Late initiation of continuous veno-venous hemofiltration therapy is associated with a lower survival rate in surgical critically ill patients with postoperative acute kidney injury

There is controversy about the appropriate timing for renal replacement therapy in patients with acute kidney injury (AKI). We are interested in the appropriate timing for initiation of continuous renal replacement therapy in critically ill surgical patients with postoperative acute kidney injury. Seventy-three critically ill surgical patients with postoperative AKI who received continuous renal replacement therapy (CRRT) were enrolled. Indications for CRRT were: 1) AKI with hyperkalemia, 2) metabolic acidosis, 3) pulmonary edema refractory to diuretics, and 4) oliguria with progressive azotemia, especially in unstable hemodynamics. Using RIFLE (Risk, Injury, Failure, Loss, End stage) classification, patients who received CRRT in the "Risk" stage were defined as early group, whereas those in the "Injury/ Failure" stage were labeled as late group. We used continuous veno-venous hemofiltration as CRRT in this series. There were 20 patients in the early group and 53 patients in the late group. The mean ages were 61.5 ± 21.8 years versus 60.8 ± 17.5 years. The mortality rate was 50 per cent versus 84.9 per cent. There were no significant differences in demographic characteristics or type of surgery or physiological scores. Our data show that late initiation of CRRT is associated with a lower survival rate in critically ill surgical patients with postoperative AKI; however, further studies are required.     

Treatment of critically ill children with kidney injury by sustained low-efficiency daily diafiltration

Background

Continuous renal replacement therapy (CRRT) and intermittent hemodialysis (IHD) offer diverse benefits and drawbacks for critically ill children with acute kidney injury (AKI). Sustained low-efficiency daily diafiltration (SLEDD-f) involves a conceptual and technical hybrid of CRRT and IHD. We report our SLEDD-f application to critically ill children in the pediatric intensive care unit (PICU).

Methods

SLEDD-f was delivered by the new Fresenius 5008 therapy system with blood flow 5?ml/kg/min, dialysate flow 260?ml/min, hemofiltration 35?ml/kg/h for 8–10?h daily. Changes in blood pressure, blood gas, electrolyte, hemoglobulin (Hb), and hematocrit (Hct) were closely monitored.

Results

From February 2010 to June 2011, 14 critical patients with a total of 60 SLEDD-f sessions were studied retrospectively. Heparin was used in 46 sessions (76.6%) with no bleeding complications. Hypertension above 135?mmHg returned to normal, hypotension below 90?mmHg showed no drop. Metabolic acidosis and hyperkalemia normalized. Elevated Hb, Hct, and their ratio revealed improving hemodilution. Three episodes of intradialytic hypotension (5.0%) and one of circuit clotting (1.7%) led to premature termination. The 28-day survival rate was 71.4%.

Conclusions

This pilot investigation demonstrates that SLEDD-f provides good hemodynamic tolerance and correction of fluid overload, pH, and electrolyte imbalance for critically ill children with AKI.     

A murine model of neurofibromatosis type 1 tibial pseudarthrosis featuring proliferative fibrous tissue and osteoclast‐like cells

Neurofibromatosis type 1 (NF1) is a common genetic condition caused by mutations in the NF1 gene. Patients often suffer from tissue‐specific lesions associated with local double‐inactivation of NF1. In this study, we generated a novel fracture model to investigate the mechanism underlying congenital pseudarthrosis of the tibia (CPT) associated with NF1. We used a Cre‐expressing adenovirus (AdCre) to inactivate Nf1 in vitro in cultured osteoprogenitors and osteoblasts, and in vivo in the fracture callus of Nf1^flox/flox and Nf1^flox/? mice. The effects of the presence of Nf1^null cells were extensively examined. Cultured Nf1^null‐committed osteoprogenitors from neonatal calvaria failed to differentiate and express mature osteoblastic markers, even with recombinant bone morphogenetic protein‐2 (rhBMP‐2) treatment. Similarly, Nf1^null‐inducible osteoprogenitors obtained from Nf1 mouse muscle were also unresponsive to rhBMP‐2. In both closed and open fracture models in Nf1^flox/flox and Nf1^flox/? mice, local AdCre injection significantly impaired bone healing, with fracture union being <50% that of wild type controls. No significant difference was seen between Nf1^flox/flox and Nf1^flox/? mice. Histological analyses showed invasion of the Nf1^null fractures by fibrous and highly proliferative tissue. Mean amounts of fibrous tissue were increased upward of 10‐fold in Nf1^null fractures and bromodeoxyuridine (BrdU) staining in closed fractures showed increased numbers of proliferating cells. In Nf1^null fractures, tartrate‐resistant acid phosphatase–positive (TRAP+) cells were frequently observed within the fibrous tissue, not lining a bone surface. In summary, we report that local Nf1 deletion in a fracture callus is sufficient to impair bony union and recapitulate histological features of clinical CPT. Cell culture findings support the concept that Nf1 double inactivation impairs early osteoblastic differentiation. This model provides valuable insight into the pathobiology of the disease, and will be helpful for trialing therapeutic compounds. © 2012 American Society for Bone and Mineral Research     

Anti‐gal antibodies in α1,3‐galactosyltransferase gene‐knockout pigs

Fang J, Walters A, Hara H, Long C, Yeh P, Ayares D, Cooper DKC, Bianchi J. Anti‐gal antibodies in α1,3‐galactosyltransferase gene‐knockout pigs. Xenotransplantation 2012; 19: 305–310. © 2012 John Wiley & Sons A/S. Abstract Serum anti‐galactose‐α1,3‐galactose (Gal) IgM and IgG antibody levels were measured by ELISA in α1,3‐galactosyltransferase gene‐knockout (GTKO) pigs (78 estimations in 47 pigs). A low level of anti‐Gal IgM was present soon after birth, and rose to a peak at 4–6 m, which was maintained thereafter even in the oldest pigs tested (at >2 yr). Anti‐Gal IgG was also present at birth, peaked at 3 m, and after 6 m steadily decreased until almost undetectable at 20 m. No differences in this pattern were seen between pigs of different gender. Total IgM followed a similar pattern as anti‐Gal IgM, but total IgG did not decrease after 6m. The data provide useful baseline data for future experimental studies in GTKO pigs, e.g., relating to the antibody response to WT pig allografts.     

Inhibition of nitric oxide can ameliorate apoptosis and modulate matrix protein gene expression in bacteria infected chondrocytes in vitro.

Bacterial infection stimulates nitric oxide (NO) production in chondrocytes. However, the role of NO in chondrocyte apoptosis after infection remains unclear. The purpose of the study was to test if inhibition of NO could ameliorate apoptosis and modulate matrix protein gene expression in bacteria-infected chondrocytes. It was shown that pre-treating chondrocytes with L-NAME (1 mM) significantly decreased the release of NO (from 72 to 14 microM) and the extent of apoptosis (from 52.9% to 18.9%). Pre-treatment with L-NAME also counteracted the bacteria-induced downregulation of Type II collagen (from 26% to 79%) and aggrecan (from 63% to 105%) mRNA levels. Inhibition of NO after the induction of infection could not decrease the extent of apoptosis and modulate matrix protein gene expression. The results of this study support the hypothesis that NO has an important role in bacteria-induced chondrocyte apoptosis. Pre-treatment but not post-treatment could ameliorate the extent of apoptosis and reestablish the cartilage matrix protein gene expression. This study suggests that in addition to NO, other mechanisms may be responsible for the sustained destruction of articular cartilage in the post-infectious arthropathy.     

Preferential expression of insulin-like growth factor binding proteins-1, -3, and -5 during early diabetic renal hypertrophy in rats

The renal insulin-like growth factor-I (IGF-I) system has been implicated in the pathogenesis of renal hypertrophy, altered hemodynamics, and extracellular matrix expansion associated with early diabetes. The relative abundance of IGF binding proteins (IGFBPs) in the renal microenvironment may modulate IGF-I actions. However, the precise IGFBPs expressed in the glomerular and tubulointerstitial compartments during diabetic renal growth have not been characterized. In the present study, in situ hybridization studies were performed to examine the expression of IGFBP-1 to -6 messenger RNAs (mRNAs) 3, 7, and 14 days after streptozotocin (STZ) injection in rats. In control, nondiabetic kidneys, all six IGFBP mRNAs were differentially expressed with a predominance of IGFBP-5. The onset of renal hypertrophy in STZ-induced diabetes was associated with a rapid and site-specific induction of IGFBP-1, -3, and -5 mRNAs. In contrast, basal expression of IGFBP-2, -4, and -6 mRNAs was not altered in diabetic rats. IGFBP-5 mRNA expression increased in diabetic glomeruli, cortical, and inner medullary peritubular interstitial cells at days 3, 7, and 14. Although normal glomeruli failed to express IGFBP-3, it was induced concomitantly with IGFBP-5 in diabetic glomeruli and cortical peritubular interstitial cells. IGFBP-1 mRNA levels also increased in cortical tubular cells at each time point tested. Peak induction of IGFBP-3 and -5 was observed at day 3, whereas IGFBP-1 was delayed until day 7. IGFBP-1, -3, and -5 mRNA levels declined by day 14, but remained persistently elevated above control. By immunoperoxidase staining, similar alterations in the pattern of IGFBP-3 and -5 protein expression were observed at each time point. The preferential and site-specific increase in IGFBP-1, -3, and -5 suggest that these IGFBPs may regulate the local autocrine and/or paracrine actions of IGF-I and contribute to the pathogenesis of the early manifestations of diabetic nephropathy.     

Preincisional dextromethorphan combined with thoracic epidural anesthesia and analgesia improves postoperative pain and bowel function in patients undergoing colonic surgery

Colonic surgery is associated with severe postoperative pain and postoperative ileus, which contribute to delayed hospital discharge. In previous studies, we demonstrated that IM dextromethorphan (DM) provided preemptive analgesia and improved postoperative pain. The benefit of thoracic epidural anesthesia (TEA) and postoperative epidural analgesia on postoperative pain was well demonstrated. The goal of this study was to investigate the effect of preincisional IM DM combined with intraoperative TEA and postoperative patient-controlled epidural analgesia (PCEA) on pain and bowel function after colonic surgery. Patients were randomized into 3 equal groups to receive: 1) chlorpheniramine maleate (CPM) 20 mg and general anesthesia (CPM-GA); 2) CPM 20 mg and GA combined with TEA (CPM-TEA); or 3) DM 40 mg (containing 20 mg of CPM) and GA combined with TEA (DM-TEA). The CPM, DM, and TEA with lidocaine were administered after GA induction via an IM injection and 30 min before the skin incision. All patients received postoperative PCEA for pain control. Analgesic effects were evaluated for 72 h after surgery using visual analog scale pain scores at rest and moving, time to first PCEA request for pain relief, total PCEA consumption, and the time to first passage of flatus. Statistically significant improvement of postoperative pain and bowel function was observed in the following order: DM-TEA > CPM-TEA > CPM-GA. Compared with the CPM-TEA group, the DM-TEA group averaged 1.6 points lower on first-hour pain scores, 40 min longer to first PCEA request, 15.8 mL less PCEA drug over 72 h, and 14.7 h earlier bowel function (all P < 0.01). We conclude that the combination of preincisional DM (40 mg IM), intraoperative TEA, and postoperative PCEA enhances analgesia and facilitates recovery of bowel function, suggesting possible synergistic interaction with local anesthetics and opioids.     

The Effects of Exogenous Administration of Human Coagulation Factors Following Pig‐to‐Baboon Liver Xenotransplantation

We sought to determine the effects of exogenous administration of human coagulation factors following pig‐to‐baboon liver xenotransplantation (LXT) using GalT‐KO swine donors. After LXT, baboons received no coagulation factors (historical control, n = 1), bolus administration of a human prothrombin concentrate complex (hPCC; 2.5 mL/kg, n = 2), continuous infusion of hPCC (1.0 mL/h, n = 1) or continuous infusion of human recombinant factor VIIa (1 µg/kg per hour, n = 3). The historical control recipient demonstrated persistent thrombocytopenia despite platelet administration after transplant, along with widespread thrombotic microangiopathy (TMA). In contrast, platelet levels were maintained in bolus hPCC recipients; however, these animals quickly developed large‐vessel thrombosis and TMA, leading to graft failure with shortened survival. Recipients of continuous coagulation factor administration experienced either stabilization or an increase in their circulating platelets with escalating doses. Furthermore, transfusion requirements were decreased, and hepatic TMA was noticeably absent in recipients of continuous coagulation factor infusions compared with the historical control and bolus hPCC recipients. This effect was most profound with a continuous, escalating dose of factor VIIa. Further studies are warranted because this regimen may allow for prolonged survival following LXT.     

Effects of temperature on radiochemical purity and immunoreactivity of radiolabeled monoclonal antibody 1H10

OBJECTIVE: This study was undertaken to investigate the effects of temperature on preserving the radiochemical purity and immunoreactivity of 125I- and 131I-labeled monoclonal antibody (MAb) 1H10--an antibody against human cervical carcinoma cell-surface antigen. METHODS: An antibody-irrelevant human melanoma cell line, H2269, served as the control group. Iodine-125 and 131I radiolabeling of MAbs 1H10 and H2669 was performed by the chloramine-T method. All the prepared MAbs were divided into aliquots and stored at 4, -20, and -70 degrees C for 2-14 d. The radiochemical purity and immunoreactivity of the labeled antibodies in set conditions were measured by thin-layer chromatography and a modified index, respectively, after a single freeze-and-thaw cycle. RESULTS: Reduced release of free radioiodide and better preservation of immunoreactivity were observed in the radiolabeled MAbs stored at -70 degrees C than in those stored at -20 degrees C or 4 degrees C. The extent of free iodide dissociation and immunologic binding degradation of 125I-labeled MAb 1H10 appeared milder than that of 131I-labeled MAb under the same conditions. However, both 125I- and 131I-labeled MAb stored at -70 degrees C or -20 degrees C retained more than 90% radiochemical purity for at least 3d. CONCLUSION: Freezing provides an appropriate alternative for reducing radiolysis and preserving immunoreactivity of radioiodinated MAbs. MAb 1H10, labeled with either 125I or 131I and stored at temperatures of -20 degrees C or below for 3 d after labeling, appeared stable in both radiolabeling and binding studies in vitro and was still acceptable for in vivo use.     

Simultaneous combined use of flexible ureteroscopy and percutaneous nephrolithotomy to reduce the number of access tracts in the management of complex renal calculi

OBJECTIVE: To present early experience in managing complex renal calculi using a combined ureteroscopic and percutaneous approach, as complex and branched renal calculi often require multiple access tracts during percutaneous nephrolithotomy (PNL), and the combined use of flexible ureteroscopy and PNL has the potential to reduce the inherent morbidity of several tracts. PATIENTS AND METHODS: The study included seven patients (mean age 54 years) with multiple, branched, large-volume renal calculi suitable for management with PNL. Preoperative data, including patient demographics, stone location and stone surface area, were recorded. After informed consent, the patients underwent combined PNL and ureteroscopy in one session. Intraoperative data, including the location of PNL puncture sites, operative duration and complications, were analysed. Stone-free rates were determined by follow-up imaging at 3 months. RESULTS: All patients had either two or more stones in separate locations in the collecting system, or staghorn stones involving multiple calyces. The mean stone burden was 666 mm(2). All patients had only one percutaneous access tract. The mean operative duration was 142 min and the mean blood loss 79 mL. Two patients had small residual stones (< 3 mm), that required ureteroscopic intervention as they failed to pass spontaneously by 3 months after the initial combined procedure. The convalescence was similar to that in our current PNL practice; imaging showed that five of the patients were stone-free. CONCLUSIONS: Combined PNL and ureteroscopic management can effectively reduce the number of percutaneous access tracts which would otherwise be required for managing complex and branched renal calculi, as stones in an unfavourable location relative to the access tract can be relocated and fragmented within easy reach of the single nephrostomy tract. This manoeuvre reduces potential patient morbidity and blood loss but with no significant effect on stone-free rates and operative durations.