Renal Collectrin Protects against Salt-Sensitive Hypertension and Is Downregulated by Angiotensin II.

Collectrin, encoded by the Tmem27 gene, is a transmembrane glycoprotein with approximately 50% homology with angiotensin converting enzyme 2, but without a catalytic domain. Collectrin is most abundantly expressed in the kidney proximal tubule and collecting duct epithelia, where it has an important role in amino acid transport. Collectrin is also expressed in endothelial cells throughout the vasculature, where it regulates L-arginine uptake. We previously reported that global deletion of collectrin leads to endothelial dysfunction, augmented salt sensitivity, and hypertension. Here, we performed kidney crosstransplants between wild-type (WT) and collectrin knockout (Tmem27Y/- ) mice to delineate the specific contribution of renal versus extrarenal collectrin on BP regulation and salt sensitivity. On a high-salt diet, WT mice with Tmem27Y/- kidneys had the highest systolic BP and were the only group to exhibit glomerular mesangial hypercellularity. Additional studies showed that, on a high-salt diet, Tmem27Y/- mice had lower renal blood flow, higher abundance of renal sodium-hydrogen antiporter 3, and lower lithium clearance than WT mice. In WT mice, administration of angiotensin II for 2 weeks downregulated collectrin expression in a type 1 angiotensin II receptor-dependent manner. This downregulation coincided with the onset of hypertension, such that WT and Tmem27Y/- mice had similar levels of hypertension after 2 weeks of angiotensin II administration. Altogether, these data suggest that salt sensitivity is determined by intrarenal collectrin, and increasing the abundance or activity of collectrin may have therapeutic benefits in the treatment of hypertension and salt sensitivity.

Ultrasound Modulates the Splenic Neuroimmune Axis in Attenuating AKI.

We showed previously that prior exposure to a modified ultrasound regimen prevents kidney ischemia-reperfusion injury (IRI) likely via the splenic cholinergic anti-inflammatory pathway (CAP) and α7 nicotinic acetylcholine receptors (α7nAChR). However, it is unclear how ultrasound stimulates the splenic CAP. Further investigating the role of the spleen in ischemic injury, we found that prior splenectomy (-7d) or chemical sympathectomy of the spleen with 6-hydroxydopamine (6OHDA; -14d) exacerbated injury after subthreshold (24-minute ischemia) IRI. 6-OHDA-induced splenic denervation also prevented ultrasound-induced protection of kidneys from moderate (26-minute ischemia) IRI. Ultrasound-induced protection required hematopoietic but not parenchymal α7nAChRs, as shown by experiments in bone marrow chimeras generated with wild-type and α7nAChR(-/-) mice. Ultrasound protection was associated with reduced expression of circulating and kidney-derived cytokines. However, splenocytes isolated from mice 24 hours after ultrasound treatment released more IL-6 ex vivo in response to LPS than splenocytes from sham mice. Adoptive transfer of splenocytes from ultrasound-treated (but not sham) mice to naïve mice was sufficient to protect kidneys of recipient mice from IRI. Ultrasound treatment 24 hours before cecal ligation puncture-induced sepsis was effective in reducing plasma creatinine in this model of AKI. Thus, splenocytes of ultrasound-treated mice are capable of modulating IRI in vivo, supporting our ongoing hypothesis that a modified ultrasound regimen has therapeutic potential for AKI and other inflammatory conditions.

The use of iodinated contrast media in patients with end-stage renal disease.

Iodinated contrast agents are well tolerated in ESRD patients. Certain types of ICM, i.e., LOCM and the nonionic agents are associated with better safety profiles. Current available evidence, although not optimal, does not support the need for additional hemodialysis for ICM removal to preserve residual renal function or to treat other potential toxicities of ICM. However, limiting exposure to ICM is a prudent measure in ESRD patients given ICM's potential toxicity; close monitoring of patients with poor cardiac function is also recommended in subjects receiving higher doses of ICM, especially those receiving HOCM.

Validation of the pulse decomposition analysis algorithm using central arterial blood pressure.

BACKGROUND: There is a significant need for continuous noninvasive blood pressure (cNIBP) monitoring, especially for anesthetized surgery and ICU recovery. cNIBP systems could lower costs and expand the use of continuous blood pressure monitoring, lowering risk and improving outcomes.The test system examined here is the CareTaker® and a pulse contour analysis algorithm, Pulse Decomposition Analysis (PDA). PDA's premise is that the peripheral arterial pressure pulse is a superposition of five individual component pressure pulses that are due to the left ventricular ejection and reflections and re-reflections from only two reflection sites within the central arteries.The hypothesis examined here is that the model's principal parameters P2P1 and T13 can be correlated with, respectively, systolic and pulse pressures. METHODS: Central arterial blood pressures of patients (38 m/25 f, mean age: 62.7 y, SD: 11.5 y, mean height: 172.3 cm, SD: 9.7 cm, mean weight: 86.8 kg, SD: 20.1 kg) undergoing cardiac catheterization were monitored using central line catheters while the PDA parameters were extracted from the arterial pulse signal obtained non-invasively using CareTaker system. RESULTS: Qualitative validation of the model was achieved with the direct observation of the five component pressure pulses in the central arteries using central line catheters. Statistically significant correlations between P2P1 and systole and T13 and pulse pressure were established (systole: R square: 0.92 (p < 0.0001), diastole: R square: 0.78 (p < 0.0001). Bland-Altman comparisons between blood pressures obtained through the conversion of PDA parameters to blood pressures of non-invasively obtained pulse signatures with catheter-obtained blood pressures fell within the trend guidelines of the Association for the Advancement of Medical Instrumentation SP-10 standard (standard deviation: 8 mmHg(systole: 5.87 mmHg, diastole: 5.69 mmHg)). CONCLUSIONS: The results indicate that arterial blood pressure can be accurately measured and tracked noninvasively and continuously using the CareTaker system and the PDA algorithm. The results further support the physical model that all of the features of the pressure pulse envelope, whether in the central arteries or in the arterial periphery, can be explained by the interaction of the left ventricular ejection pressure pulse with two centrally located reflection sites.

Ultrasound prevents renal ischemia-reperfusion injury by stimulating the splenic cholinergic anti-inflammatory pathway.

AKI affects both quality of life and health care costs and is an independent risk factor for mortality. At present, there are few effective treatment options for AKI. Here, we describe a nonpharmacologic, noninvasive, ultrasound-based method to prevent renal ischemia-reperfusion injury in mice, which is a model for human AKI. We exposed anesthetized mice to an ultrasound protocol 24 hours before renal ischemia. After 24 hours of reperfusion, ultrasound-treated mice exhibited preserved kidney morphology and function compared with sham-treated mice. Ultrasound exposure before renal ischemia reduced the accumulation of CD11b(+)Ly6G(high) neutrophils and CD11b(+)F4/80(high) myeloid cells in kidney tissue. Furthermore, splenectomy and adoptive transfer studies revealed that the spleen and CD4(+) T cells mediated the protective effects of ultrasound. Last, blockade or genetic deficiency of the α7 nicotinic acetylcholine receptor abrogated the protective effect of ultrasound, suggesting the involvement of the cholinergic anti-inflammatory pathway. Taken together, these results suggest that an ultrasound-based treatment could have therapeutic potential for the prevention of AKI, possibly by stimulating a splenic anti-inflammatory pathway.

Assessment of intravascular volume status and volume responsiveness in critically ill patients.

Accurate assessment of a patient's volume status, as well as whether they will respond to a fluid challenge with an increase in cardiac output, is a critical task in the care of critically ill patients. Despite this, most decisions regarding fluid therapy are made either empirically or with limited and poor data. Given recent data highlighting the negative impact of either inadequate or overaggressive fluid therapy, understanding the tools and techniques available for accurate volume assessment is critical. This review highlights both static and dynamic methods that can be utilized to help in the assessment of volume status.

Higher doses of erythropoietin-stimulating agents and hyporesponsiveness to their effects are associated with increased mortality among prevalent hemodialysis patients.

BACKGROUND: Attempts to achieve near-normal hemoglobin levels have been associated with higher mortality among chronic kidney disease patients. Evidence suggests a higher mortality rate for those with resistance to erythropoietin-stimulating agents (ESA). We investigated the association between responsiveness to ESA, dose of ESA and mortality in our hemodialysis population. METHODS: A retrospective cohort study of chronic hemodialysis patients receiving dialysis was conducted at the University of Virginia facilities. We collected data on patient demographics, comorbidities, dialysis vintage, vascular access type, body weight, ESA dose and hemoglobin, as well as data on known risk factors for ESA hyporesponsiveness. Vital status was determined 30 months later. The association between ESA responsiveness and mortality was investigated by using the Cox proportional hazard model adjusting for demographics, comorbidities, access type, dialysis adequacy, serum albumin, serum parathyroid hormone and ferritin concentrations. RESULTS: A total of 606 patients were included. The overall 30-month mortality was 35.8%. Compared to those in the lowest tertile of ESA hyporesponsiveness, patients in the middle and upper tertiles had significantly higher mortality (hazard ratio, HR: 1.64, 95% CI: 1.14-2.37, and HR: 2.08, 95% CI: 1.46-2.97, respectively). In the Cox proportional hazard model each unit increment in the ESA resistance index was associated with an HR of 2.27 (95% CI: 1.60-3.23) for mortality. In this model each 1-unit increment in ESA dose/kg or each 100-µg increment in absolute darbepoetin alfa dose were associated with a 9% increased risk of mortality (HR: 1.09, 95% CI: 1.04-1.13, and HR: 1.09, 95% CI: 1.03-1.15, respectively). CONCLUSIONS: Among prevalent hemodialysis patients, a higher degree of resistance to and higher doses of ESA are associated with increased mortality.

The choice of vascular access for therapeutic apheresis.

Therapeutic apheresis (TA) is performed using either centrifugation-based or filter-based systems. The blood flow rate (BFR) used for TA using centrifugation-based systems is less than 100 mL/min. Because of this low BFR requirement, even peripheral veins can be considered as an option for TA, especially for less-frequent treatments and those performed for short periods. Other options for vascular access (VA) include central venous catheters (temporary or tunneled), totally implantable ports, and arteriovenous fistulae (AVF) or grafts (AVG). Nontunneled catheters should be considered as the choice of VA for relatively short-term treatments mainly in the inpatient settings. For long-term treatments, ports and tunneled catheters should be considered because of lower rates of infections compared to nontunneled catheters. However, studies in hemodialysis (HD) patients have demonstrated significantly higher morbidity and mortality rates associated with the use of tunneled catheters as compared to AVF. Therefore, if TA is being considered for several years, AVG and AVF would be the preferred options of VA. Studies in HD population indicate far better outcomes with the use of AVF as compared to AVG. This article, as presented at the Therapeutic Apheresis Academy in September 2011, is an overview of the available VA options for TA based on indication and duration of treatment. Pros and cons of each option are mentioned briefly. Finally, for those considered for AVF placement for chronic TA, specific recommendations are made for the care of AVF based on our own experience at University of Virginia.

Recent advances in the pharmacological management of sepsis-associated acute kidney injury.

INTRODUCTION: Acute kidney injury is a common occurrence in patients with sepsis and portends a high mortality as well as increased morbidity with numerous sequelae including the development of chronic kidney disease. Currently, there are no specific therapies that either prevent AKI or hasten its recovery. Thus, clinicians typically rely on management of the underlying infection, optimization of hemodynamic parameters as well as avoidance of nephrotoxins to maximize outcomes. AREAS COVERED: Recent advances in understanding the mechanisms of sepsis as well as how these pathways may interact to lead to acute kidney injury have opened the door to the development of new, targeted therapies. This review focuses on the operative pathways in sepsis that have been identified as critical in leading to acute kidney injury and associated therapeutic agents that target these pathways. EXPERT OPINION: Despite increased understanding of the pathogenesis of sepsis, development of effective therapeutics to decrease the incidence of AKI have lagged. This is likely due to the complex pathophysiology with overlapping pathways and need for multiple therapies guided by specific biomarkers. Biomarkers that detail operative pathways may be able to guide the institution of more specific therapies with the hope for improved outcomes.