Author Interview: N.D. Vaziri M.D., MACP
Professor of Medicine, Physiology and Biophysics
Division of Nephrology and Hypertension
Schools of Medicine & Biological Sciences
University of California, Irvine
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Disintegration of colonic epithelial tight junction in uremia: a likely cause of CKD-associated inflammation
Vaziri ND, Yuan J, Rahimi A, Ni Z, Said H, Subramanian VS
Nephrol Dial Transplant. 2011 Nov 29. [Epub ahead of print]PMID: 22131233)
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What are the main findings of the study? |
As you are well aware ESRD and advanced CKD are invariably associated with systemic inflammation which is major mediator of progression of kidney disease, and CKD-associated complications including: atherosclerosis, cardiovascular disease, ESA-resistant anemia, immune deficiency, wasting and cachexia, among numerous other complications.
Several factors contribute to the pathogenesis of inflammation in CK including: oxidative stress, retained uremic metabolites, exogenous toxins, co-morbid conditions (e.g. diabetes and autoimmune diseases), infections (blood access, PD catheters, hepatitis etc), iron overload, hypervolemia, increased LDL inflammatory activity, impaired HDL anti-inflammatory properties, and immune activation by extracorporeal circuit and influx of impurities from dialysate compartment during dialysis, among others.
However, little attention has been paid to the role of the gut and its microbial community as a potential source of inflammation in CKD/ESRD.
Although anatomically situated in the most central region of the body, the GI tract is actually an extension of the external environment within humans and animals. Therefore in addition to absorption of nutrients and secretion of waste, the GI tract serves as a barrier to prevent influx of microbes, harmful microbial byproducts and other noxious compounds into the host’s internal milieu.
The intestinal epithelial barrier consists of: I-The apical plasma membrane of the enterocytes which regulates passive and active trans-cellular transport of solutes, usually via specific transport channels, and II-The apical junctional complex which forms the barrier against paracellular permeation of luminal substances. It includes the tight junction and the subjacent adherens junction of which the tight junction is the most luminal component. The tight junction complex consists of: I-The adhesive trans-membrane proteins (occludin, claudin family, and junctional adhesion molecule-A) which form the barrier to diffusion of fluids and solutes by linking the plasma membranes of the adjacent cells, II- The actin-binding cytosolic tight junction proteins (zonula occludens [ZO] family) which regulate the organization and positioning of the apical junction complex, and III-The peri-junctional ring of actin and myosin which regulate paracellular permeability by modulating the structure and function of the tight junction.
There is indirect evidence that intestinal barrier function is impaired in uremia. These include the following observations: I- presence of endotoxemia in uremic patients without detectable infection (Gonçalves et al, 2006; Szeto et al, 2008), II- increased intestinal permeability to high molecular weight polyethylene glycol in the uremic humans and animals (Magnusson et al, 1990,1991), III- detection of luminal bacteria in mesenteric lymph nodes of the uremic animals (de Almeida Duarte et al 2004 ), and IV- diffuse inflammation throughout the GI tract (esophagitis, gastritis, duodenitis, enteritis, colitis) in ESRD patients maintained on dialysis (Vaziri et al 1985).
In view of the evidence for increased intestinal permeability in the uremic humans and animals and the critical role of the epithelial tight junction in the mucosal barrier function, I hypothesized that uremia may result in disruption of the intestinal tight junction complex. To test this hypothesis we measured the abundance and localization of the tight junction proteins and their corresponding mRNA transcripts in the ascending and descending colon of animals rendered chronically uremic by subtotal nephrectomy or adenine induced chronic tubulointerstitial nephritis.
The study revealed from 70-95% reduction of all protein constituents of the epithelial tight junction in the uremic rats pointing to severe disintegration of the colonic barrier structure.
This phenomenon can contribute to the systemic inflammation by allowing the entry of endotoxin and other pro-inflammatory and toxic products from the lumen of the gut to the systemic circulation.
Interestingly, the observed depletion of the tight junction proteins was accompanied by normal or even elevated mRNA levels, suggesting that uremia either reduces the capacity to synthesize the tight junction proteins or rapidly destroys them after they are made.
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Were any of the findings unexpected? |
To the extent that this phenomenon had not been demonstrated previously, it could be considered unexpected.
However, in retrospect these findings could have been predicted based on the indirect evidence cited above.
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What should clinicians and patients take away from this study? |
There is an enormous value for us as clinicians to understand the underlying mechanism of the disease regardless of what we may be able to do about. Understanding of the mechanism is the first step in finding strategies to remedy the problem.
From a practical standpoint, we should avoid circumstances which may further aggravate the problem. For instance, I believe we should be more gentle with the rate of ultra-filtration to avoid intra-dialytic/post-dialytic hypotension which by inducing transient bowel ischemia my further damage the tight junction and cause bacteremia
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What recommendations do you have for future studies as a result of your study? |
We are currently conducting a series of in vivo as well as in vitro colonic cell culture experiments to identify the mechanism by which uremia/CKD damages colonic tight junction.
We are also exploring the effect of a number of therapeutic interventions that we hope may help ameliorate this biologically important abnormality and resulting systemic inflammation
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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
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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.
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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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