Recovery of Graft Function Early Posttransplant Determines Long-Term Graft Survival in Deceased Donor Renal Transplants

Introduction

Because kidneys show remarkable resilience and can recover function, we examined the impact on long-term graft survival in deceased donor renal transplants of both immediate graft function (IGF) and the rate of renal function recovery over the first 3 months after transplantation.

Methods

We included all cadaveric renal transplants from 1990 to 2007 (n = 583). Delayed graft function (DGF) was defined as the need for dialysis in the first 7 days posttransplant. Slow graft function (SGF) and IGF were defined by serum creatinine falls of <20% or >20% in the first 24 hours posttransplant respectively. Recovery of renal function was expressed as either the best creatinine clearance (CrCl) in the first 3 months post-renal transplantation (BCrCl-3mos) as calculated using the Cockcroft-Gault formula or as a percentage of actual versus expected value (as calculated from the donors' CrCl at procurement).

Results

There were 140 (23.6%) subjects who received extended criteria donor (ECD) organs. The overall graft survival at 1 and 5 years was 87.8% and 74%, respectively. The 5-year graft survivals for patients with IGF, SGF, and DGF were 85%, 76%, and 54%, respectively (P < .02). ECD kidneys showed twice the DGF rate (49% vs 23%, P < .001). BCrCl-3mos of <30 mL/min displayed a 5-year graft survival of 34%; 30 to 39 mL/min, 72%; 40 to 49 mL/min, 85%; and >50 mL/min, 82% (P < .001). Similarly, a recovery within 90% of expected CrCl in the first 3 months posttransplant correlated with 5-year graft survival of 81%; a recovery of 70% to 90%, with 65%; and a recovery of <70%, with 51% (P < .001).

Conclusion

Early graft function in the first 3 months showed a significant impact on long-term graft survival after deceased donor renal transplantation.     

Claudin-2 is selectively enriched in and promotes the formation of breast cancer liver metastases through engagement of integrin complexes

The liver represents the third most frequent site of metastasis in patients with breast cancer. We performed in vivo selection using 4T1 breast cancer cells to identify genes associated with the liver metastatic phenotype. Coincident with the loss of numerous tight-junctional proteins, we observe claudin-2 overexpression, specifically in liver-aggressive breast cancer cells. We further demonstrate that claudin-2 is both necessary and sufficient for the ability of 4T1 breast cancer cells to colonize and grow in the liver. The liver-aggressive breast cancer cells display a claudin-2-mediated increase in their ability to adhere to extracellular matrix (ECM) components, such as fibronectin and type IV collagen. Claudin-2 facilitates these cell/matrix interactions by increasing the cell surface expression of α(2)β(1)- and α(5)β(1)-integrin complexes in breast cancer cells. Indeed, claudin-2-mediated adhesion to fibronectin and type IV collagen can be blocked with neutralizing antibodies that target α(5)β(1) and α(2)β(1) complexes, respectively. Immunohistochemical analyses reveal that claudin-2, although weakly expressed in primary human breast cancers, is readily detected in all liver metastasis samples examined to date. Together, these results uncover novel roles for claudin-2 in promoting breast cancer adhesion to the ECM and define its importance during breast cancer metastasis to the liver.     

Arterial stiffness and wave reflections in patients with sickle cell disease

We tested the hypothesis that lower blood pressure and increased vasodilatation reported in sickle cell disease (SCD) patients with hemoglobin SS genotype (SS) are translated by lower arterial stiffness determined by pulse wave velocity (PWV) and wave reflections assessed by augmentation index (AI). We enrolled 20 SS (8 females; 12 male) patients closely matched for age, gender, height, and body mass index to 20 subjects with hemoglobin AA genotype (AA). Carotid-femoral PWV (PWV(CF)) and carotid-radial PWV (PWV(CR)) were recorded with the Complior device. Aortic AI was derived from pressure wave analysis (SphygmocoR). PWV(CF) and PWV(CR) were lower in SS than in AA (4.5+/-0.7 m/s versus 6.9+/-0.9 m/s, P<0.0001 and 6.6+/-1.2 m/s versus 9.5+/-1.4 m/s, P<0.0001, respectively). AI was lower in SS than in AA (2+/-14% versus 11+/-8%, P=0.02). Multivariate analysis revealed that both PWV(CF) and PWV(CR) were negatively associated with hemoglobin SS type and positively related to mean arterial pressure (MAP), whereas AI was positively associated with MAP and total cholesterol (all P<0.0001). Multivariate analysis restricted to SS indicated a positive association between PWV(CF) and PWV(CR) with age but a negative association with MAP (R2=0.57 and 0.51, respectively, both P<0.001), whereas MAP and heart rate were independently associated with AI (R2=0.65, P<0.001). This study provides the first evidence that SCD is associated with both lower arterial stiffness and wave reflections. SS patients have a paradoxical negative association between PWV and MAP, suggesting that low MAP does not protect them against arterial stiffness impairment.     

Nonalcoholic Fatty Liver Disease: Noninvasive Methods of Diagnosing Hepatic Steatosis

Hepatic steatosis is the buildup of lipids within hepatocytes. It is the simplest stage in nonalcoholic fatty liver disease (NAFLD). It occurs in approximately 30% of the general population and as much as 90% of the obese population in the United States. It may progress to nonalcoholic steatohepatitis, which is a state of hepatocellular inflammation and damage in response to the accumulated fat. Liver biopsy remains the gold standard tool to diagnose and stage NAFLD. However, it comes with the risk of complications ranging from simple pain to life-threatening bleeding. It is also associated with sampling error. For these reasons, a variety of noninvasive radiological markers, including ultrasound, computed tomography, magnetic resonance spectroscopy, and the controlled attenuation parameter using transient elastography and Xenon-133 scan have been proposed to increase our ability to diagnose NAFLD, hence avoiding liver biopsy. The aim of this review is to discuss the utility and accuracy of using available noninvasive diagnostic modalities for fatty liver in NAFLD.     

Pancreatic cancer and predictors of survival: comparing the CA 19-9/bilirubin ratio with the McGill Brisbane Symptom Score

Introduction

Few tools predict survival from pancreatic cancer (PAC). The McGill Brisbane Symptom Score (MBSS) based on symptoms at presentation (weight loss, pain, jaundice and smoking) was recently validated. The present study compares the ability of four strategies to predict 9-month survival: MBSS, carbohydrate antigen 19-9 (CA 19-9) alone, CA19-9-to-bilirubin ratio and a combination of MBSS and the CA19-9-to-bilirubin ratio.

Methodology

A retrospective review of 133 patients diagnosed with PAC between 2005 and 2011 was performed. Survival was determined from the Quebec civil registry. Blood CA 19-9 and bilirubin values were collected (n = 52) at the time of diagnosis. Receiver-operating characteristic (ROC) curves were used to determine a cutoff for optimal test characteristics of CA 19-9 and CA19-9-to-total bilirubin ratio in predicting survival at 9 months. Predictive characteristics were then calculated for the four strategies.

Results

Of the four strategies, the one with the greatest negative predictive value was the MBSS: negative predictive value (NPV) was 90.2% (76.9–97.3%) and the positive likelihood ratio (LR) was the greatest. The ability of CA 19-9 levels alone, at baseline, to predict survival was low. For the CA19-9-to-bilirubin ratio, the test characteristics improved but remained non-significant. The best performing strategy according to likelihood ratios was the combined MBSS and CA19-9 to the bilirubin ratio.

Conclusion

CA19-9 levels and the CA19-9-to-bilirubin ratio are poor predictors of survival for PAC, whereas the MBSS is a far better predictor, confirming its clinical value. By adding the CA19-9-to-bilirubin ratio to the MBSS the predictive characteristics improved.     

Norepinephrine and traumatic brain injury: a possible role in post-traumatic edema

Unilateral cerebral contusion is associated with an early (30 min) increase in norepinephrine (NE) turnover followed by a later (6–24 h) depression of turnover which is bilateral and widespread throughout the brain. Blockade of NE function during the first few hours after traumatic brain injury (TBI) impedes subsequent recovery of function without enlarging the size of the lesion. The current studies were carried out to characterize further the timing of the switch from increased to decreased NE turnover and to investigate the pathogenesis of the delayed recovery of function associated with blocking NE function. Adult male rats had unilateral somatosensory cortex contusions made with a 5 mm diameter impact piston. They were killed after 2 h and their brains analyzed for NE turnover by HPLC with electrochemical detection. In general, NE turnover (the ratio of 3-methoxy-4-hyroxyphenylglycol to NE levels) had returned to sham-lesion control levels in most brain regions by 2 h after either left or right sided contusions. The only exceptions were a persistent 87% increase at the lesion site after right-sided contusions and 22% and 32% increases in the contralateral cerebellum after right- and left-sided contusions, respectively. Blockade of α₁-adrenoceptors by treatment with prazosin (3 mg/ kg, i.p.) 30 min prior to TBI produced edema in the striatum and hippocampus at 24 h which was not seen saline-treated rats nor in rats where NE reuptake was blocked with desmethylimipramine (DMI; 10 mg/kg, i.p.). DMI increased edema at the lesion site at 24 h, however. These data suggest that the early increase in NE release following unilateral cerebral contusion is protective and that this may act to stabilize the blood–brain barrier in areas adjacent to the injury site. Drugs that interfere with this enhanced noradrenergic function might enhance the damage caused by TBI.     

Primary and secondary prevention among adults: An analysis with comments on screening and health education

A review of the literature relating to a variety of diseases afflicting adults shows that only a small number is preventable by risk factor modification, and in the majority, the risk factors are the societal intoxicants alcohol and tobacco. There is also only a small number of diseases in which there is clear evidence that detection in the early presymptomatic stages results in an outcome different from that observed if the disease is detected when symptoms occur. If primary (risk factor modification) or secondary (early intervention) approaches to medicine are to be effective, health education efforts will have to be augmented markedly. An analysis of health knowledge and patterns of licit and illicit intoxicant use in four schools or school systems suggests that current health education programs are not achieving their stated objectives. A review of current screening practices for asymptomatic persons suggests that the battery of tests used might be significantly altered in order to focus efforts on those diseases that present data show reasonably convincingly can be modified by secondary prevention. A 10-point program of selective screening and risk factor modification is proposed which is believed to be achievable, practical, and acceptable to consumers.