Trends in anemia care in non-dialysis-dependent chronic kidney disease (CKD) patients in the United States (2006-2015).

BACKGROUND: The objective of the study was to examine overall anemia management trends in non-dialysis patients with chronic kidney disease (CKD) from 2006 to 2015, and to evaluate the impact of Trial to Reduced Cardiovascular Events with Ananesp Therapy (TREAT)'s study results (October 2009) and the US Food and Drug Administration (FDA)'s (June 2011) safety warnings and guidelines on the use of ESA therapy in the current treatment of anemia. METHODS: A retrospective cohort analysis of anemia management in CKD patients using Truven MarketScan Commercial and Medicare Supplemental databases was conducted. Monthly rates and types of anemia treatment for post-TREAT and post-FDA safety warning periods were compared to pre-TREAT period. Anemia management included ESA, intravenous iron, and blood transfusion. A time-series analysis using Autoregressive Integrated Moving Average (ARIMA) model and a Generalized Estimating Equation (GEE) model were used. RESULTS: Between 2006 and 2015, CKD patients were increasingly less likely to be treated with ESAs, more likely to receive intravenous iron supplementation, and blood transfusions. The adjusted probabilities of prescribing ESAs were 31% (odds ratio (OR) = 0.69, 95% confidence interval (CI): 0.67-0.71) and 59% (OR = 0.41, 95% CI: 0.40, 0.42) lower in the post-TREAT and post-FDA warning periods compared to pre-TREAT period. The probability of prescribing intravenous iron was increased in the post-FDA warning period (OR = 1.11, 95% CI: 1.03-1.19) although the increase was not statistically significant in the post-TREAT period (OR = 1.03, 95% CI: 0.94-1.12). The probabilities of prescribing blood transfusion during the post-TREAT and post-FDA warning periods increased by 14% (OR = 1.14, 95% CI: 1.06-1.23) and 31% (OR = 1.31, 95% CI: 1.22-1.39), respectively. Similar trends of prescribing ESAs and iron supplementations were observed in commercially insured CKD patients but the use of blood transfusions did not increase. CONCLUSIONS: After the 2011 FDA safety warnings, the use of ESA continued to decrease while the use of iron supplementation continued to increase. The use of blood transfusions increased significantly in Medicare patients while it remained stable in commercially insured patients. Results suggest the TREAT publication had effected treatment of anemia prior to the FDA warning but the FDA warning solidified TREAT's recommendations for anemia treatment for non- dialysis dependent CKD patients.

Multi-Modal Neurorehabilitation for Persisting Post-Concussion Symptoms.

Treatment of the chronic sequela that persist after a mild traumatic brain injury has been challenging with limited efficacy. The aim of this work was to report outcomes obtained from persons who met the criteria of persisting post-concussive symptoms (PPCS), utilizing a novel combination of modalities in a structured neurorehabilitation program. This work was designed as a retrospective, pre-post chart review of objective and subjective measures collected from 62 outpatients with PPCS a mean of 2.2 years post-injury, before and after a multi-modal 5-day treatment protocol. The subjective outcome measure was the 27-item modified Graded Symptom Checklist (mGSC). Objective outcome measures were motor speed/reaction time, coordination, cognitive processing, visual acuity, and vestibular function. Interventions included non-invasive neuromodulation, neuromuscular re-education exercises, gaze stabilization exercises, orthoptic exercises, cognitive training, therapeutic exercises, and single/multi-axis rotation therapy. Pre-post differences in measures were analyzed using the Wilcoxon signed-rank test, with effect size determined by the rank-biserial correlation coefficient. Pre-post treatment comparisons for the subjective mGSC overall, combined symptom measures, individual components of the mGSC, and cluster scores significantly improved for all items. Moderate strength relationships were observed for the mGSC composite score, number of symptoms, average symptom score, feeling in a "fog," "don't feel right," irritability, and physical, cognitive, and affective cluster scores. Objective symptom assessment significantly improved for trail making, processing speed, reaction time, visual acuity, and Standardized Assessment of Concussion. Patients suffering from PPCS ∼2 years after injury may have significant benefits with some moderate effect sizes from an intensive, multi-modal neurorehabilitation program.

Congestive renal failure: the pathophysiology and treatment of renal venous hypertension.

Longstanding experimental evidence supports the role of renal venous hypertension in causing kidney dysfunction and "congestive renal failure." A focus has been heart failure, in which the cardiorenal syndrome may partly be due to high venous pressure, rather than traditional mechanisms involving low cardiac output. Analogous diseases are intra-abdominal hypertension and renal vein thrombosis. Proposed pathophysiologic mechanisms include reduced transglomerular pressure, elevated renal interstitial pressure, myogenic and neural reflexes, baroreceptor stimulation, activation of sympathetic nervous and renin angiotensin aldosterone systems, and enhanced proinflammatory pathways. Most clinical trials have addressed the underlying condition rather than venous hypertension per se. Interpreting the effects of therapeutic interventions on renal venous congestion are therefore problematic because of such confounders as changes in left ventricular function, cardiac output, and blood pressure. Nevertheless, there is preliminary evidence from small studies of intense medical therapy or extracorporeal ultrafiltration for heart failure that there can be changes to central venous pressure that correlate inversely with renal function, independently from the cardiac index. Larger more rigorous trials are needed to definitively establish under what circumstances conventional pharmacologic or ultrafiltration goals might best be directed toward central venous pressures rather than left ventricular or cardiac output parameters.

Emerging therapies for heart failure: renal mechanisms and effects.

Improved understanding of the pathophysiology of salt and water homeostasis has provided a foundation for explaining the renal mechanisms of emerging therapies for heart failure, as well as why renal function might potentially be improved or harmed. These aspects are reviewed in this article for a number of newer therapies including adenosine, endothelin, and vasopressin receptor antagonists, as well as extracorporeal ultrafiltration. An appreciation of the complexity and sometimes opposing pathways of these approaches may explain their limited efficacy in early trials, in which there has not been a substantial improvement in patient or renal outcomes. In that there is often a balance between beneficial and maladaptive receptor actions and neurohumoral responses, this physiologic approach also provides insight into the rationale for combining therapies. Multi-agent strategies may thus maximize their effectiveness while minimizing adverse effects and tolerance. In this paper, the theoretical impact of the emerging agents based on their mechanism of action and pathophysiology of the disease is initially addressed. Then, the available clinical evidence for each class of drugs is reviewed with special emphasis on their effect on kidney-related parameters. Finally, a general overview of the complexity of the interpretation of trials is offered along with a number of potential explanations for the observed results.

Chronic kidney disease and end-stage renal disease predict higher risk of mortality in patients with primary upper gastrointestinal bleeding.

BACKGROUND: The outcome of gastrointestinal bleeding in chronic kidney disease (CKD) and end-stage renal disease (ESRD) patients is difficult to discern from the literature. Many publications are small, single-center series or are from an era prior to advanced interventional endoscopy, widespread use of proton pump inhibitors or treatment for Helicobacter pylori infections. In this study, we quantify the role of CKD and ESRD as independent predictors of mortality in patients admitted to the hospital with a principal diagnosis of primary upper gastrointestinal bleeding (UGIB). METHODS: We used the Nationwide Inpatient Sample that contains data on approximately 8 million admissions in 1,000 hospitals chosen to approximate a 20% stratified sample of all US facilities. Patients discharged with the principal diagnosis of primary UGIB, CKD or ESRD were identified through the ninth revision of the International Classification of Diseases, clinical modification (ICD-9-CM) codes. The outcome variables included frequency and in-hospital mortality of UGIB in CKD and ESRD patients as compared to non-CKD patients and were analyzed using logistic regression modeling. RESULTS: In 2007, out of a total of 398,213 admissions with a diagnosis of primary UGIB, 35,985 were in CKD, 14,983 in ESRD, and 347,245 in non-renal disease groups. The OR for primary UGIB hospitalization in CKD and ESRD was 1.30 (95% CI 1.17-1.46) and 1.84 (95% CI 1.61-2.09), respectively. The corresponding all-cause mortality OR was 1.47 (95% CI 1.21-1.78) and 3.02 (95% CI 2.23-4.1), respectively. CONCLUSION: Patients with CKD or ESRD admitted with primary UGIB have up to three times higher risk of all-cause in-hospital mortality, warranting heightened vigilance by their clinicians.

Perioperative fluid balance and acute kidney injury.

BACKGROUND: Positive fluid balance (FB) has been linked to adverse clinical outcomes. We performed this study to explore the relationship between perioperative fluid balance and acute kidney injury (AKI). METHODS: The relationships between FB and AKI were explored using a prospective, observational design. Patients were divided into quartiles based on FB status in the first 24 h from initiation of surgery in order to further explore this relationship. RESULTS: One hundred adult patients undergoing cardiovascular surgery were included in the analysis. The major finding of the study was that positive FB occurred early in the intraoperative period and progressed into the postoperative period and that fluid administration was not clearly associated with any identifiable volume-sensitive event. The evolution of positive FB preceded the rise in serum creatinine. Progressive severity of positive FB was associated with increased incidence of AKI. The highest quartile FB group had a five-fold increased risk for AKI (adjusted odds ratio 4.98, 95 % confidence interval 1.38-24.10, p = 0.046) compared to the lowest quartile group, higher postoperative peak serum creatinine values (p < 0.001), surgery-related complications (p < 0.001) and intensive care unit (p < 0.001) and hospital length of stay (p = 0.048). CONCLUSIONS: Positive FB was associated with increased incidence of AKI.

Ultrafiltration therapy for cardiorenal syndrome: physiologic basis and contemporary options.

BACKGROUND: Heart failure (HF) has a high readmission rate in part due to conventional and recently developed therapeutic options having suboptimal results. Extracorporeal and peritoneal ultrafiltration have been advocated as more beneficial methods for fluid removal in decompensated or refractory HF, respectively. METHODS: Traditional and emerging concepts explaining the pathophysiology of HF and the cardiorenal syndrome are reviewed. Extracorporeal and peritoneal ultrafiltration clinical trials are then discussed in terms of potential physiologic benefits, feasibility and their effects on both cardiac and renal function. RESULTS: Ultrafiltration therapy can efficiently correct volume overload in the acute setting, improve cardiac functional and quality of life parameters, and is associated with long-lasting benefits such as reduced HF-related readmissions. Although excessive fluid removal can adversely affect the kidneys, there is evidence that careful protocols can restore diuretic sensitivity and maintain stable renal function; crafting safe parameters has yet to be studied. CONCLUSION: While extracorporeal ultrafiltration is an appealing therapeutic option for patients with acute decompensated HF, determining the optimal fluid removal rate and the impact on renal function need further investigation. Peritoneal dialysis may be an appropriate alternative in the setting of chronic refractory HF, but controlled studies are needed. Further trials are warranted to determine the long-term outcomes from both ultrafiltration modalities in HF.

Evolution of treatment strategies for calciphylaxis.

Treatment strategies for calciphylaxis are limited by inadequate understanding of its pathophysiology. Mortality reaches 80%, due to progressive skin ischemia, necrosis and infections. In addition to calcium and parathyroid disorders, hypercoagulability can have a role: primary thrombotic disorders as well as secondary, such as proposed warfarin procoagulant effects. Traditional care addresses the calcium-phosphate-PTH axis: minimizing calcium intake, calcimimetics, cautious vitamin D analogs, strict phosphate control, and surgical parathyroidectomy if necessary. Newer approaches focus on extraosseous mineralization: dissolution of calcium deposits, altering osteoprotegerin and NF-κB pathways, and treating macrophage or cytokine-mediated inflammation. Sodium thiosulfate has reported success, and is thought to be due to enhanced calcium solubility and dialysis clearance. Bisphosphonates may have efficacy by lowering bone turnover or a variety of vascular tissue mechanisms. The literature for both agents is very limited, and optimal dosing regimens remain unclear. Patients responsive to a medication will have decreasing pain in days and lesions beginning to heal within approximately 2 weeks. Due to high mortality, early use of combination therapy is advocated, although specific protocols have not been well established. The often dramatic improvements in case-based literature are very encouraging and will hopefully lead to more rigorous studies.

Intrarectal Xyloglucan Administration Reduces Disease Severity in the Dextran Sodium Sulfate Model of Mouse Colitis.

BACKGROUND: The pathophysiology of inflammatory bowel diseases remains poorly understood and treatment remains suboptimal for many patients. We hypothesize that the inflammatory milieu secondarily prolongs the injury and attenuates healing. We propose primary or adjuvant therapy with biocompatible adhesives to restore a barrier to protect submucosal structures, particularly stem cells. METHODS: We used the well-described mouse dextran sodium sulfate (DSS) model of colitis resembling human ulcerative colitis to test the therapeutic efficacy of intrarectal administration of the tamarind plant-derived xyloglucan (TXG) polymer adhesive which underwent extensive analytic characterization. Mice in control, DSS-only, TXG-only, and DSS + TXG groups were studied for gross (weight, blood in stool, length of colon) and multiple histologic parameters. RESULTS: Compared to DSS-only mice, TXG prevented the weight loss, occurrence of blood in the stool and colon shortening, with all those parameters not being statistically different from treatment naïve animals. Histologically, there was dramatic and highly statistically significant reduction in the total inflammatory index and protection from goblet cell loss, cellular infiltration, crypt abscess formation, epithelial erosion, granulation tissue, epithelial hyperplasia crypt irregularity and crypt loss. The TXG purity and characterization were established by nuclear magnetic resonance, infrared spectroscopy, differential scanning calorimetry, and texture analysis. CONCLUSION: The striking attenuation of disease severity by intrarectal TXG use warrants future investigations of natural bioadhesives with well-established high safety profiles, and which could potentially be derivatized to include therapeutically active moieties for local drug delivery.

Embryonic stem cells proliferate and differentiate when seeded into kidney scaffolds.

The scarcity of transplant allografts for diseased organs has prompted efforts at tissue regeneration using seeded scaffolds, an approach hampered by the enormity of cell types and complex architectures. Our goal was to decellularize intact organs in a manner that retained the matrix signal for differentiating pluripotent cells. We decellularized intact rat kidneys in a manner that preserved the intricate architecture and seeded them with pluripotent murine embryonic stem cells antegrade through the artery or retrograde through the ureter. Primitive precursor cells populated and proliferated within the glomerular, vascular, and tubular structures. Cells lost their embryonic appearance and expressed immunohistochemical markers for differentiation. Cells not in contact with the basement membrane matrix became apoptotic, thereby forming lumens. These observations suggest that the extracellular matrix can direct regeneration of the kidney, and studies using seeded scaffolds may help define differentiation pathways.

Improved outpatient haemodialysis adequacy using queued schedules.

BACKGROUND: Although technical advances help achieve haemodialysis adequacy, we hypothesise remediable non-therapy factors exacerbate patient dissatisfaction, non-adherence to treatment time and failure to meet dialysis goals. Scheduling inefficiencies lead to the total time in the unit far greater than actual treatment time, impacting facility efficiency and patient frustration. OBJECTIVES: We used queuing theorem principles to optimise schedules by incorporating timing and workflow for every dialysis process step to design a new schedule, rather than the whole-shift blocks at baseline. DESIGN: The goals were to: (1) craft schedules that maximised efficiency and economics from a facility perspective, and (2) minimise total time in the dialysis unit from a patient viewpoint. As dialysis units are held to a national standard of urea clearance, reduction ratios (URRs) were measured for the 3 months before and after the new scheduling was implemented. RESULTS: Dialysis staff and process parameters were measured to craft queued schedules of staggered small groups of patients instead of baseline blocks of 2 large shifts, 24 each. A total of 65 patients changed to groups of 8, with entry-to-exit at 290 minutes for four hours treatments. The URRs improved from 72.8 ± 6.9 to 75.2 ± 5.4% (p < 0.001). Before implementation, only 89% of subjects reached the URR facility compliance target of 65%, and afterwards 97% (p < 0.001). CONCLUSION: Queuing theorem principles can be successfully adopted to optimise haemodialysis scheduling. The resultant staggered timing increases facility efficiency, minimises the long wait time dissatisfier, and is associated with improved URRs with more patients reaching target clearance thresholds.

Use of the esa resistance index to guide dosing for anaemia management.

BACKGROUND: Identifying erythropoiesis-stimulating agent (ESA) resistance is important for treating reversible causes, reaching target haemoglobin levels with minimal dosing, avoiding adverse effects and reducing costs. The resistance index (RI, dose/kg weight/g haemoglobin/dl) is reportedly superior to absolute or weight-based dosing. OBJECTIVES: With the growing number of ESA classes and medications, our goal was to develop methodology to establish RI ranges in otherwise healthy haemodialysis patients as a structured approach to identify remediable causes of anaemia. DESIGN: We retrospectively studied anaemia management with darbepoetin in 100 chronic haemodialysis patients and a subgroup of 48 without identifiable conditions that impair erythropoiesis. Data included inflammatory and bone marrow conditions, medications with hematologic effects, catheter use, iron, parathyroid and dialysis measures. RESULTS: The haematologically healthy group was aged 57.1 ± 1.9 SEM years, 33% diabetic, with haemoglobin 10.4 ± 0.2 g/dl. The darbepoetin RI (DRI) values were 0.05 ± 0.01, absolute dose 38.5 ± 3.5 mcg/week and weight-based 0.50 ± 0.05 mcg/kg. Regression analyses included iron saturation, ferritin, parathyroid hormone and urea reduction ratio. DRI was superior to other dosing approaches based on the distribution of results (kurtosis) and discordance between the measures that occurred in 17% of patients at haemoglobin target. CONCLUSIONS: We demonstrate the value of determining the RI for use with expanding ESA choices, using as an example how DRI values can be established for healthy haemodialysis patients so as to guide dosing. When elevated, the RI can trigger evaluation for remediable factors causing hyporesponsiveness even when haemoglobin goals have been reached.

Contemporary trends in the pharmacological and extracorporeal management of heart failure: a nephrologic perspective.

Heart failure and chronic kidney disease share a number of risk factors and pathophysiological pathways. These 2 pathological processes coexist in large numbers of patients. Whereas the presence of chronic kidney disease in patients with heart failure adversely influences their survival, cardiovascular disease is the major cause of mortality in individuals with chronic kidney disease. The management of heart failure by cardiologists has recently expanded from pharmacological treatment to extracorporeal strategies; the interaction between (and concurrent use of) these approaches traditionally has been part of nephrology care and training. The purpose of this review is to explore these management strategies from a nephrologic standpoint and cover the pathophysiology of diuretic resistance, new pharmaceutical strategies to induce natriuresis or aquaresis, and the physiological basis and theoretical advantages of fluid removal by nontraditional peritoneal or hemofiltration approaches. This review also focuses on the technical features, safety, and potential risks of dedicated ultrafiltration devices that do not require dialysis staff or facilities and that are now readily available to nonnephrologists.

Oral paricalcitol for the treatment of secondary hyperparathyroidism in patients on hemodialysis or peritoneal dialysis.

BACKGROUND/AIMS: Secondary hyperparathyroidism is a common complication of chronic kidney disease, resulting from inactivation of vitamin D receptor signaling and phosphate retention. Selective activation of vitamin D receptors with intravenous paricalcitol significantly reduced parathyroid hormone (PTH) levels with no significant hypercalcemia or hyperphosphatemia in predialysis and hemodialysis (HD) patients. This study investigates the effects of oral paricalcitol to reduce PTH in patients receiving chronic HD and peritoneal dialysis (PD). METHODS: Eighty-eight patients were randomized in double-blind fashion to receive paricalcitol or placebo for 12 weeks. The dose of the study drug was adjusted weekly using the previous week's intact PTH (iPTH) level as well as calcium and Ca x P product levels. The primary end points were efficacy (two consecutive iPTH decreases of >or=30%) and safety (two consecutive calcium measurements >11.0 mg/dl). Markers of biochemical bone activity were followed. RESULTS: Demographic characteristics were similar between treatment groups. The mean paricalcitol doses (three times a week) over the entire treatment period for subjects with baseline iPTH 500 pg/ml were 3.9 and 7.6 microg, respectively. A statistically significant decrease in iPTH was seen after week 1, with a mean 30% reduction occurring by week 3. A significantly greater proportion of both HD and PD paricalcitol subjects [83% (33/40) and 100% (18/18), respectively] achieved two consecutive >or=30% decreases in iPTH. The treatment groups were not statistically different in regard to the hypercalcemia safety end point. Phosphate binder use and mean serum phosphorus levels were not different between the treatment groups. The markers of bone activity improved in the treated subjects and worsened in those on placebo. CONCLUSION: Paricalcitol provides a rapid and sustained reduction of PTH in both HD and PD patients with minimal effect on serum calcium and phosphorus and no significant difference in adverse events as compared with placebo.

Shortened hemofilter survival time due to lipid infusion in continuous renal replacement therapy.

BACKGROUND: Continuous renal replacement therapy is widely used for the treatment of critically ill patients with acute renal failure in critical care units. The survival time of the extracorporeal circuit is an important factor in providing renal replacement therapy. Despite rigorous efforts to maintain hemofilter patency, clinicians are occasionally faced with an unexplained short circuit survival time. METHODS: We present a critically ill patient undergoing continuous venovenous hemofiltration with regional citrate anticoagulation for management of acute renal failure in the context of sepsis. Once the patient was started on lipid infusion as part of total parenteral nutrition, we observed a shortened circuit survival due to premature hemofilter failure necessitating frequent changes of the hemofilter. The known potential causes for this phenomenon were ruled out. RESULTS: Evaluation revealed grossly lipemic serum associated with severe hypertriglyceridemia. Discontinuation of the lipid infusion was followed by a rapid return of circuit survival time to its baseline. Evaluation of the hemofilter by electron microscopy revealed that the rapid blockage of the hollow fibers was caused by lipid microparticles and fibrin deposits. CONCLUSION: Since total parenteral nutrition is commonly administered to malnourished and hypercatabolic critically ill patients on continuous renal replacement therapy, we suggest that intravenous lipid therapy might be a previously unreported and unappreciated remediable cause of premature hemofilter failure.

Interventions to improve hemodialysis adequacy: protocols based on real-time monitoring of dialysate solute clearance.

BACKGROUND: The monitoring of dialysate ultraviolet (UV) absorbance is a validated technology to measure hemodialysis adequacy and allows for continuous and real-time tracking every session as opposed to the typical once-monthly assessments. Clinical care guidelines are needed to interpret the findings so as to troubleshoot problematic absorbance patterns and intervene during an individual treatment as needed. METHODS: When paired with highly structured clinical care protocols that allow autonomous nursing actions, this technology has the potential to improve treatment outcomes. These devices measure the UV absorbance of dialysate solutes to calculate and then display the delivered as well as predicted clearance for that session. Various technical factors can affect the course of dialysate absorbance, confound the device's readout of clearance results and thus lead to challenges for the dialysis unit staff to properly monitor dialysis adequacy. We analyze optimal and problematic patterns to the device's 'clearance' display (e.g. due to thrombosis of hollow fibers, inadequate access blood flow or recirculation) and provide specific interventions to ensure delivery of an adequate dialysis dose. A rigorous algorithm is presented with representative device monitor display profiles from actual hemodialysis sessions. Procedural rationale and interventions are described for each individual scenario. CONCLUSION: Real-time hemodialysate UV absorbance patterns can be used for protocol-based intradialytic interventions to optimize solute clearance.

Transient acid exposure increases sevelamer HCl phosphate binding.

The patient-to-patient variability in the dosing of sevelamer HCl for phosphate control led us to test whether the binder's transient exposure to acidic environments (such as the stomach) might alter the compound so as to change its subsequent binding capacity in the more alkaline small intestine. We hypothesized that an acid milieu could either increase the reactive sites (protonated amine groups) or make the polymer more hydrophilic (hydration and swelling allowing more phosphate to reach those sites). Eight hundred milligrams of Renagel tablets were exposed to pHs 1, 2.3, and 7 (n = 7 each acidity level) for 1 h. NaCl was added to keep ionic strength the same. Measured by atomic emission phosphate uptake after 3 h at pH 7 was, respectively, 3.13 +/- 0.21, 2.72 +/- 0.35, and 1.85 +/- 0.46 mequiv./g (p = 0.0006, pH 1 vs. pH 7). Semi-automated computerized image analysis was then performed to measure swelling of the particles. We constructed a glass continuous-flow cell that allowed stationary particles and real-time photography. Using digitized optical measurements there was no difference (p > 0.8) between the swelling after 1 h of pH 1 or 7 solutions (60.2 +/- 14.8% vs. 59.5 +/- 9.8% increase in diameter). Our findings support the importance of transient acid exposure in enhancing phosphate binding, due to increased protonated sites rather than by more swelling. Patients with acquired or pharmacologic achlorhydria would not benefit from this unexpected in vivo reaction. Possibly manufacturing sevelamer with a higher degree of protonation or administering it with appropriately acidic vehicles or beverages remains to be investigated.