Filtration Markers, Cardiovascular Disease, Mortality, and Kidney Outcomes in Stable Kidney Transplant Recipients: The FAVORIT Trial.

Cystatin C and beta-2-microglobulin (B2M) are filtration markers associated with adverse outcomes in nontransplant populations, sometimes with stronger associations than for creatinine. We evaluated associations of estimated glomerular filtration rate from cystatin C (eGFRcys ), B2M (eGFRB2M ), and creatinine (eGFRcr ) with cardiovascular outcomes, mortality, and kidney failure in stable kidney transplant recipients using a case-cohort study nested within the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial. A random subcohort was selected (N = 508; mean age 51.6 years, median transplant vintage 4 years, 38% women, 23.6% nonwhite race) with enrichment for cardiovascular events (N = 306; 54 within the subcohort), mortality (N = 208; 68 within the subcohort), and kidney failure (N = 208; 52 within the subcohort). Mean eGFRcr , eGFRcys , and eGFRB2M were 46.0, 43.8, and 48.8 mL/min/1.73m2 , respectively. After multivariable adjustment, hazard ratios for eGFRcys and eGFRB2M <30 versus 60+ were 2.02 (95% confidence interval [CI] 1.09-3.76; p = 0.03) and 2.56 (1.35-4.88; p = 0.004) for cardiovascular events; 3.92 (2.11-7.31) and 4.09 (2.21-7.54; both p < 0.001) for mortality; and 9.49 (4.28-21.00) and 15.53 (6.99-34.51; both p < 0.001) for kidney failure. Associations persisted with additional adjustment for baseline eGFRcr . We conclude that cystatin C and B2M are strongly associated with cardiovascular events, mortality, and kidney failure in stable kidney transplant recipients.

Estimated GFR for Living Kidney Donor Evaluation.

All living kidney donor candidates undergo evaluation of GFR. Guidelines recommend measured GFR (mGFR), using either an endogenous filtration marker or creatinine clearance, rather than estimated GFR (eGFR), but measurement methods are difficult, time consuming and costly. We investigated whether GFR estimated from serum creatinine (eGFRcr) with or without sequential cystatin C is sufficiently accurate to identify donor candidates with high probability that mGFR is above or below thresholds for clinical decision making. We combined the pretest probability for mGFR thresholds <60, <70, ≥80, and ≥90 mL/min per 1.73 m(2) based on demographic characteristics (from the National Health and Nutrition Examination Survey) with test performance of eGFR (categorical likelihood ratios from the Chronic Kidney Disease Epidemiology Collaboration) to compute posttest probabilities. Using data from the Scientific Registry of Transplant Recipients, 53% of recent living donors had predonation eGFRcr high enough to ensure ≥95% probability that predonation mGFR was ≥90 mL/min per 1.73 m(2) , suggesting that mGFR may not be necessary in a large proportion of donor candidates. We developed a Web-based application to compute the probability, based on eGFR, that mGFR for a donor candidate is above or below a range of thresholds useful in living donor evaluation and selection.

Baseline neutrophil-to-lymphocyte ratio as a predictive and prognostic biomarker in patients with metastatic castration-resistant prostate cancer treated with cabazitaxel versus abiraterone or enzalutamide in the CARD study.

BACKGROUND: There is growing evidence that a high neutrophil-to-lymphocyte ratio (NLR) is associated with poor overall survival (OS) for patients with metastatic castration-resistant prostate cancer (mCRPC). In the CARD study (NCT02485691), cabazitaxel significantly improved radiographic progression-free survival (rPFS) and OS versus abiraterone or enzalutamide in patients with mCRPC previously treated with docetaxel and the alternative androgen-receptor-targeted agent (ARTA). Here, we investigated NLR as a biomarker. PATIENTS AND METHODS: CARD was a multicenter, open-label study that randomized patients with mCRPC to receive cabazitaxel (25 mg/m2 every 3 weeks) versus abiraterone (1000 mg/day) or enzalutamide (160 mg/day). The relationships between baseline NLR [< versus ≥ median (3.38)] and rPFS, OS, time to prostate-specific antigen progression, and prostate-specific antigen response to cabazitaxel versus ARTA were evaluated using Kaplan-Meier estimates. Multivariable Cox regression with stepwise selection of covariates was used to investigate the prognostic association between baseline NLR and OS. RESULTS: The rPFS benefit with cabazitaxel versus ARTA was particularly marked in patients with high NLR {8.5 versus 2.8 months, respectively; hazard ratio (HR) 0.43 [95% confidence interval (CI) 0.27-0.67]; P < 0.0001}, compared with low NLR [7.5 versus 5.1 months, respectively; HR 0.69 (95% CI 0.45-1.06); P = 0.0860]. Higher NLR (continuous covariate, per 1 unit increase) independently associated with poor OS [HR 1.05 (95% CI 1.02-1.08); P = 0.0003]. For cabazitaxel, there was no OS difference between patients with high versus low NLR (15.3 versus 12.9 months, respectively; P = 0.7465). Patients receiving an ARTA with high NLR, however, had a worse OS versus those with low NLR (9.5 versus 13.3 months, respectively; P = 0.0608). CONCLUSIONS: High baseline NLR predicts poor outcomes with an ARTA in patients with mCRPC previously treated with docetaxel and the alternative ARTA. Conversely, the activity of cabazitaxel is retained irrespective of NLR.

Use of verapamil to control an inappropriate chronic sinus tachycardia.

Sinus tachycardia is an expected physiologic response to endogenous catecholamine stimulation, although it may limit the use of exogenous agents. We report a case in which persistent sinus tachycardia occurring in a patient with severe bronchospastic pulmonary disease was effectively treated with verapamil.

Preferential uptake of rubidium from extracellular space by glial cells compared to neurons in leech ganglia.

Glial cells play a significant role in maintaining extracellular space (ECS) potassium (K) by temporarily buffering or accumulating excess ECS K and then returning that K to neurons. Yet, little is known about the relative affinity of neurons or glial cells for K when both cells are simultaneously exposed to the same ECS K, in situ. Also, the process by which glial cells return K to neurons remains unknown. Therefore, electron probe X-ray microanalysis was used to measure rubidium (Rb) uptake, as a K tracer, into leech packet neurons and glial cells, and to measure the distribution of cell water content, K, Na and Cl. When ECS Rb was increased from 4 mM to 20 mM, there was a clear preferential Rb uptake into glial cells compared to neurons. At 4 mM extracellular Rb there was only a small difference between uptake velocity of neurons and glial cells (maximum mean uptake velocity at 4 mM Rb was 1.09 for glia, and 0.41 mmol Rb/kg dry wt/s for neurons), whereas at 20 mM extracellular Rb, glial uptake velocity was dramatically greater than of neurons (max. mean Rb uptake velocity for glia was 4.3 compared to 1.47 mmol Rb/kg dry wt/s for neurons). Glial Rb uptake velocity was enhanced by low temperature (max. mean Rb uptake velocity at 20 mM ECS Rb at 6 degrees C was 6.04 for glia compared to 0.78 mmol Rb/kg dry wt/s for neurons) and by substitution of Cl with isethionate (max. mean Rb uptake velocity was 10.6 for glia compared to 1.33 mmol Rb/kg dry wt/s for neurons).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of serotonin and carbachol on glial and neuronal rubidium uptake in leech CNS.

Effects of serotonin (5-HT) and carbachol on Rb uptake (used as a K marker) in leech neuron and glia were studied by electron probe microanalysis (EPMA). Hirudo medicinalis ganglia were perfused 60 s in 4 mM Rb substituted normal leech Ringer's with and without 5-HT (dosage range 5-500 microM) or carbachol (range 10-1000 microM), quench frozen cryosectioned, and subjected to EPMA to determine elemental mass fractions and cell water content. Both 5-HT and carbachol altered leech neuron and glial cell elemental distribution and water content. In glial cells, a dose-dependent increase in Rb uptake was observed following 5-HT (control: 26 +/- 2 microM; 5 microM: 47 +/- 4; 50 microM: 62 +/- 4; 500 microM: 82 +/- 11 mmol/kg dry wt. +/- S.E.M.) and carbachol (10 microM: 35 +/- 3; 100 microM: 52 +/- 3; 1000 microM: 68 +/- 3 mmol/kg dry wt. +/- S.E.M.). In neurons, 5-HT and carbachol had small effects. 5-HT decreased glial and neuronal cell water content. Carbachol decreased neuronal (but not glial) water content by approximately the same amount (mean decrease 9%) regardless of dose. Both 5-HT and carbachol affected glial cell K-accumulating properties, providing evidence that certain neurotransmitters may modulate invertebrate glial cells' K clearance function.

Perioperative prophylaxis with sulbactam and ampicillin compared with metronidazole and cefotaxime in the prevention of wound infection in children undergoing appendectomy.

Sulbactam is a beta-lactamase inhibitor, which when administered with ampicillin, increases the latter agents antibacterial activity against beta-lactamase producing organisms. One hundred children between the ages of 5 and 14 undergoing emergency appendectomy were entered into a prospective randomized trial comparing sulbactam and ampicillin (SA) with metronidazole and cefotaxime (MC) as prophylaxis against postoperative wound infection. Patients in whom the appendix was perforated or gangrenous received a 72-hour course of antibiotics, others received a single dose only. The overall wound infection rate was 8% (14% in patients with perforation or gangrene and 4% in those without). There was no difference in infection rate between the two antibiotic groups; there were three wound infections and one subphrenic abscess in patients receiving SA and four wound infections in patients receiving MC. SA, therefore, appears to be a suitable antibiotic combination for use as prophylaxis in appendicitis in children.

A review of 155 extra-anatomic bypass grafts.

Extra-anatomic bypass grafting has been used as treatment for patients with aorto-iliac disease who were considered unfit for aortic surgery. Eighty five percent of the patients had ischaemic pain at rest or skin necrosis. One hundred and three femorofemoral (FF) grafts, 40 axillounifemoral and 12 axillobifemoral grafts were performed. Femoropopliteal extension grafts were performed in 39 cases. The three year cumulative graft patency rate was 69% for FF grafts and 48% for both types of axillofemoral (AF) graft, falling to 61% for FF grafts and 32% for AF grafts at five years. The long term patient survival rate was poor, particularly for AF grafts, 27% at five years, reflecting the poor general condition of these patients. In addition almost a quarter of AF grafts required declotting at some stage. However, worthwhile limb salvage rates were obtained with both types of grafts, 69% for FF and 72% for AF at three years and 61% for FF and 65% for AF at five years, suggesting that these grafts should be employed as a means of avoiding amputation in poor risk patients.

The late results of renal transplantation and the importance of chronic rejection as a cause of graft loss.

The results of 279 renal transplants performed in a single centre between 1974 and 1986 are reviewed. Improvements in the management of acute rejection and a reduction in mortality have resulted in an improvement in 1-year actuarial graft survival rates from 44% for transplants performed before 1980 to 68% for those performed after 1983. After the second year post-transplant there has been a steady rate of graft failure (6% per annum), mainly due to chronic rejection. In total 52 grafts have developed chronic rejection (19% of the total and 30% of those at risk at 6 months). Chronic rejection is assuming greater relative importance as a cause of graft loss as early results improve.

Characteristics of cadaveric renal allograft recipients developing chronic rejection.

As the early results of renal transplantation improve, chronic rejection is increasing in relative importance as a cause of graft loss. The aetiology of the condition is unknown. In order to identify possible predisposing factors, the characteristics of 22 patients with chronic rejection were compared with those of 50 patients with stable graft function 2 years or more after transplantation. Patients with chronic rejection had significantly more acute rejection episodes in the first 6 months after transplant (P less than 0.01), a higher incidence of acute rejection with vascular features (P less than 0.01), and longer ischaemic times (P less than 0.05) compared to patients with stable graft function. In a logistic regression analysis both frequency and severity of acute rejection episodes were significantly associated with the subsequent development of chronic rejection. Thus chronic rejection is associated with early injury to the transplanted kidney.