Rapid removal of DFO-chelated aluminum during hemodialysis using polysulfone dialyzers

Aluminum (Al) removal following deferoxamine (DFO) therapy in hemodialysis patients was evaluated in a paired-fashion comparing cuprophane (Travenol 12.11) and polysulfone (Fresenius F-80) dialyzers. QB and QD were held constant at 250 and 500 ml/min, respectively. The polysulfone dialyzer increased total plasma Al clearance from 20.0 +/- 2.8 to 80.5 +/- 7.6 ml/min (P less than 0.01), and reduced the t 1/2 of plasma Al during hemodialysis from 538 +/- 113 to 112 +/- 12 min (P less than 0.01). The polysulfone F-80 dialyzer increased Al removal during the first hour of hemodialysis from 518 +/- 191 to 1812 +/- 720 micrograms/hr (P less than 0.01). During a four hour hemodialysis the F-80 dialyzer returned plasma Al levels to pre-DFO values (103 +/- 36 vs. 93 +/- 23, P less than 0.05), suggesting complete removal of the DFO chelated Al complex. In one patient Al removal was evaluated using cuprophane, F-40, F-60 and F-80 dialyzers and the t 1/2 for Al removed decreased from 484.6 to 276.1 and 108 to 99 minutes, respectively. These data show the Fresenius F-80 polysulfone dialyzer effects the rapid removal of DFO-Al complexes. We propose use of the Fresenius F-80 dialyzer in conjunction with reduced DFO doses and i.m. administration of DFO the day prior to dialysis to limit DFO exposure as a method to decrease DFO-related side-effects in hemodialysis patients.     

Acute kidney injury in older adults

Aging kidneys undergo structural and functional changes that decrease autoregulatory capacity and increase susceptibility to acute injury. Acute kidney injury associates with duration and location of hospitalization, mortality risk, progression to chronic kidney disease, and functional status in daily living. Definition and diagnosis of acute kidney injury are based on changes in creatinine, which is an inadequate marker and might identify patients when it is too late. The incidence of acute kidney injury is rising and increases with advancing age, yet clinical studies have been slow to address geriatric issues or the heterogeneity in etiologies, outcomes, or patient preferences among the elderly. Here we examine some of the current literature, identify knowledge gaps, and suggest potential research questions regarding acute kidney injury in older adults. Answering these questions will facilitate the integration of geriatric issues into future mechanistic and clinical studies that affect management and care of acute kidney injury.     

Beta-2-microglobulin-associated amyloidosis in chronic hemodialysis patients with carpal tunnel syndrome

The clinical manifestations of beta-2-microglobulin (beta 2M)-associated amyloidosis in chronic hemodialysis patients with carpal tunnel syndrome from a medical center hospital are presented. The predominant morbidity of beta 2M-amyloid was musculoskeletal, with deposits identified in surgical or biopsy specimens from trigger fingers, carpal tunnels, fractures, and radiolucent bone lesions. Lucent bone lesions were the characteristic radiologic finding of beta 2M-amyloidosis and were most commonly found in carpal bones, humeral heads, and femoral heads. Carpal tunnel syndrome occurred in greater than 20% of our chronic hemodialysis patients. The longer the period of time on chronic hemodialysis the greater the morbidity from beta 2M-amyloid. Although significant amounts of beta 2M-amyloid were detected in the perivascular regions of viscera, clinical compromise of internal organs from this type of amyloid was not documented. In acute studies, beta 2M clearance during hemodialysis was markedly increased using the Fresenius polysulfone dialyzers compared to cuprophane dialyzers. In summary, beta 2M-amyloid is common and causes significant morbidity in chronic hemodialysis patients. Long-term dialysis with highly permeable membranes effects greater beta 2M clearance which may result in less tissue deposition of beta 2M-amyloid, and therefore, fewer clinical complications.     

Prognostic significance of neutrophil-lymphocyte ratio and platelet-lymphocyte ratio in patients treated with selective internal radiation therapy

Background

Elevated neutrophil-to-lymphocyte (NLR) and platelet-to-lymphocyte ratios (PLR) may represent markers of a suboptimal host immune response to cancer and have been shown to correlate with prognosis in multiple tumor types across different treatment modalities, including radiation therapy. Limited data suggest that NLR may predict for survival and disease control in patients receiving selective internal radiation therapy (SIRT). The correlation between clinical outcomes and change in NLR and PLR after SIRT has not been evaluated.

Methods

We retrospectively reviewed 339 consecutive patients with primary (n=37) or metastatic (n=79) liver cancer treated with SIRT from 2006 to 2014. Complete blood counts with differential were available for 116 patients both before and after (median, 29 and 20 days, respectively) SIRT. Survival and progression were calculated from date of initial SIRT. Patient and tumor characteristics evaluated for ability to predict overall survival (OS) and progression free survival (PFS) included pre- and post-treatment neutrophil, platelet, and lymphocyte counts (LCs), as well as NLR, PLR, and relative change in NLR and PLR. Cutoff values were determined for variables that were significant on multivariate analysis (MVA) for OS and/or PFS.

Results

Median follow-up of surviving patients was 12 months. Median OS was 8 months from SIRT and 20 months from date of liver metastasis diagnosis. Significant factors on univariate analysis (UVA) for both lower OS and PFS included higher post-treatment neutrophil count (NC), higher post-treatment NLR, higher liver tumor volume, higher percentage liver tumor burden, and worse Eastern Cooperative Oncology Group (ECOG) performance status. Significant factors on MVA for lower OS and PFS were ECOG performance status ≥2, higher liver tumor volume, higher pretreatment PLR, and increase in PLR after SIRT. Post-treatment increase in PLR >3-fold was the most predictive early marker for increased risk of death when compared with those whose PLR did not increase or increased <3-fold. Pretreatment PLR >78 was the most predictive serum marker associated with improved OS prior to therapy.

Conclusions

This is the largest study to evaluate the association between NLR and PLR with clinical outcomes in patients receiving SIRT, with results that confirm that pre- and/or post-treatment NLR and/or PLR are predictive of clinical outcomes. The largest increase in risk of death as well as local and extrahepatic disease progression was related to change in PLR, a datum not well reported in the literature. The impact of SIRT on blood count changes and the underlying implications of these ratios should be further characterized in a prospective study.     

Pathophysiology of ischemic acute kidney injury

Acute kidney injury (AKI) as a consequence of ischemia is a common clinical event leading to unacceptably high morbidity and mortality, development of chronic kidney disease (CKD), and transition from pre-existing CKD to end-stage renal disease. Data indicate a close interaction between the many cell types involved in the pathophysiology of ischemic AKI, which has critical implications for the treatment of this condition. Inflammation seems to be the common factor that links the various cell types involved in this process. In this Review, we describe the interactions between these cells and their response to injury following ischemia. We relate these events to patients who are at high risk of AKI, and highlight the characteristics that might predispose these patients to injury. We also discuss how therapy targeting specific cell types can minimize the initial and subsequent injury following ischemia, thereby limiting the extent of acute changes and, hopefully, long-term structural and functional alterations to the kidney.     

Measuring glomerular filtration rate in acute kidney injury: Yes,but not yet

Acute kidney injury has become a major focus for nephrologists and critical care physicians. The development of structural biomarkers is proceeding, but the results to date have been disappointing. The use of a shortened creatinine clearance as a functional acute kidney injury biomarker is not new but has not been compared with that of other diagnostic approaches. A rapid, repeatable, and accurate measured glomerular filtration rate would be the gold standard for a functional biomarker and is not far off.Acute kidney injury (AKI) remains a vexing clinical problem resulting in unacceptably high patient mortality, development of chronic kidney disease, and enhanced progression to end-stage kidney disease [1]. Although clinical risk factors for developing AKI have been identified, there is no reasonable surveillance technique (''biomarker'') to either definitively and rapidly diagnose the injury or determine the extent of its severity. Since patient outcomes correlate with the extent of injury and effective therapy requires early intervention, the ability to rapidly diagnose and stratify patients by their level of kidney injury is of paramount importance for therapeutic progress. Therefore, a search for a biomarker of kidney injury has intensified and is now considered by many experts to be the highest priority in the field of AKI [2]. It is likely that a combination of structural and functional markers of AKI will provide the highest clinical utility.Glomerular filtration rate (GFR), which measures the amount of plasma filtered through glomeruli within a given period of time, is clinically the most widely used indicator of kidney function. Yet a rapid quantitative technique with clinical utility has not been developed. Reduction in the GFR, secondary to kidney injury, is the hallmark of AKI and results in increased levels of blood urea nitrogen (BUN) and serum creatinine. Unfortunately, the rates of increase in BUN and serum creatinine do not parallel the fall in GFR in a time frame that is clinically useful. In addition, since both creatinine production from muscle and GFR determine the serum creatinine level, using serum creatinine as an indicator of GFR is highly patient-specific and often problematic or even misleading. These issues have been described elsewhere [3].Achieving the ability to rapidly and accurately measure GFR in an early stage of AKI would be beneficial for many reasons. It would rapidly identify and determine the extent of injury, allowing early pharmacologic or dialytic treatment (or both), enrollment and stratification for clinical studies, and prognostic information. It could also be used to determine the effect of a clinical maneuver on GFR, such as volume resuscitation and the use of pressors to support blood pressure, and enable appropriate drug dosing for agents cleared by the kidney or nephrotoxins.On this well-known background, Pickering and colleagues [1] set out to determine the clinical utility of a 4-hour creatinine clearance (CrCl), compared with plasma creatinine, for diagnosing AKI. The authors found that CrCl increased the likelihood of diagnosing AKI; a decreasing CrCl correlated with increased kidney injury severity, death, or dialysis; and the CrCl was most helpful when patients began with a serum creatinine in the normal range. Although the receiver operating characteristics were not impressive, the study was a small pilot study.This is not the first time a shortened CrCl has been used to estimate GFR in clinical settings. Herget-Rosenthal and colleagues [4] used a 2-hour CrCl in stable patients and found an acceptable and repeatable correlation with the 24-hour CrCl. However, the accuracy and utility of a shortened collection in unstable patients were questioned by two studies conducted in patients with AKI [5,6]. This limitation may relate to reduced production of creatinine in sepsis [7], increased production of creatinine with trauma, increased metabolism including the use of glucocorticoids, or the changing of GFRs during the collection periods. Pickering and colleagues did not attempt to validate their 4-hour CrCl rates with 6-hour iohexol or iothalamate infustion studies, currently the gold standard for clinical studies. This validation could have been done nearly simultaneously with the 4-hour CrCl urine collection. Until such studies are conducted, confidence for using a CrCl may be limited.A clinically useful technique to measure GFR in AKI has been a long-sought-after goal [8]. The cumbersome, time-consuming, and expensive techniques currently available have not met this important clinical need. The development and use of estimating formulas based on serum creatinine or cystatin C have been disappointing for several well-explained reasons [3]. Therefore, the development of a rapid, accurate, safe, easy, and in-expensive technique has high clinical importance both in and out of the hospital. An approach being developed commercially, used primarily in preclinical studies to date, is the use of bedside techniques to measure GFR. The use of inexpensive, nontoxic, easily sized fluorescent molecules has emerged as a likely candidate, and several groups are now working with this approach in preclinical models [9,10]. It is likely that several of these approaches will enter clinical phase studies, and improvements in design and clinical utility are continually being developed. Test rapidity, convenience, cost, safety, accuracy, and repeatability are all critical characteristics. Hopefully, one or more of these approaches will emerge and alleviate the need for multiple-hour urine collection and analysis.     

Site and mechanism of enhanced gastrointestinal absorption of aluminum by citrate

Clinical and experimental studies have shown that citrate markedly enhances the intestinal absorption of aluminum (Al), but the site and mechanism of enhanced absorption are unknown. To determine where in the gastrointestinal tract aluminum citrate (Alcitr) was absorbed. Alcitr was gavaged with D-[1-3H] glucose in male Sprague-Dawley rats. Plasma Al levels increased rapidly and simultaneously peaked with D-[1-3G] glucose, suggesting early proximal bowel absorption. In in vitro duodenal and jejunal everted gut preparations, Alcitr incubation resulted in increased tissue Al levels and markedly enhanced transmural transport of Al and citr. Unlike citr, the transmural movement of Al was independent of temperature (37 degrees C vs. 4 degrees C). On the other hand, Al lactate (al Lac) increased tissue associated Al levels but had no effect on transmural Al movement. To determine if this large flux of Al following Alcitr administration was due to paracellular movement, ruthenium red and Ussing chamber studies were used to evaluate the morphologic and functional integrity of cellular tight junctions. Alcitr, as opposed to AlCl3, markedly increased ruthenium red deposits in intercellular spaces, especially around goblet cells, and induced a prolonged significant reduction in transmural resistance. Alcitr also resulted in rapid and nearly complete (99.7%) chelation of free calcium, an event known to disrupt cellular tight junction integrity. Taken together, these data suggest that enhanced Al absorption following administration of Alcitr occurs in the proximal bowel via the paracellular pathway due to the opening of cellular tight junctions.     

Effect of beta-lactamase inhibitors on the activities of various beta-lactam agents against anaerobic bacteria.

The in vitro activities of several new beta-lactam-beta-lactamase inhibitor combinations (piperacillin plus tazobactam, ceftizoxime and cefonicid with sulbactam and clavulanic acid, and ampicillin plus 8 micrograms of sulbactam per ml) were tested with anaerobic bacteria and compared with known beta-lactam-beta-lactamase inhibitor combinations and other potent antianaerobe agents. All the combinations tested (except for the cefonicid-inhibitor combinations) were active against almost all strains of the Bacteroides fragilis group. This report indicates that beta-lactamase inhibitors may improve the activity of beta-lactam agents with marginal activity against the B. fragilis group.