Diagnostic Value of Monitoring Human Cytomegalovirus Late pp67 mRNA Expression in Renal-Allograft Recipients by Nucleic Acid Sequence-Based Amplification

The diagnostic value of monitoring human cytomegalovirus (HCMV) late pp67 mRNA expression by nucleic acid sequence-based amplification (NASBA) after renal-allograft transplantation was evaluated. RNAs were isolated from 489 whole-blood specimens of 42 patients for the specific amplification of the late pp67 (UL65) mRNA. NASBA results were compared to results from the pp65 antigenemia assay, virus isolation by cell culture, and serology. The sensitivity value for NASBA proved to be higher than that for the antigenemia assay (50 versus 35%) for the detection of HCMV infection, while the sensitivity values of cell culture and NASBA were comparable (54 and 50%, respectively). NASBA detected the onset of HCMV infection simultaneously with cell culture and the antigenemia assay. Both the antigenemia assay and NASBA are very specific (100%) and highly predictive (100%) for the onset of HCMV infection. Antiviral therapy with ganciclovir resulted in negative results for cell culture, the antigenemia assay, and NASBA. In conclusion, monitoring HCMV pp67 mRNA expression by NASBA is a highly specific method for the detection of HCMV infection in renal-allograft recipients and is more sensitive than the antigenemia assay. Furthermore, NASBA can be used to monitor the progression of HCMV infections and the effect of antiviral therapy on viral activity.     

A mutation update for the FLNC gene in myopathies and cardiomyopathies

Filamin C (FLNC) variants are associated with cardiac and muscular phenotypes. Originally, FLNC variants were described in myofibrillar myopathy (MFM) patients. Later, high‐throughput screening in cardiomyopathy cohorts determined a prominent role for FLNC in isolated hypertrophic and dilated cardiomyopathies (HCM and DCM). FLNC variants are now among the more prevalent causes of genetic DCM. FLNC‐associated DCM is associated with a malignant clinical course and a high risk of sudden cardiac death. The clinical spectrum of FLNC suggests different pathomechanisms related to variant types and their location in the gene. The appropriate functioning of FLNC is crucial for structural integrity and cell signaling of the sarcomere. The secondary protein structure of FLNC is critical to ensure this function. Truncating variants with subsequent haploinsufficiency are associated with DCM and cardiac arrhythmias. Interference with the dimerization and folding of the protein leads to aggregate formation detrimental for muscle function, as found in HCM and MFM. Variants associated with HCM are predominantly missense variants, which cluster in the ROD2 domain. This domain is important for binding to the sarcomere and to ensure appropriate cell signaling. We here review FLNC genotype–phenotype correlations based on available evidence.     

Body composition in renal transplant patients: bioimpedance analysis compared to isotope dilution, dual energy X-ray absorptiometry, and anthropometry

Whether multifrequency bioelectrical impedance analysis (MF-BIA), a relatively new method for measuring body composition, is also applicable for accurate body composition measurements in renal transplant (RTx) patients is not known. Therefore, the use of MF-BIA is validated in 77 RTx patients with a stable renal function at least 2 yr posttransplantation. MF-BIA is compared to isotope dilution techniques for measurement of body water compartments, and to dual energy x-ray absorptiometry (DEXA) and anthropometry for measurement of fat and fat free mass. Finally, DEXA and anthropometry are compared to each other. Method agreement is assessed by intraclass correlation coefficients (ICC) and plotted by Bland and Altman analysis. MF-BIA significantly underestimates total body water (TBW, 0.7+/-2.1 L) and overestimates the extracellular water (ECW, 3.3+/-1.8 L) compared to isotope dilution; the ICC between both techniques is 0.943 for TBW and 0.846 for ECW. The percentage body fat (BF) measured by MF-BIA is significantly higher than both BF measured by DEXA (3.4+/-4.7%) or by anthropometry (5.5+/-5.2%). The ICC between MF-BIA and DEXA is 0.887 and between MF-BIA and anthropometry 0.856. BF measured by DEXA is significantly higher than BF measured by anthropometry (2.1+/-4.4%); their ICC is 0.913. In conclusion, MF-BIA seems to be suitable for measurement of TBW in RTx patients; however, method agreement between isotope dilution and MF-BIA for the measurement of ECW is not satisfactory. In the assessment of fat and fat free mass, the reliability of MF-BIA appears to be questionable. Method agreement between DEXA and anthropometry seems to be slightly better.     

Effect of immunosuppressive agents on long-term survival of renal transplant recipients: focus on the cardiovascular risk

In the control of acute rejection, attention is being focused more and more on the long-term adverse effects of the immunosuppressive agents used. Since cardiovascular disease is the main cause of death in renal transplant recipients, optimal control of cardiovascular risk factors is essential in the long-term management of these patients. Unfortunately, several commonly used immunosuppressive drugs interfere with the cardiovascular system. In this review, the cardiovascular adverse effects of the immunosuppressive agents currently used for maintenance immunosuppression are thoroughly discussed. Optimising immunosuppression means finding a balance between efficacy and safety. Corticosteroids induce endothelial dysfunction, hypertension, hyperlipidaemia and diabetes mellitus, and impair fibrinolysis. The use of corticosteroids in transplant recipients is undesirable, not only because of their cardiovascular effects, but also because they induce such adverse effects as osteoporosis, obesity, and atrophy of the skin and vessel wall. Calcineurin inhibitors are the most powerful agents for maintenance immunosuppression. The calcineurin inhibitor ciclosporin (cyclosporine) not only induces these same adverse effects as corticosteroids but is also nephrotoxic. Tacrolimus has a more favourable cardiovascular risk profile than ciclosporin and is also less nephrotoxic. It has little or no effect on blood pressure and serum lipids; however, its diabetogenic effect is more prominent in the period immediately following transplantation, although at maintenance dosages, the diabetogenic effect appears to be comparable to that of ciclosporin. The diabetogenic effect of tacrolimus can be managed by reducing the dose of tacrolimus and early corticosteroid withdrawal. The effect of tacrolimus on endothelial function has not been completely elucidated. The proliferation inhibitors azathioprine and mycophenolate mofetil (MMF) have little effect on the cardiovascular system. Yet, indirectly, by inducing anaemia, they may lead to left ventricular hypertrophy. MMF is an attractive alternative to azathioprine because of its higher potency and possibly lower risk of malignancies. Sirolimus also induces anaemia, but may be promising because of its antiproliferative features. Whether the hyperlipidaemia induced by sirolimus counteracts its beneficial effects is, as yet, unknown. It may be combined with MMF, however, initial attempts resulted in severe mouth ulcers.     

The influence of obesity on short- and long-term graft and patient survival after renal transplantation

To determine short- and long-term patient and graft survival in obese [body mass index (BMI) >or= 30 kg/m(2)] and nonobese (BMI < 30 kg/m(2)) renal transplant patients we retrospectively analyzed our national-database. Patients 18 years or older receiving a primary transplant after 1993 were included. A total of 1,871 patients were included in the nonobese group and 196 in the obese group. In the obese group there were significantly more females (52% vs. 38.6%, P < 0.01) and patients were significantly older [52 years (43-59) vs. 48 years (37-58); P < 0.05]. Patient survival and graft survival were significantly decreased in obese renal transplant recipients (1 and 5 year patient survival were respectively 94% vs. 97% and 81% vs. 89%, P < 0.01; 1 and 5 year graft survival were respectively 86% vs. 92% and 71% vs. 80%, P < 0.01). Initial BMI was an independent predictor for patient death and graft failure. This large retrospective study shows that both graft and patient survival are significantly lower in obese renal transplant recipients.