Susan T. Crowley

Renalase is a novel, soluble monoamine oxidase that regulates cardiac function and blood pressure

The kidney not only regulates fluid and electrolyte balance but also functions as an endocrine organ. For instance, it is the major source of circulating erythropoietin and renin. Despite currently available therapies, there is a marked increase in cardiovascular morbidity and mortality among patients suffering from end-stage renal disease. We hypothesized that the current understanding of the endocrine function of the kidney was incomplete and that the organ might secrete additional proteins with important biological roles. Here we report the identification of a novel flavin adenine dinucleotide-dependent amine oxidase (renalase) that is secreted into the blood by the kidney and metabolizes catecholamines in vitro (renalase metabolizes dopamine most efficiently, followed by epinephrine, and then norepinephrine). In humans, renalase gene expression is highest in the kidney but is also detectable in the heart, skeletal muscle, and the small intestine. The plasma concentration of renalase is markedly reduced in patients with end-stage renal disease, as compared with healthy subjects. Renalase infusion in rats caused a decrease in cardiac contractility, heart rate, and blood pressure and prevented a compensatory increase in peripheral vascular tone. These results identify renalase as what we believe to be a novel amine oxidase that is secreted by the kidney, circulates in blood, and modulates cardiac function and systemic blood pressure.

Intensity of renal replacement therapy in acute kidney injury: perspective from within the Acute Renal Failure Trial Network Study

Determination of the optimal dose of renal replacement therapy in critically ill patients with acute kidney injury has been controversial. Questions have recently been raised regarding the design and execution of the US Department of Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network (ATN) Study, which demonstrated no improvement in 60-day all-cause mortality with more intensive management of renal replacement therapy. In the present article we present our rationale for these aspects of the design and conduct of the study, including our use of both intermittent and continuous modalities of renal support, our approach to initiation of study therapy and the volume management during study therapy. In addition, the article presents data on hypotension during therapy and recovery of kidney function in the perspective of other studies of renal support in acute kidney injury. Finally, we address the implications of the ATN Study results for clinical practice from the perspective of the study investigators.

Comparison of side hole versus non side hole high flow hemodialysis catheters

Current literature suggests that side holes may be detrimental to dialysis catheter performance. Today, these catheters are primarily available with side holes. The purpose of this study was to compare flow rates, infection rate, and survival of side hole vs. non side hole hemodialysis catheters. Over a 16‐month period patients were arbitrarily assigned to either a 14.5 F MAHURKAR® MAXID™ cuffed dual lumen tunneled catheter with side holes or a 14.5 F MAHURKAR MAXID cuffed dual lumen tunneled catheter without side holes (“non side hole catheters”). We performed a retrospective analysis of catheter flow rates, patency, catheter survival, and catheter‐related infections. Information was gathered for the life of the catheter or up to 28 weeks. A total of 54 patients were enrolled in the study. Thirty‐seven of 54 (68%) patients received a catheter with side holes for a total of 3,930 catheter days and 17/54 (32%) received a similar catheter without side holes for a total of 2,188 catheter days. Catheter infection necessitating removal of the catheter occurred in 10/37 catheters with side holes and 1/17 without side holes. Infection rates per 1,000 catheter days were 2.545 with side holes and 0.254 without side holes (p<0.001). Slightly improved catheter survival (p<0.05) was recorded with the non side hole catheters. No insertion complication (e.g., air embolization, bleeding, or kinking) occurred with either catheter. One catheter without side holes had to be repositioned 5 days after insertion because of poor flows. No significant difference was recorded in mean blood flow rates between the catheters. Results indicate reduced catheter infection rate in hemodialysis patients with the use of non side hole dual lumen tunneled cuffed catheters.

Validation of the SpaceLabs 90207 ambulatory blood pressure device for hemodialysis patients.

BACKGROUND Background Ambulatory blood pressure monitoring (ABPM) has been used increasingly in assessing dialysis patients. However, devices have not been validated formally for this population. Formal device validation is important in order to guarantee adequate performance for populations with special characteristics, such as patients undergoing hemodialysis. OBJECTIVE To achieve formal validation of the SpaceLabs 90207 ambulatory blood pressure device (SLD) using a modified British Hypertension Society protocol. METHODS Eighty-five hemodialysis patients were studied, generating 255 readings. Readings were obtained with patients supine (in a dialysis chair) over 5-10 min during hemodialysis. Simultaneous, same-arm readings were obtained through the use of a T connector to a calibrated mercury manometer. The mean differences between readings obtained by observers and those obtained by the device were calculated. Limits of agreement between observers and SLD were determined and plotted according to the method of Bland and Altman. For grading of performance, we determined the number of readings for which the readings obtained by the device were within 5, 10, and 15mmHg of manometer readings. Final gradings were ascribed according to British Hypertension Society criteria. RESULTS The mean blood pressure (+/-SD) was 141/76+/-31/15mmHg (observers) and 141/77+/-27/15mmHg (SLD), and the mean (+/-SD) difference between observers and device (observer-device) was -0.5+/-7.5mmHg for systolic blood pressure (SBP) and -0.2+/-5.2mmHg for diastolic blood pressure (DBP). The device was less accurate in extreme ranges of SBP. In fact, there was a positive correlation between average [(observer+device)/2] and difference (observer-device) for SBP (r =0. 54, P <0.0001), showing that underestimation in higher ranges, and overestimation in lower ranges of blood pressure occurred for SBP. For SBP, 53% of readings were within 5mmHg of those obtained by the observers, 85% were within 10mmHg, and 97% within 15mmHg. For DBP, 78% were within 5mmHg, 96% within 10mmHg, and 98% within 15mmHg. These observations conferred on the device grade C for SBP and grade B for DBP. The type of vascular access and the presence of non-functioning arteriovenous grafts and fistulas in the ipsilateral arm did not alter these results significantly. CONCLUSIONS These data validate the use of this device for hemodialysis patients. However, caution should be exercised in the evaluation of upper and lower ranges of SBP.

Lessons for successful study enrollment from the Veterans Affairs/National Institutes of Health acute renal failure trial network study

BACKGROUND AND OBJECTIVES Design elements of clinical trials can introduce recruitment bias and reduce study efficiency. Trials involving the critically ill may be particularly prone to design-related inefficiencies. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Enrollment into the Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network Study was systematically monitored. Reasons for nonenrollment into this study comparing strategies of renal replacement therapy in critically ill patients with acute kidney injury were categorized as modifiable or nonmodifiable. RESULTS 4339 patients were screened; 2744 fulfilled inclusion criteria. Of these, 1034 were ineligible by exclusion criteria. Of the remaining 1710 patients, 1124 (65.7%) enrolled. Impediments to informed consent excluded 21.4% of potentially eligible patients. Delayed identification of potential patients, physician refusal, and involvement in competing trials accounted for 4.4, 2.7, and 2.3% of exclusions. Comfort measures only status, chronic illness, chronic kidney disease, and obesity excluded 11.8, 7.8, 7.6, and 5.9% of potential patients. Modification of an enrollment window reduced the loss of patients from 6.6 to 2.3%. CONCLUSIONS The Acute Renal Failure Trial Network Studys enrollment efficiency compared favorably with previous intensive care unit intervention trials and supports the representativeness of its enrolled population. Impediments to informed consent highlight the need for nontraditional acquisition methods. Restrictive enrollment windows may hamper recruitment but can be effectively modified. The low rate of physician refusal acknowledges clinical equipoise in the study design. Underlying comorbidities are important design considerations for future trials that involve the critically ill with acute kidney injury.

Plasma Biomarkers and Kidney Function Decline in Early and Established Diabetic Kidney Disease

Biomarkers of diverse pathophysiologic mechanisms may improve risk stratification for incident or progressive diabetic kidney disease (DKD) in persons with type 2 diabetes. To evaluate such biomarkers, we performed a nested case-control study (n=190 cases of incident DKD and 190 matched controls) and a prospective cohort study (n=1156) using banked baseline plasma samples from participants of randomized, controlled trials of early (ACCORD) and advanced (VA NEPHRON-D) DKD. We assessed the association and discrimination obtained with baseline levels of plasma TNF receptor-1 (TNFR-1), TNFR-2, and kidney injury molecule-1 (KIM-1) for the outcomes of incident DKD (ACCORD) and progressive DKD (VA-NEPHRON-D). At baseline, median concentrations of TNFR-1, TNFR-2, and KIM-1 were roughly two-fold higher in the advanced DKD population (NEPHRON-D) than in the early DKD population (ACCORD). In both cohorts, patients who reached the renal outcome had higher baseline levels than those who did not reach the outcome. Associations between doubling in TNFR-1, TNFR-2, and KIM-1 levels and risk of the renal outcomes were significant for both cohorts. Inclusion of these biomarkers in clinical models increased the area under the curve (SEM) for predicting the renal outcome from 0.68 (0.02) to 0.75 (0.02) in NEPHRON-D. Systematic review of the literature illustrated high consistency in the association between these biomarkers of inflammation and renal outcomes in DKD. In conclusion, TNFR-1, TNFR-2, and KIM-1 independently associated with higher risk of eGFR decline in persons with early or advanced DKD. Moreover, addition of these biomarkers to clinical prognostic models significantly improved discrimination for the renal outcome.

Acute Kidney Injury in the Intensive Care Unit

Acute kidney injury (AKI) is common among critically ill patients and results in increased mortality in this population. This review focuses on the diagnosis and management of AKI. The authors first explore new aspects of diagnosis, including new criteria that take into account even modest changes in renal function, and the development of novel biomarkers to allow earlier identification and better differential diagnosis of AKI. The authors also explore the available data on choice of dialysis modality and dialysis dose for the treatment of AKI, as well as the breakthrough development of the bioartificial kidney. Last, the authors review co-interventions that may have relevance to prognosis of AKI, such as intensive insulin therapy and the use of erythropoietin.

Targeting Access to Kidney Care Via Telehealth: The VA Experience

The Veterans Affairs (VA) is the largest integrated health care system in the United States and is responsible for the care of a population with a disproportionately high rate of CKD. As such, ensuring access to kidney health services is a VA imperative. One facet of the VAs strategy to reduce CKD is to leverage the use of teletechnology to expand the VAs outreach to Veterans with kidney disease. A wide array of teletechnology services have been deployed to both pull in Veterans and push out kidney health services to Veterans in their preferred health care venue. Teletechnology, thus, expands Veteran choice, facilitates their access to care, and furthers the goal of delivering patient-centered kidney specialty care. The VA has demonstrated the feasibility of virtual delivery of kidney specialty care services and education via synchronous and asynchronous approaches. The challenges ahead include determining the relative health care value of kidney telehealth services, identifying Veterans most likely to benefit from specific technologies and optimizing the adoption of effective kidney telehealth services by both providers and patients alike to ensure optimal and timely kidney health care delivery.

Systemic Diseases with Renal Manifestations

This article discusses the epidemiology, recognition, screening, and management of six systemic diseases that commonly present with renal manifestations: diabetic nephropathy, lupus nephritis, congestive heart failure, HIV, liver disease, and dysproteinemias. Diabetic nephropathy remains the leading cause of end-stage renal disease in the United States. The outlook for patients who have lupus nephritis and HIV-associated nephropathy has improved in the last decade. Kidney disease is common in patients who have advanced liver disease, and creatinine-based methods do not provide an accurate estimation of renal function in this population. Dysproteinemias are associated with protean renal manifestations, and renal disease may be the presenting manifestation.

Renal Replacement Therapy and Incremental Hemodialysis for Veterans with Advanced Chronic Kidney Disease

Each year approximately 13,000 Veterans transition to maintenance dialysis, mostly in the traditional form of thrice‐weekly hemodialysis from the start. Among >6000 dialysis units nationwide, there are currently approximately 70 Veterans Affairs (VA) dialysis centers. Given this number of VA dialysis centers and their limited capacity, only 10% of all incident dialysis Veterans initiate treatment in a VA center. Evidence suggests that, among Veterans, the receipt of care within the VA system is associated with favorable outcomes, potentially because of the enhanced access to healthcare resources. Data from the United States Renal Data System Special Study Center “Transition‐of‐Care‐in‐CKD” suggest that Veterans who receive dialysis in a VA unit exhibit greater survival compared with the non‐VA centers. Substantial financial expenditures arise from the high volume of outsourced care and higher dialysis reimbursement paid by the VA than by Medicare to outsourced providers. Given the exceedingly high mortality and abrupt decline in residual kidney function (RKF) in the first dialysis year, it is possible that incremental transition to dialysis through an initial twice‐weekly hemodialysis regimen might preserve RKF, prolong vascular access longevity, improve patients’ quality of life, and be a more patient‐centered approach, more consistent with “personalized” dialysis. Broad implementation of incremental dialysis might also result in more Veterans receiving care within a VA dialysis unit. Controlled trials are needed to examine the safety and efficacy of incremental hemodialysis in Veterans and other populations; the administrative and health care as well as provider structure within the VA system would facilitate the performance of such trials.