Cardiac arrest is a devastating complication of hemodialysis treatments. RenalWEB obtained a copy of an internal memo from Fresenius Medical Care North America (FMC) dated Nov. 4, 2011 that indicates that FMC had knowledge that there was a significant increased risk of cardiac arrest and death during hemodialysis treatments associated with their Granuflo® dialysis concentrate product that contains sodium diacetate. Top FMC officials knew about the source of this potential problem since the product’s introduction in 2003. When a clinical problem finally became evident to the Fresenius Medical Services division around 2010, it appears that the top FMC executives not only chose not to properly report this problem to the FDA and other government agencies, but that they also decided to withhold this information from non-FMC physicians and clinics that were using the Granuflo product. It appears there was collusion involving individuals in several FMC departments and organizations to hide, mislead, and obscure information about this patient safety hazard in order to maintain their market share as well as to minimize and diffuse the legal risks for FMC. Also possibly related to this situation, the Chief Medical Officer of FMC, Raymond Hakim, MD, PhD, abruptly left his position in a November 2011 announcement.
Fresenius Medical Care North America is the largest division of Fresenius Medical Care AG, headquartered in Germany, and is the largest dialysis services and products company in both the U.S. and the world. FMC is uniquely vertically integrated in its business environment in that FMC both owns thousands of dialysis clinics and it also manufactures the dialysis machines and nearly all the medical products used in dialysis care including dialyzers, blood lines, needles, dialysis concentrate, etc. FMC has separate business divisions for clinic operations and for product manufacturing and sales. The FMC products division “sells” products not only to its own clinics’ division, but also to many of its leading competitors, including DaVita, DCI, Renal Ventures, and many others.
When the possible correlation between Granuflo use, alkalosis, and cardiopulmonary arrest was finally made by the Fresenius Medical Services division around 2010, FMC made this information and urgent medical recommendations solely available to its own physicians and clinics. Sudden cardiac death is the leading cause of death for dialysis patients. The internal FMC memo specifically recommended action for patients with pre-dialysis bicarbonate levels of >28mEq/L and especially for those who also had pre-dialysis serum potassium levels of <4 mEq/L. This 6-page internal FMC memo shows that for at least 15 months, FMC did not share this information with the thousands of non-FMC physicians and clinics that were using the Granuflo product. It then appears that FMC received an inquiry on March 27, 2012 from the FDA specifically about Granuflo-related products and alkalosis. Only then did FMC provide a scientifically-ambiguous, 2-page memo with far less actionable information to its non-FMC customers on March 29, 2012. The March 29 memo did not mention any patient blood levels. The most at-risk population of all, “acute” dialysis patients, are not mentioned in either memo.
The March 29th memo to non-FMC clinics and physicians contained only one of ten medical references that the FMC internal memo did. The March 29th memo also bundled the risks of Granuflo with another FMC acid concentrate product, Naturalyte®. The March 29th memo to non-FMC clinics and physicians also had a "Reply Form" attached that requested that a clinic representative sign it to "confirm that I have received and read the information presented to me in the accompanying letter regarding the risk of Alkalosis with Naturalyte® Liquid and Granuflo® Acid Concentrates."
Since its introduction in 2003, the Granuflo product has steadily increased its market share. It is now used by the majority of nearly 400,000 hemodialysis patients in the U.S. In the internal FMC memo, Granuflo use is associated with increased serum bicarbonate levels and alkalosis, as well as the increased possibility of cardiopulmonary arrests. Also in the internal FMC memo, Fresenius Medical Services noted that its own patients’ serum pre-dialysis bicarbonate levels had gradually increased from 2004 to 2011. Despite FMS’s knowledge of this patient safety risk, more non-FMC clinics are being converted to the Granuflo product even today without knowledge of the risks that are made clear in the internal FMC memo. Despite these patient safety issues and possible Federal Trade Commission violations and penalties, the FMC product sales division continues to aggressively market the product and routinely bundles Granuflo with other FMC products for pricing discounts.
The strategy that FMC executives seemed to arrive at to remedy this situation without either being noticed or without losing market share seems to take two approaches, one for FMC clinics and one for non-FMC clinics. FMC physicians and clinics were being instructed to remedy the situation immediately by making large changes to the hemodialysis machine settings, a somewhat inelegant solution that could raise other clinical problems for some patients. FMC physicians who questioned the change and wanted to use a different product could be dissuaded with a number of tactics. This may raise anti-trust issues.
For non-FMC clinics, it appears that FMC officials were hoping to quickly attain FDA approval of a new product that contained citric acid instead of sodium diacetate. Citric acid products are gaining in popularity in hemodialysis clinics because they appear to provide a number of additional clinical benefits. While FMC does currently license a citric acid product from another company, it is highly priced for a low-volume niche patient market and it also contains acetate. It appears that the FMC officials were planning to switch non-FMC Granuflo customers primarily to its new citric acid product as soon as it was FDA approved. The additional clinical benefits of the citric acid product could easily be touted as the justification for the widespread switch without raising too many questions in non-FMC clinics. The Granuflo product could then be discontinued or relaunched with far better clinician education programs.
If non-FMC clinics knew of the problem, they likely would have demanded further explanations, and many would have switched to other companies’ products. These non-FMC clinics also would likely not have discouraged affected patients and their families from pursuing legal actions.
Intriguingly, unbeknownst to thousands of U.S. nephrologists, FMC may have shifted some of its liability for this product to nephrologists by utilizing FMC personnel’s leadership positions on industry standard-setting committees. FMC is the only company that markets a Granuflo-related product with sodium diacetate. The Association for the Advancement of Medical Instrumentation (AAMI)’s committee for Renal Disease and Detoxification is co-chaired by a FMC Renal Therapies Group employee. In recent years, language concerning the sodium di-acetate and uncertain bicarbonate levels was inserted into the AAMI standards for dialysis. As the Medicare Conditions of Coverage hold the physicians responsible for providing dialysis care that adheres to AAMI standards, these nephrologists may unknowingly share legal responsibility for alkalosis resulting from the use of Granuflo.
Background Information on Dialysate and Granuflo
Dialysate is the solution that passes through the artificial kidney to clean the blood during hemodialysis. The dialysate is continuously mixed and heated within the dialysis machine during a hemodialysis treatment. Dialysate is a mixture of three fluids: ultrapure water, bicarbonate concentrate, and acid concentrate. Bicarbonate concentrate contains sodium bicarbonate mixed in ultrapure water. Acid concentrate adds additional sodium, as well as the needed potassium, calcium, magnesium, and the acid/acetate. Levels of all these components must be carefully controlled.
The Granuflo acid concentrate powder product from Fresenius Medical Care (FMC) received FDA approval for marketing in 2003. This product allows dialysis clinics to mix their own acid concentrate solutions using ultrapure water and packets of dry chemicals, the “Granuflo” formulations. By mixing their own acid concentrates, clinics can lower shipping costs and storage space associated with traditional 55 gallon drums. FMC also sells traditional, pre-mixed, liquid acid concentrate formulations under the brand name “Naturalyte.”
To control the pH of the dialysate, all acid concentrates must contain an acid and/or a form of acetate. Traditionally, most products have used acetic acid, which is liquid. Granuflo formulations are the only marketed products to contain the “dry” powder form of acetic acid, sodium diacetate. Recently, an increasing number of dialysis clinics have begun using citric acid products as evidence has been increasing that its use provides a number of clinical benefits.
Acidosis, Bicarbonate and Total Buffer Levels
Patients requiring dialysis normally suffer from acidosis, a buildup of acid in their blood. This is corrected (buffered/neutralized) during hemodialysis treatments with bicarbonate from two sources. The first and main source is the bicarbonate from the bicarbonate concentrate. Bicarbonate in the dialysate passes through the membrane of the artificial kidney and into the patient’s blood.
The second source of bicarbonate for the patient is the acetate in the acid concentrate. This acetate actually performs two functions. Most importantly, it controls the final pH level of the dialysate solution. Secondly, acetate also passes into the patient’s blood, where it is rapidly converted into bicarbonate by the patient’s tissues/liver.
A new term, total buffer level, refers to both bicarbonate and acetate in the dialysate. If there are 33 mEq/L from the bicarbonate concentrate and 4 mEq/L of acetate from the acid concentrate, the total buffer level is 37 mEq/L. Disparities between the prescribed dialysate bicarbonate levels, total buffer levels, and bicarbonate settings and readings on the dialysis machines have been an ignored long-term problem in dialysis care. Until very recently, almost all dialysis care professionals – as well as the FDA and CMS surveyors – did not consider the effects of the acetate in the acid concentrate when prescribing bicarbonate levels.
Recently Discovered Problem of Widespread Alkalosis… and Its Possible Causes
Evidence is now showing that a significant percentage of dialysis patients have unexpectedly high levels of bicarbonate in their blood and are actually suffering from alkalosis, the opposite of acidosis. The association between higher dialysate bicarbonate levels, pre-dialysis serum bicarbonate levels, and increased mortality was the topic of a presentation at the Annual Meeting of the American Society of Nephrology in November 2011. This problem appears to have been growing virtually unnoticed for many years, but apparently with the increased market share of Granuflo in the US and a lack of clinical knowledge about total buffer levels, more clinical problems have become evident.
Granuflo formulations are unique in that they use sodium diacetate (note the “di”). What was virtually unnoticed by the prescribing physicians with the introduction of Granuflo in 2003 is that it doubles the amount of acetate in dialysate compared to formulations made with acetic acid. Instead of adding 4 mEq/L of acetate, it adds 8mEq/L. This means that for dialysates made from Granuflo, the total buffer level is 8 mEq/L higher than the bicarbonate level delivered from the bicarbonate concentrate.
Lacking clinical knowledge, as well as a lack of effective product-related education from the manufacturer, often exacerbates this situation. If a physician orders a bicarbonate level of 37 mEq/L for the patient, the clinic may set the dialysis machine to deliver 37 mEq/L from the bicarbonate concentrate alone. If the clinic is using Granuflo, the patient may receive a total buffer load of 45 mEq/L instead of the 37 mEq/L of bicarbonate normally prescribed by the physician. Some clinics may have delivered, or may still be delivering, total buffer levels as high as 48 mEq/L.
(Additional information added May 21, 2:30 am EDT: In my effort to simplify the chemistry involved, I added an error to the article.
Sodium diacetate is made up of equal parts of acetic acid and sodium acetate. The acetic acid will become CO2 (carbon dioxide)and water, not bicarbonate in the body. The sodium acetate can become sodium bicarbonate in the body.)
The FDA’s Role
Dialysate concentrates are treated as medical devices by the FDA, not as drugs, although they can dramatically alter patients’ electrolytes, bicarbonate level, and blood pH. When the Granuflo product was submitted to the FDA in 2003 (510K #K030497), it was described as equivalent to predicate products that were already on the market. Sodium diacetate was considered equivalent to glacial acetic acid despite the fact that it had double the amount of acetate.
Many medications and physiological processes function normally or optimally only when blood pH levels are maintained within a very narrow range.
Part II – What occurred within FMC… despite its Patient Safety Organization?
I received copies of both the internal FMC memo and the FMC memo that was sent to non-FMC customers regarding this bicarbonate/alkalosis issue on Saturday, May 12, 2012 . After comparing them for approximately one hour, I began contacting the executives of dialysis clinic corporations whose patients may have been at risk. These organizations then began obtaining their own copies of the internal FMC memo from FMC sources. I have not provided copies of the internal FMC memo to anyone. Using this methodology, within a few days, action was taken to safeguard at least 2000 patients who were found to be at risk. I have also contacted the National Renal Adminstrators Association and the Renal Physicians Association and have urged them to employ the same method.
I have been in contact with the FDA. They have replied that they are aware of the issue and will be providing appropriate information to the public shortly.