Hemodialysis.com | Dr. Schepers: Dimethylarginine Proinflammatory Agent in CKD
Author Interview: Eva Schepers
PhD, MBioScE
Labo Nephrology, University Hospital Ghent
De Pintelaan 185, 9000 Ghent, Belgium
Publication:
Author Interview: Eva Schepers
Symmetric Dimethylarginine as a Proinflammatory Agent in Chronic Kidney Disease.
Schepers E, Barreto DV, Liabeuf S, Glorieux G, Eloot S, Barreto FC, Massy Z, Vanholder R.
Department of Internal Medicine, University Hospital Gent, Gent, Belgium;
Clin J Am Soc Nephrol. 2011 Aug 4.
What are the main findings of the study?
In our study we demonstrated both in vitro and in vivo, that SDMA, a uremic retention solute, is associated to the chronic inflammatory status in CKD patients. In vitro, SDMA activates NF-κB in monocytes resulting in an increased expression of TNF-α and IL-6 and both these effects were abbrogated by NAC. The pro-inflammatory character of SDMA was further confirmed in a clinical study in patients at different stages of CKD in which SDMA, besides being a marker for renal function, was shown to be associated with several markers of inflammation, like IL-6 and TNF-α.
ADMA, the structural counterpart of SDMA, was evaluated in parallel, but showed no in vitro effects and its association with inflammatory parameters in the clinical study was less pronounced.
Were any of the findings unexpected?
SDMA was for a long time considered to be inert while ADMA, an inhibitor of NOS, was generally accepted to be a marker of endothelial dysfunction and a predictor of cardiovascular disease. Therefore SDMA had rarely been considered in in vitro or clinical trials until recently.
In vitro, our group demonstrated that SDMA induced ROS production in monocytes involving Ca2+ influx, while ADMA did not. Also, in a holistic in vitro approach evaluating ten guanidino compounds SDMA exerted the highest number of pro-inflammatory and vascular damaging effects. Therefore, it was no surprise that SDMA induced cytokine production. The fact that ADMA showed no effect at all in vitro, even at rather high concentrations, was not necessarily expected.
The fact that SDMA was a better marker for renal function than ADMA might be attributed to their different removal from the body. While SDMA is completely eliminated by the kidneys in healthy conditions, ADMA is mainly enzymatically removed. Correlations of both compounds with inflammation described in literature are rather scarce, but are in correspondence to our in vitro findings.
What should clinicians and patients take away from this study?
SDMA concentrations gradually increase with progressive stages of CKD and a good correlation is shown between SDMA and epi-GFR. Moreover, SDMA is correlated with several inflammatory parameters in se (cytokines), next to clinical parameters influenced by inflammation, such as BMI, hemoglobin and albumin.
Thus SDMA might contribute to the chronic inflammatory state although a cause-effect relationship cannot be demonstrated based on the present cross-sectional study and extended research is necessary. Now, it becomes interesting to study removal of this molecule by dialysis and to assess methods to improve this removal.
What recommendations do you have for nephrology health care providers as a result of your study?
In vitro we demonstrated that NAC inhibits the cytokine production induced by SDMA and a higher statin use was observed in the low SDMA group of our study population, next to a negative correlation between SDMA and statin use.
Therefore medical treatment with one of these drugs might improve outcome long before dialysis is needed in the future. Again further research remains necessary to know whether the interventional modification of the effect of SDMA with one of these drugs will be associated with a change of the inflammatory status in CKD patients. Furthermore, ways to remove SDMA better by dialysis or other strategies should be explored.
Abstract:
Summary Background & objectives Chronic kidney disease (CKD) is characterized by chronic inflammation, considered a nontraditional risk factor for cardiovascular disease, the major cause of death in CKD. Symmetric dimethylarginine (SDMA) was recently demonstrated to induce reactive oxygen species in monocytes. The present study further investigates the inflammatory character of SDMA compared with its structural counterpart asymmetric dimethylarginine (ADMA). Design, setting, participants, & measurements In vitro, the effect of SDMA on intracellular monocytic expression of IL-6 and TNF-α was studied followed by an evaluation of nuclear factor (NF)-κB activation. Additionally, an association of SDMA with inflammatory parameters in consecutive stages of CKD was evaluated in vivo.
Results Monocytes incubated with SDMA showed increased IL-6 and TNF-α expression and a rise in active NF-κB. N-acetylcysteine abrogated both these effects. No significant effects were observed with ADMA. In vivo, 142 patients (67 ± 12 years) at different stages of CKD showed an inverse association between serum SDMA and ADMA and renal function. Correlations between SDMA and IL-6, TNF-α, and albumin were more significant than for ADMA, while multiple regression analysis only retained TNF-α at a high significance for SDMA (P < 0.0001). In receiver operating characteristic analysis for inflammation, defined as an IL-6 level above 2.97 pg/ml (median), the discriminative power of SDMA (area under the curve [AUC]: 0.69 ± 0.05) directly followed that of C-reactive protein (AUC: 0.82 ± 0.04) and albumin (AUC: 0.72 ± 0.05; for all, P < 0.0001) and preceded that of ADMA (P = 0.002).
Conclusions The present study shows that SDMA is involved in the inflammatory process of CKD, activating NF-κB and resulting in enhanced expression of IL-6 and TNF-α, which is corroborated by the clinical data pointing to an in vivo association of SDMA with inflammatory markers in CKD at different stages.
Home Dialysis Summit Recommends Policy Changes to Increase Home Dialysis Usage
WASHINGTON, April 25, 2012 /PRNewswire -- On the heels of the first National Summit on Home Dialysis Policy, Summit organizers released a report reflecting the views of the delegates -- leaders in the kidney disease patient, clinician, facility and industry communities -- on federal policy steps to improve utilization of home dialysis for patients who can benefit from this often advantageous form of treatment. Many of the organizers also announced they have formed a new alliance, called the Alliance for Home Dialysis, to advance the recommendations identified at the Summit.
The Summit's "Report of the Delegates" highlights key findings from a March 29th meeting in Washington, DC where experts probed why, despite widely accepted and well-documented benefits of home dialysis -- improved outcomes, enhanced patient satisfaction, improved quality of life, and lower costs-- fewer than ten percent of the more than 390,000 current U.S. dialysis patients receive treatment at home. Current rates of home dialysis utilization reflect a steep decline from the 1970s, when almost 40% of U.S. dialysis patients were treated in-home.
Specifically, delegates found that policymakers should work with stakeholders in the dialysis community to confront three areas:
Accessibility: Patients and clinicians face array of hurdles in education, training, and infrastructure that hinder equalized access to home dialysis.
Accountability: Utilization of home dialysis can be improved through measures within government programs that are designed to recognize and support excellence in the delivery of home dialysis services.
Aligning Incentives: Reimbursement policies, regulation of new technologies and other policy incentives can be realigned to better support federal policy goals of expanding access to home dialysis.
The Report includes 15 recommendations to serve these goals, including that federal policymakers should:
Maintain parity for home and in-center dialysis in Medicare reimbursement;
Support home dialysis mentoring programs, particularly those that use existing patients as mentors; and
Align federal and state regulatory requirements for home therapies, such as revising the Centers for Medicare and Medicaid Services Conditions for Coverage requirements, to reflect differences in home and in-center dialysis.
Summit supporters will begin work through the new Alliance to dialogue with federal policymakers and advance policy improvements in the three consensus areas that emerged at the Summit.
SOURCE National Summit on Home Dialysis Policy
National Kidney Foundation's Top 10 Things Every Dialysis Patient Should Know.
You have treatment choices. Options exist for how, where and when you dialyze. Dialysis can be done in a hospital, in a dialysis unit that is not part of a hospital, or at home. You and your doctor will decide which place is best, based on your medical condition and your wishes. There are different types of dialysis - peritoneal and hemodialysis. Work with your health care team to determine a treatment plan that makes you feel comfortable. Recent studies show that the majority of patients beginning in-center hemodialysis (HD) know very little, if anything, about the option to dialyze at home. Once informed, 40% or more of patients are interested in this treatment option, and yet less than 10% actually begin home dialysis. If you're dissatisfied with the type of dialysis treatment that you're receiving, ask your healthcare team if another type of dialysis treatment would be better.
You can compare in-center dialysis facilities online. Information on over 5,600 US-based dialysis centers is available online through the Medicare website. To help you make choices about your care, you can compare different facilities side-by-side and evaluate each facility based upon clinic characteristics and quality measures. You can search for dialysis facilities by name or geographic proximity. After completing an initial facility comparison to determine which facilities best meet your needs - such as the number of hemodialysis stations at a particular location and whether there are evening shifts available - visit the facilities that you're most interested in. Talk to the staff and other patients, as well as your doctor to ensure that this dialysis facility is a good fit for you.
There are ways to prepare ahead for an emergency. Ask your dialysis facility about their emergency plan in case of a snow storm, fire, power outage or other natural disaster. As back up, make sure you have the names, locations and phone numbers of other dialysis units and hospitals in your area. Since regular community transportation services may not be working in an emergency, be prepared to make other arrangements for getting to dialysis. You may need to contact the police and Emergency Medical Services (EMS) for assistance. If you dialyze at home, make sure you have at least two weeks' worth of unexpired supplies on hand. If you have to miss a dialysis treatment, begin your emergency meal plan.
There is an easy way to transfer patient records between clinics. There is an easy, secure way for your health care team to transfer your treatment records online. In 2009, the Centers for Medicare and Medicaid Services (CMS) created a centralized web-based data collection system called CROWNWeb to help reduce and eliminate patient treatment interruptions. This central system helps to streamline patient care regardless of the reason for changing dialysis centers. For example, if you've been admitted to the hospital, or if you needed to relocate during an emergency evacuation, your doctors and health care team can access up-to-date information about your dialysis so that you continue to receive appropriate care no matter where you are.
You can travel while on dialysis.
Dialysis centers are located in every part of the United States and in many foreign countries. The treatment is standardized, but you need to plan ahead by making an appointment for dialysis at another center before you go. The staff at your center may help you make these appointments.
You can be your own best advocate. Know what key questions to ask your doctor or other healthcare professionals. Take notes so that you can refer back to them later. Partner with your doctor and decide on a treatment plan together. Advocate for yourself and share how you're feeling.
You have many rights. You as a patient have a great deal of control over your treatments. Patients have a bill of rights which includes receiving quality care, counseling about your medical information, and an expectation of privacy.
You also have responsibilities. Once you decide on a course of treatment, it's important to follow the recommendations of your health care team. If you decide to receive in-center dialysis, arrive at dialysis on time so that you can receive the full treatment without delays.
You can receive insurance coverage. If you have end stage renal failure, you are likely eligible for Medicare insurance coverage. Speak with your health care team and social worker for help filling out insurance paperwork.
You may need to follow a special diet. When your kidneys are not working properly, you may not be able to eat everything you like, and you may need to limit how much you drink. Your diet may vary according to the type of dialysis you receive. It is important to speak with a renal dietitian so that you are able to understand what you can and cannot eat based on your full health history.
Dialysis patients can work. Many dialysis patients can go back to work or school after they have gotten used to dialysis. After establishing a dialysis routine, many patients have more energy and find that they are able to time to work around this new schedule. Some patients even find creative ways to work remotely from dialysis with the use of a laptop or cell phone, depending on their field of expertise.
New Book to Help Educate Patients with Chronic Kidney Disease who may be facing Dialysis or Hemodialysis:
Help, I Need Dialysis! How to have a good future with kidney disease
By Dori Schatell, MS and Dr. John Agar
An internationally known nephrologist and life-long kidney patient educator explain how dialysis works, each of the ways to do it, and how your treatment choice may affect your diet, energy level, work, travel, sexuality and fertility, sleep, and survival. Comprehensive and fully referenced, this book is a must-read if you face the life-changing choices that come with kidney failure.
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