Obstetric and long‐term kidney outcomes in renal transplant recipients: a 40‐yr single‐center study

Female renal transplant recipients of childbearing age may ask what the outcomes are for pregnancy and whether pregnancy will affect graft function. We analyzed obstetric and transplant outcomes among renal transplant recipients in our center who have been pregnant between 1973 and 2013. A case?cohort study was performed identifying 83 pairs of pregnant and non‐pregnant controls matched for sex, age, transplant vintage, and creatinine. There were 138 pregnancies reported from 89 renal transplant recipients. There were live births in 74% of pregnancies with high prevalence of prematurity (61%), low birth weight (52%), and pre‐eclampsia (14%). Lower eGFR (OR 0.98; p = 0.05) and higher uPCR (OR 1.86; p = 0.02) at conception were independent predictors for poor composite obstetric outcome. Lower eGFR (OR 0.98; p = 0.04), higher uPCR (OR 1.50; p = 0.04), and live organ donation (OR 0.35; p = 0.02) were predictors of ≥20% loss of eGFR between immediately pre‐pregnancy and one yr after delivery. There was no difference in eGFR at one, five, and 10 yr in pregnant women compared with non‐pregnant controls and a pregnancy was not associated with poorer 10‐yr transplant or 20‐yr patient survival. Despite high rates of obstetric complications, most women had successful pregnancies with good long‐term transplant function.     

Early initiation of dialysis fails to prolong survival in patients with end-stage renal failure

There is a trend to start dialysis earlier in patients with chronic renal failure. Studies that suggest improved survival from earlier initiation of dialysis are flawed in that they have measured survival from start of dialysis rather than from a time point before dialysis, when patients have the same renal function. This flaw is termed lead-time bias. Using the electronic patient record at the renal unit of Glasgow Royal Infirmary, all patients were identified who had received dialysis for chronic renal failure and who had sufficient data to calculate the time point at which they reached an estimated creatinine clearance (eC(Cr)) of 20 ml/min (n = 275). This date was used to time survival. The patients were divided into early and late start groups by the median eC(Cr) for all patients at initiation of dialysis, which was 8.3 ml/min. There was no significant benefit in patient survival from earlier initiation of dialysis. A Cox proportional hazards model demonstrated a significant inverse relationship between eC(Cr) at start of dialysis and survival (hazard ratio, 1.1; P = 0.02), i.e., patients who started dialysis with a lower eC(Cr) tended to survive longer. This relationship retained significance when gender, age, weight, presence of diabetes, mode of first dialysis, initial dialysis access, hemoglobin, serum albumin, blood leukocyte count, Wright/Khan index, and eC(Cr) at the start of dialysis were taken into account. This study fails to support a policy of earlier initiation of dialysis for patients with end-stage renal failure.     

Increased atherogenicity of low-density lipoprotein in heavy proteinuria

Background: Heavy proteinuria is associated with marked abnormalities of lipoprotein metabolism and increased risk of atherogenesis. It is possible that qualitative as well as quantitative changes occur in lipoproteins to contribute to increased cardiovascular risk; for example, it is known that LDL exhibits heterogeneity, with small, dense LDL III particles being more atherogenic. Methods: We investigated LDL subfractions (measured by density gradient ultracentrifugation), VLDL subfractions, and post-heparin lipases in 12 patients with primary glomerular disease and 24-h albuminuria >2.5 g. These were compared to 23 age- and sex-matched controls. Results: Total LDL concentrations were similar in proteinuric patients and controls; however, there was a shift in subfraction distribution. The larger LDL I and LDL II particles were lower in the proteinuric group (29±24 vs 62±26 mg/dl P=0.011 and 121±80 vs 197±74 mg/dl P=0.028), whereas the concentration of atherogenic LDL III (small dense) was higher (135±64 vs 75±71 mg/dl P=0.0016). The concentration of total VLDL and both its subfractions were increased in the patients with proteinuria. Post-heparin hepatic and lipoprotein lipase levels were similar to normal. Conclusions: These findings suggest that the atherogenicity of LDL is increased in patients with heavy proteinuria because of the redistribution towards smaller denser particles. Since small, dense LDL has a lower affinity for the LDL receptor, the altered nature of the lipoprotein in proteinuria may decrease its clearance by the receptor-mediated pathway and contribute to the reduced clearance of LDL observed in this population. This may contribute to progression of renal failure or the accelerated vascular disease found in patients with heavy proteinuria.     

Assessment and interpretation of isokinetic muscle strength during growth and maturation

The majority of strength studies examining changes during growth and maturation have investigated isometric actions, which tell us little about the muscle under dynamic conditions. There are numerous methodological issues in the isokinetic testing of paediatric populations that require further investigation. However, several studies have indicated that children can be reliably assessed isokinetically using both concentric and eccentric actions. Most paediatric studies have examined the knee joint and more data are needed to elucidate the reliability of upper body isokinetic strength testing. The age- and sex-associated development of isokinetic strength is less well understood. Studies have indicated that isokinetic strength increases with age but the mechanisms associated with this increase require further investigation. Current data are also conflicting regarding the age at which sex differences become apparent in isokinetic strength. More work is needed to examine the influence of maturation on isokinetic strength development, but available data suggest that maturation is a non-significant contributory factor once stature and body mass are accounted for. Most studies have demonstrated a significant relationship between stature, body mass and isokinetic strength during growth and maturation. The importance that changes in body composition during growth have on isokinetic strength has been investigated using fat-free mass and muscle cross-sectional area. Data have shown that although fat-free mass and muscle cross-sectional area are important contributors to isokinetic strength, other unexplained factors also influence isokinetic strength development. Additional work needs to investigate possible qualitative changes in muscle during growth and maturation. More work is also needed to examine changes in eccentric strength with age and to investigate sex differences in upper body isokinetic strength. Future studies should preferably be longitudinal in nature and examine known covariates simultaneously using appropriate statistical techniques.     

Two "knockout" mouse models demonstrate that aortic vasodilatation is mediated via alpha2a-adrenoceptors located on the endothelium

UK-14,304 [5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine]-mediated vasodilator responses were studied on wire myograph-mounted mouse aorta to determine the cells involved, mechanisms of action, and subtypes of alpha(2)-adrenoceptors. In the presence of induced tone, UK-14,304 produced concentration-related vasodilatation that was abolished by rauwolscine, N(omega)-nitro-L-arginine methyl ester (L-NAME), or endothelium removal, indicating that endothelial alpha(2)-adrenoceptors can release nitric oxide. In the alpha(2A)-adrenoceptor knockout mouse and the D79N mouse, a functional knockout of the alpha(2A)-adrenoceptor, these relaxant effects of UK-14,304 were lost, indicating the involvement of the alpha(2A)-adrenoceptor. UK-14,304 could also contract aorta: a small contraction occurred at high concentrations, was enhanced by L-NAME, and was absent in the alpha(1D)-adrenoceptor knockout mouse, indicating activation of the alpha(1D)-adrenoceptor. There was no evidence for a contractile alpha(2)-adrenoceptor-mediated response. A fluorescent ligand, quinazoline piperazine bodipy, antagonized the relaxant action of UK-14,304. This compound could be visualized on aortic endothelial cells, and its binding could be prevented by rauwolscine, providing direct evidence for the presence of alpha(2)-adrenoceptors on the endothelium. Norepinephrine reduced tone in the alpha(1D)-adrenoceptor knockout and controls, an effect blocked by rauwolscine and L-NAME but not by prazosin. This suggests that norepinephrine activates endothelial alpha(2)-adrenoceptors. In conclusion, the endothelium of mouse aorta has an alpha(2A)-adrenoceptor that responds to norepinephrine; promotes the release of nitric oxide, causing smooth muscle relaxation; and that can be directly visualized. Knockout or genetic malfunction of this receptor should increase arterial stiffness, exacerbated by raised catecholamines, and contribute to heart failure.     

Interleukin-4 mediates the neuroprotective effects of rosiglitazone in the aged brain

Increased expression of proinflammatory cytokines, like interleukin-1 beta (IL-1 beta), is a feature of the aged brain and it is generally accepted that the primary cell source of these cytokines is activated microglia. In hippocampus of aged rats, the increase in IL-1 beta is accompanied by microglial activation and impaired long-term potentiation (LTP). Peroxisome proliferator-activated receptors (PPARs) possess anti-inflammatory properties that target microglia. In this study the PPAR gamma agonist, rosiglitazone, was orally administered to young and aged rats, and we report that the age-related increases in NO and IL-1 beta production were attenuated in hippocampus of rosiglitazone-treated aged rats and that this was associated with a restoration of LTP. In addition, treatment with rosiglitazone increased interleukin-4 (IL-4) mRNA and reversed the age-related decrease in hippocampal IL-4 concentration. Significantly, while rosiglitazone attenuated the LPS-induced increase in MHCII and IL-1 beta concentration in glia prepared from wildtype mice, it failed to exert an effect in glia prepared from IL-4(-/-) mice, thereby suggesting that the anti-inflammatory actions of rosiglitazone are mediated by its ability to increase IL-4 expression.