: 36.9+/-6% vs. 36.4+/-6%. There were no serious adverse events. One patient had to be excluded because of noncompliance. CONCLUSIONS: Conversion from CNI-based immunosuppression to MMF and Sir in HTx patients with chronic renal failure was safe, preserved graft function, and improved renal function.     

D1 dopamine receptor signaling involves caveolin-2 in HEK-293 cells

BACKGROUND: Dopamine receptors in the kidney, especially those belonging to the D1-like receptor family, are important in the regulation of renal function and blood pressure. Because of increasing evidence that G protein-coupled receptors (GPCRs) are associated with caveolae and lipid rafts, we tested the hypothesis that the D1 dopamine receptor (D1R) and signaling molecules are regulated by caveolin in caveolae or lipid rafts. METHODS: Six experimental approaches were used: (1) construction of tagged human D1Rs (hD1Rs) and transfectants; (2) cell culture [human embryonic kidney (HEK)-293 and immortalized rat renal proximal tubule cells] and biotinylation; (3) cell fractionation by sucrose gradient centrifugation; (4) immunoprecipitation and immunoblotting; (5) immunofluorescence and confocal microscopy; and (6) adenylyl cyclase assays. RESULTS: hD1Rs, heterologously expressed in HEK-293 cells, formed protein species with molecular mass ranging from 50 to 250 kD, and were localized in lipid rafts and nonraft plasma membranes. The hD1Rs cofractionated with caveolin-2, G protein subunits, and several signaling molecules. Both exogenously expressed hD1Rs and endogenously expressed rat D1Rs colocalized and coimmunoprecipitated with caveolin-2. A D1R agonist (fenoldopam) increased the amount of caveolin-2beta associated with hD1Rs and activated adenylyl cyclase to a greater extent in lipid rafts than in nonraft plasma membranes. Reduction in the expression of caveolin-2 with antisense oligonucleotides attenuated the stimulatory effect of fenoldopam on cyclic adenosine monophosphate (cAMP) accumulation. CONCLUSION: The majority of hD1Rs are distributed in lipid rafts. Heterologously and endogenously expressed D1Rs in renal cells are associated with and regulated by caveolin-2.     

Effect of mycophenolate mofetil on kidney graft function and body weight in patients with chronic allograft nephropathy

BACKGROUND: Chronic allograft nephropathy (CAN) is the most common cause of late graft loss. A beneficial effect of mycophenolate mofetil (MMF) on CAN was observed, although, due to the loss of body weight (BW) under MMF, serum creatinine (sCr) and reciprocal sCr may be unsuitable markers of graft function. METHODS: In 17 kidney transplant patients with CAN, azathioprine (Aza) was replaced by MMF. The remaining therapy was not changed; specifically, the cyclosporine (CsA) dose was not decreased. The mean values and regression coefficients of reciprocal sCr, CCr, urinary creatinine excretion (uCr x V), proteinuria, BW, blood pressure (BP), serum cholesterol (sChol), and serum triglycerides (sTG) versus time were analyzed 12 months before and after institution of MMF by a paired-comparison t test. RESULTS: The mean regression coefficient of reciprocal sCr differed significantly before and after conversion to MMF (mean -0.01 +/- 0.01 vs +0.012 +/- 0.029 mg/dL per month), suggesting improved graft function. However, the mean values of BW (74 +/- 15 vs 71 +/- 15 kg, P <.001) and uCr x V (1152 +/- 321 vs 1065 +/- 266 mg per 24 hours, P=.0897) decreased, making the increase in CCr less significant (mean -1.16 +/- 2.69 vs 0.40 +/- 1.79 mL/min per month, P <.05). BP, sChol, sTG, and proteinuria before and after conversion did not differ significantly. Among patients with long-term stable graft function at 36.5 +/- 16.9 months after conversion to MMF there was an almost significant improvement in renal protein excretion. CONCLUSIONS: MMF improved graft function, although this effect was overestimated using reciprocal sCr. Other risk factors, such as BP, sChol, and sTG, showed no significant differences, suggesting that MMF accounted for the improvement in CAN. The course of proteinuria under MMF seems to be of prognostic significance.     

Effect of plantar flexor muscle stiffness on selected gait characteristics

Although plantar flexor muscle strength is known to affect gait characteristics, the effect of plantar flexor (PF) muscle stiffness on gait is unknown. The purpose of this study was to determine the effect of PF muscle stiffness, in addition to PF strength, on the gait characteristics of subjects with diabetes and peripheral neuropathy (DM & PN) and age-matched controls. Thirty-four subjects were tested (17 DM & PN, 17 controls), 10 males and seven females in each group. PF muscle strength (concentric peak torque) explained a significant amount of variance in all gait variables (20–37%). Passive stiffness added a unique contribution to plantar flexor peak moment and walking speed (10–11%). Plantar flexor stiffness, in addition to strength, may be an important factor contributing to gait characteristics. Treatment techniques designed to preserve or increase stiffness may be indicated for patients with limited PF strength.     

Radio-frequency ablation of renal cell carcinoma: early clinical experience

PURPOSE: To report the authors' early experience with radio-frequency (RF) ablation of renal cell carcinoma. MATERIALS AND METHODS: Twenty-four percutaneous RF ablation treatments for nine tumors were performed in eight patients with renal cell carcinoma. Indications included coexistent morbidity, previous surgery, or solitary kidney in patients with a life expectancy shorter than 10 years. Smaller (3 cm) and/or central lesions (n = 6) were treated with cluster or multiple electrodes. Patients returned for a second treatment when follow-up imaging depicted tumor enhancement. Follow-up imaging was performed at 1 and 3 months and then at 6-month intervals, with a mean follow-up of 10.3 months. Seven patients were alive at least 6 months after their initial treatment. RESULTS: All five exophytic tumors were free of enhancement. One of three central tumors was free of enhancement. One tumor had both central and exophytic components and was free of enhancement. Three tumors were 3 cm or smaller and free of enhancement. Of the six tumors larger than 3 cm, four were free of enhancement. CONCLUSION: Percutaneous RF ablation is a promising treatment for select patients with renal cell carcinoma. The ultimate role of this modality will continue to evolve and warrants further study.     

Primary intrasellar schwannoma: clinical, aetiopathological and surgical considerations

Schwannomas originating within the sella turcica are extremely rare. We describe the clinical, radiological and intraoperative findings of a patient with an intrasellar and suprasellar schwannoma. Gross total tumour removal was performed by a trans-sphenoidal approach. Perivascular or ectopic Schwann cells, lateral nerve plexus within the cavernous sinus, as well as Schwann cells from small nerve twigs of the dura are some of the current histopathological hypotheses for the origin of these lesions.     

Improved Performance of Hip DXA Using a Novel Region of Interest in the Upper Part of the Femoral Neck: In Vitro Study Using Bone Strength as a Standard of Reference

We tested the hypothesis that bone mineral density (BMD) and bone mineral content (BMC) in proximal human femur specimens in the upper neck region of interest (ROI) and femoral neck axis length (FNAL) provide a significantly better prediction of femoral bone strength than standard ROIs in vitro. BMD and BMC were measured in 110 proximal femur specimens using a standard dual-energy X-ray absorptiometry (DXA) scanner. The analysis included a new ROI in the upper neck as well as the standard ROIs. FNAL was obtained from the scan images. The specimens' failure-load was measured in a mechanical loading device, simulating a fall on the greater trochanter. For the standard ROIs, correlations between failure-load and BMD ranged from R2 = 0.64 (shaft ROI) to R2 = 0.70, p < 0.001 (femoral neck). Prediction of strength by BMD did not significantly differ from those of BMC (R2 ranging from 0.65 to 0.75, p < 0.001). In the upper neck ROI, for both BMD and BMC correlations with failure-load were higher (R2 = 0.76 and 0.81, respectively; p < 0.001). A lower, yet still significant, correlation was found between FNAL and bone strength (R2 = 0.23, p < 0.001). Normalization of failure-load with respect to FNAL did not significantly increase the correlations with densitometric measures. This study provides in vitro evidence indicating that among the ROIs of the proximal femur the newly defined upper neck ROI provides the best prediction of bone strength. Only a weak association was observed between failure load and FNAL.     

Comparison of ventral corpectomy and plate-screw-instrumented fusion with dorsal laminectomy and rod-screw-instrumented fusion for treatment of at least two vertebral-level spondylotic cervical myelopathy

The objective of the article is to verify the hypothesis that the dorsal multilevel laminectomy and rod-screw-instrumented fusion (DLF) for multilevel spondylotic cervical myelopathy (MSCM) is less strenuous for patients, and less prone to perioperative complications, than ventral multilevel corpectomy and plate-screw-instrumented fusion (VCF), while clinical outcome is comparable. One hundred and three successive patients were treated for at least two vertebral-level MSCM, 42 of them by VCF and 61 by DLF. The two patients groups were retrospectively compared. VCF patients were slightly younger than DLF patients (62.5 ± 10.61 years versus 66 ± 12.4 years, P = 0.012). In VCF patients, a median of 2 (2–3) corpectomies and in DLF patients a median of 3 (2–5) laminectomies were performed. In VCF patients, surgery lasted longer than in DLF patients (229 ± 60 min versus 183 ± 46 min, P ≤ 0.001). Between the VCF and the DLF patients groups, no significant difference was found in perioperative complications (e.g. hardware failure rates of 16.7% in VCF and of 6.6% in the DLF patients) and mortality rates. The postoperative outcome, as assessed by the postoperative change of the Nurick scores, the change of neck pain, the patients’ satisfaction, and the change of the subaxial Cobb angle of the spine did not differ between the two patients groups. However, when comparing the postoperative Nurick scores directly, VCF patients fared somewhat better than DLF patients [median of 2 (0–5) versus 3 (1–5), P = 0.003]. The hypothesized advantages of DLF over VCF in the surgical treatment of at least two vertebral-level MSCM could not be confirmed in this retrospective study. A prospective randomized study is warranted to clarify this issue.     

Body mass index-adapted prospective coronary computed tomography angiography. Determining the lowest limit for diagnostic purposes

Purpose

To investigate the value of 4 different protocols for prospectively triggered 256-slice coronary computed tomography angiography (coronary CTA).

Methods

Two hundred and ten patients underwent prospectively triggered coronary CTA for suspected or known coronary artery disease (CAD). Patients with heart rate >75 bps before the scan despite ß-blocker administration and with arrhythmia were excluded. From January to September 2010, 60 patients underwent coronary CTA using a non-tailored protocol (120 kV; 200 mAs) and served as our ‘control’ group. From September 2010 to April 2012, based on the body mass index (BMI) of the examined patients (BMI subgroups of < 25; 25–28; 28–30, and ≥ 30 kg/m²) current tube voltage and tube current were: (1) slightly, (2) moderately or (3) strongly reduced, resulting into the 3 following BMI-adapted acquisition groups: (1) a ‘standard’ (100/120 kV; 100–200 mAs; n = 50), 2) a ‘low dose’ (100/120 kV; 75–150 mAs; n = 50), and 3) an ‘ultra-low dose’ (100/120 kV; 50–100 mAs; n = 50) protocol.

Results

Patients examined using the non-tailored protocol exhibited the highest radiation exposure (3.2 ± 0.4 mSv), followed by the standard (1.6 ± 0.7 mSv), low-dose (1.2 ± 0.6 mSv) and ultra-low dose protocol (0.7 ± 0.3 mSv) (radiation savings of 50%, 63% and 78% respectively). Overall image quality was similar with standard dose (1.9 ± 0.6) and low-dose (2.0 ± 0.5) compared to the non-tailored group (1.9 ± 0.5) (p = NS for all). In the ultra-low dose group however, image quality was significant reduced (2.7 ± 0.6), p < 0.05 versus all other groups).

Conclusion

Using BMI-adapted low dose acquisitions image quality can be maintained with simultaneous radiation savings of ∼65% (dose of ∼1 mSv). This appears to be the lower limit for diagnostic coronary CTA, whereas ultra-low dose acquisitions result in significant image degradation.