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The SDMA Test In 2018

What Abnormal Results Mean - What They Don't Mean

Ron Hines DVM PhD

 

Kidney Disease In Your Dog & Cat- Its Diagnosis And Treatment In 2018

Is The SDMA Test Really Any More Accurate Than The Traditional Tests Your VeterinarianUses To Diagnose Kidney Problems In Your Cat Or Your Dog ?
Can The SDMA Test Be A False Alarm When Deciding If My Pet Has Kidney Issues ?
Back Door Problems Other Than Kidney Disease That Can Make SDMA Levels Rise :
Kidney (Renal) Blood Flow
Front Door Non-kidney Problems That Can Generate SDMA:
Liver Issues
Blood Vessel Inflammation And Heart Issues
Autoimmune Disease
Low-Grade Inflammation Elsewhere In The Body
A Side Effect Of Medications:


Anti-Arthritic/Anti-Pain Medications NSAIDs
Diet

High Bloods Pressure – Hypertension
Digestive Tract / Gastrointestinal Issues
Stress Exercise And Increased Sympathetic Tone
Infections
Hemorrhage And Trauma
How Can So Many Different Things Influence Blood SDMA Levels?
So - On The Whole - What Do You Think Of The Value Of The SDMA Test?

Why Did You Write This Article?

 

I am going to tell you everything I know about your pet’s SDMA test. For many of you, it’s considerably more than you want – just click on the section above to reach the parts that interest you. If you’re an in-depth medical research junky, you can read the whole thing.

The SDMA test for dogs and cats became available in the US and Canada in 2015. Idexx Laboratories is the sole Corporation offering it. In Europe it was rolled out in 2016. Idexx offers the test as a new way to judge your pet’s kidney health. Their main selling point is their claim that the test will discover kidney problems earlier than the tests your veterinarian has relied upon in the past.

 

The SDMA test is intensively marketed and promoted. It will take some time for veterinarians to sort out its true value in diagnosing chronic kidney disease (CKD) and any value the test might have in managing CKD once it is confirmed. In this article I hope to give you a more balanced, independent picture of what scientists know about SDMA, what they do not know, and factors other than kidney disease that might make SDMA levels in your dog or cat's blood stream go up or down.

We veterinarians have traditionally relied on your pet’s blood urea nitrogen levels (BUN) and its blood creatinine (sCr) levels to judge the health of your pet’s kidneys. As the wear and tear of Time and, perhaps, specific diseases decrease the efficiency of your pet’s kidneys in cleansing its blood, the amounts of those two waste products rise in your pet’s blood stream. However, they don’t begin to rise until the kidneys have lost over half of their original filtering (cleansing) power. Once the kidney’s little glomeruli responsible for that filtration have been lost, there is no known treatment that will bring them back.

That is why veterinarians and physicians have been so interested in finding a test that might catch the problem earlier than the BUN and Creatinine tests.

Body compounds that veterinarians measure to indicate the health of an organ are called biomarkers. The urine microalbuminuria test was a recent additional biomarker we hoped would detect kidney problems a bit earlier. It does – but it can be positive for a number of reasons other than kidney damage.

Society has a lot more interest and resources devoted to solving human health problems than our pet’s health problems. For many years, kidney specialists (nephrologists) have been screening all the compounds that went up as the heath of their kidney dialysis patients went down - looking for some Holy Grail to measure improvement or decline. They noticed that SDMA and ADMA were two compounds that went up in the blood as their patients declined. Some hoped that SDMA might give them better insights than creatinine levels did. One big drawback was that an accurate decision as to what constituted “normal” SDMA levels could not be agreed upon. The other big problem was the complicated and time-consuming ways SDMA and ADMA had to be measured (HPLC). (ref) Because HPLC testing was so cumbersome and expensive – it wasn't something you veterinarian could perform in the back room.

Idexx Laboratories of Westbrook, Maine found a way around that. In 2013 they patented a much simpler way to test your pet’s blood for its SDMA level, an ELISA test. (ref) ( An ELISA test for SDMA may have actually been the brainchild of a group of researchers in Neuss, Germany looking for a reliable way to diagnose lupus autoimmune disease) . [ref]

SDMA stands for Symmetric dimethylarginine, a byproduct of protein metabolism and rearrangement of proteins throughout your pet’s body. It contains, as its main component, the amino acid, L-arginine. All pets produce it; all humans produce it. The "twin" of SDMA is ADMA , ADMA was thought to do all the work (constricting blood vessels) and SDMA was thought to be inert (we know that's probably wrong now [ref]). Together with a third compound derived from arginine, (monomethylarginine [aka NMMA, MMA,N-NMMA]) they are called the methylarginines. Anything that influences the amount of production of one methylarginine appears to influence the amount of all three methylarginines. They tend to go up and down together. If you enlarge the diagram above the second to the last heading in this article, you can see a representation of what's thought to be occurring.

Idexx markets the SDMA test as being able to detect kidney health problems earlier than the tests veterinarians have been using – they say perhaps when as little as 25 - 40% your pet’s kidney function has been lost. They claim that this is about a year before the older tests will pick up the early stages of CKD. (ref) They quote a great many studies that they alone, or in duet with, Hills Pet Foods funded to back up their claims. They needed to convince veterinarians to use the SDMA test. One of their reviews mentions 41 articles in all. Here are just a few: (1 , 2 , 3 , 4 , 5 , 6 , 7 , 8) Idexx sponsored webinars. They ran Ad campaigns in journals veterinarians were likely to read. (ref) Others saw sales opportunities too. (ref) Everyone was convinced, the campaign was a sterling, crackerjack success! (ref)

But Is The SDMA Test Really Any More Accurate Than The Traditional Tests Your Veterinarian Uses To Diagnose Kidney Problems In Your Cat Or Your Dog ?

No. It is less accurate.

You can read about those traditional tests and treatments here.

To work, biomarker tests like SDMA have to do three things. They have to be sensitive in detecting the compound they are looking for. That’s called sensitivity. I believe that the SDMA test is quite sensitive. They also have to be attempting to measure something whose levels are quite stable in the body from hour to hour and from day to day. But most importantly, they have to have specificity. That is where the SDMA test fails. When a blood test signals that there's a problem it needs to accurately point to the organ that is causing the problem. Few tests are perfect, but they have to perform reasonably well in the last two thing. Sensitivity is not enough. If they are not specific, they’re going to have too many false positives due to non-kidney issues or transient physiological states ("a bad day"). If they don't have specificity, tests like SDMA are a gun with a hair trigger. They are going to go off due to a variety of unanticipated, unidentified and sometimes unidentifiable causes.

That’s always been the problem with SDMA. Idexx was not the first to try to use it to measure kidney function. Biocrates Life Sciences applied for a patent on an SDMA test in 2009 and spoke to me about their experiences. (ref) Realizing the difficulty making sense of the numbers based on SDMA levels alone, they tagged it to 5 other kidney biomarkers that were simultaneously measured. The project was eventually abandoned. Since nobody is content with creatinine levels being an ideal marker for early CKD, the search continues. (ref1, ref2, ref3, ref4) No research scientists I know of in the field (unassociated with Idexx) is suggesting that SDMA can stand on its own two feet in earlier kidney disease detection or adds additional information in advanced cases of CKD. There is only one human lab that offers the SDMA test commercially. They market it as a novel way to detect heart disease, blood vessel disease (cardiovascular issues) and diabetes. They only mention kidneys in passing. They say nothing about it being able to pick up kidney disease earlier than blood creatinine levels. (ref) As I mentioned in my updated kidney treatment article, some decision makers at the National Kidney Foundation have little faith in the kidney specificity of the SDMA test either. (ref) That was the same reservation, among others, of a seasoned enzyme biochemist I know. (ref)

Can The SDMA Test Be A False Alarm When Deciding If My Pet Has Kidney Issues ?

Most certainly so.

SDMA levels in your pet’s blood can go up in two ways. They can go up on the backside – when the natural amounts of SDMA your pet produces can no longer leave its body rapidly enough through its damaged kidneys. But blood SDMA levels can also go up at the front door side when abnormally high amounts of SDMA are created. I mentioned SDMA’s "twin", ADMA earlier. There is much more information available on situations that cause ADMA blood levels to rise than there is on SDMA. Although SDMA and ADMA leave the body in different ways, they are created in tandem. (ref1 ref2) The basics of kidney function, the compounds involved and the processes that go on do not differ much between mammals (although normal blood levels do) . Most of what we know about kidneys and SDMA we learned using rats or human subjects. That's why you won't see as many of my refs pertaining to dogs and cats as you will to humans and animal models. The basic concepts are valid just the same.

Back Door Problems That Can Make Your Pet's SDMA Levels Rise :

 

Kidney (Renal) Blood Flow

Kidney disease can certainly elevate your cat or dog's SDMA test results. But so can anything that decreases blood flow through your pet’s kidneys. Things like dehydration – drinking too little or heat prostration. Dehydration can also be the result of vomiting or diarrhea.

Many older dogs take diuretics like Lasix because of heart issues. Those products can cause low blood potassium. Abnormally low blood potassium levels (hypokalemia) lowers the amount of blood that passes through your pet’s kidneys too. (ref1, ref2) Vomiting and diarrhea sometimes cause low potassium levels as well. All causes of hypokalemia have the potential to affect SDMA levels.

A failing heart is often the underlying cause of reduced kidney blood flow. (ref1, ref2) But since heart issues in themselves can elevate SDMA, we really cannot say if it is kidney issues or a heart issue or both that are keeping them high. The same goes for the known association of heartworm disease and high SDMA levels. It could be heart and blood vessel (vascular) issues, secondary kidney issues or both that are responsible. (ref) Perhaps the author was unaware of that. It's not only inflammatory heart disease, valvular heart disease - so common in the toy breeds – will also decrease GFR and would likely cause SDMA blood levels to rise as well. I give a lot of human (refs) about that further down. I do not know of any studies on that that were performed in dogs or cats.


Front Door Problems That Generate SDMA:

As much SDMA comes in the front door as goes out the back. Cats and dogs almost certainly have non-kidney situations where they produce more SDMA than normal. In those situations, their SDMA blood levels also will be higher than normal. Very few have studied this in pets, but it is quite well documented in laboratory animals and humans. Here are some of the causes that have been found:

Liver Issues

Despite simplistic marketing campaigns, some believe that it is not just be the kidneys that excrete SDMA. The liver does too. The portal vein collects SDMA, the liver actively excretes it, and it leaves in the bile. More leaves through the kidneys, but a healthy liver is important in maintaining normal SDMA levels as well. (ref1, ref2, ref3, ref4) There are a lot of things that can injure your dog or cat’s liver. Some are transient, some are not. Aflatoxin poisoning due to moldy pet food ingredients commonly causes liver damage. Internationally, it is one of the top reasons dog and cat foods are recalled. (ref) Triad disease is quite common in older cats. Sometimes the symptoms are severe, but sometimes the effects on your cat’s liver and gall bladder are mild and mistaken for other things. That too could potentially affect a pet’s SDMA levels. No studies I know of explore that.

Many studies that track elevated SDMA levels in liver disease were done in humans. Many of those patients had kidney as well as liver damage. But SDMA levels went up even in the ones that showed no signs of kidney problems. (ref) In another study increased blood SDMA levels were thought to be associated with elevated liver (portal vein) blood pressure seen in hepatitis. (ref)

Blood Vessel Inflammation And Heart Issues

All the blood and lymphatic vessels in your pet’s body are lined with endothelium , a thin layer of cells that form a barrier between blood and the structure of the vessel that contains it. Endothelial cells have multiple, critical functions. (ref) These same endothelial cells line the heart and even form portions of the kidney glomeruli filters that your pet relies upon to filter its blood.

It appears that anything that disturbs these cells in any part of the body can increases the production of SDMA and its "twin" , ADMA. That has been documented best in the endothelial cells that line the heart. (ref1, ref2, ref3, ref4) It’s not only in humans that this applies. Methylarginines can go up in heart failure in dogs as well. (ref)

One well-designed study I found of interest attempted to decide what normal methylarginine levels were in people (of ADMA, SDMA's "twin"). They were interested in developing a blood test for coronary heart disease. In passing, they also tracked SDMA levels. They tracked ADMA levels quite closely. In their conclusions they noted that the difference between normal methylarginine levels and those with heart disease were only 11% and they found this small difference too small to be useful in predicting disease in individual patients. (ref).

SDMA levels go up in brain hemorrhage as well. (ref) The brain blood vessels that rupture are lined with endothelium too. Methylarginine levels go up in aneurisms as well. (ref) SDMA/ADMA also go up in carotid artery disease. (ref)

SDMA can also go up due to diabetes. (rptref) Most feel that endothelial inflammation is the cause of that as well. But the diabetic studies were in humans and many diabetic people have kidney problems along with their diabetes, so it is hard to tell which was the cause.

Autoimmune Disease

Methylarginines are known to go up in autoimmune diseases as well. (ref) Idexx was aware of that. When they patented the SDMA detection method in 2013, they hadn’t quite decided what the test might be good for, so for good measure, they threw in lupus (SLE), a form of autoimmune disease. They knew it went up in cardiovascular disease as well. (rptref)

Low-Grade Inflammation Elsewhere In The Body

Granted, a lot of dogs and cats with kidney disease or heart disease have periodontal disease as well. (ref) But periodontal disease in itself can elevate blood inflammatory biomarkers like C-reactive proteins. (ref) Dental/periodontal issues also elevate ADMA levels. They come down again after gum treatment. (ref) I did not run across any studies that tracked SDMA levels; but these two similar compounds usually rise and fall in tandem in response to inflammation.

Its not only inflammation associated with major blood vessels that can raise SDMA blood levels. In women, both SDMA and ADMA go up in polycystic ovary syndrome. Kidney function tests in those women found no difference between the normal control group of women and the group with the ovarian problems (ref)

A Side Effect Of Medications:

ACE Inhibitors

I think you are beginning to understand that blood levels of all the products that your pet’s kidney filter and remove can go up and down for reasons other than kidney/glomerular health. That should apply to SDMA too. For instance, when your pet with kidney disease receives an ACEe inhibitor like benazepril, its creatine level often takes a small to moderate “bump” upward. Veterinarians and physicians theorize that is probably due to the decreased kidney blood pressure that ACE inhibitors cause (in many ways a good thing). This has been documented for creatinine. To my knowledge, this has never been examined for SDMA. But it has for SDMA’s "twin" ADMA. (ref) In my opinion, until I see otherwise, a moderate rise in SDMA (if one occurs) when on ACE inhibitors is not reason enough to discontinue using them. That is because most nephrologists believe keeping that pressure down is very important in slowing the progress of kidney/renal failure. (ref)

Anti-Arthritic/Anti-Pain Medications NSAIDs

Dog owners can be faced with a Hobson’s choice when it comes to controlling arthritic and joint pain in their pets. Most of these pets are elderly. I already mentioned that kidneys naturally loose some of their reserves as they age. (ref) I am not sure why the author of that study does not consider aspirin a NSAID. Most folks do. In any case dogs do not tolerate aspirin well - don't give them any and never ever give Tylenol to a cat. I do not use any NSAID products in cats – although some vets feel they can be used if the dose is given less frequently. Tramadol is not a NSAID. Tramadol seems not to live up to expectations in dogs (ref) but it does in cats (ref) - but that's off topic. I do not know what influence NSAIDs might have on SDMA levels. On one hand, NSAIDs are no friend of the kidneys. On the other, NSAIDs decrease inflammation in the linings of blood vessels (the endothelium) throughout the body – a major source of SDMA. At least aspirin does. (ref) What influences the more modern NSAIDs like Rimadyl ®, Previcox ® or Galliprant® might have on the endothelium and SDMA levels is unknown.

Diet

In their patent (rptref) Idexx states that high-fat, high-cholesterol diets increases SDMA serum levels without affecting kidney (renal) function. A study of the effect of dietary lipids (fats/oils) on methylarginine tended to confirm it. In that case, it was attributed to generalized blood vessel inflammation (endothelial inflammation/atherosclerosis) caused by the high fat diet. (ref) The way the author named the compound, it could have been ADMA or SDMA, or both. The authors of another study of SDMA levels in kidney hemodialysis patients actually attributed a rise in their patients SDMA levels to better nutritional status due to higher dietary protein intake and a drop in the malnutrition that is so common in late stage kidney disease. (ref) They thought the SDMA rise was a positive sign. Perhaps other explanations could have been found - I do not know. If nothing else, it tells you loud and clear how slippery the interpretation of the meaning of SDMA levels can be.

In 2013, a medical biochemist in Italy found that commonly eaten vegetables contained SDMA. (ref) He was uncertain how much of it was absorbed but he thought that dietary sources of SDMA should be considered when attempting to decide the meaning of elevated SDMA blood levels. I asked him if he had ever quantified the amount of SDMA in meat. He said he had not, but thought their presence in meat was “very probable”. Others disagree on the significance of dietary SDMA. I bounced the same question off a research meat biochemist at Texas A&M University. His answer: “It is possible, but the amounts absorbed are likely negligible”.

High Bloods Pressure – Hypertension

The effects of high blood pressure on SDMA levels are hard to separate from the effects of an inflamed blood vessel lining (endothelium) that I discussed earlier with heart and blood vessel issues. I believe they are one in the same. We do not know how these problems link to higher SDMA levels, but they all do. Like the studies I mentioned earlier, the majority track ADMA rather than SDMA because ADMA is thought to be the more active of the two. When SDMA was tracked, it was in a condition where blood pressure was particularly high in the arteries of the lungs. They tracked SDMA in humans with the problem and in rats in which the problem was created. In both, SDMA levels went up. (ref) In systemic (generalized) high blood pressure where only ADMA was tracked. It went up. (ref1, ref2, ref3)

Digestive Tract / Gastrointestinal Issues

Inflammatory bowel disease (IBD) is common in dogs. It occurs in cats as well. (ref) In cats, the signs of IBD can overlap with triad disease. In humans, SDMA goes up in inflammatory bowel disease. (ref) I do not know anyone who has formally tracked SDMA levels in in dogs or cats with similar digestive tract issues. But I recently had a cat in declining health where assuming that its elevated SDMA levels were related to a kidney problem would have been a diagnositic error. (ref)

Stress Exercise And Increased Sympathetic Tone

Your pets body has a different nervous system to run its organs than it does to run its muscles of locomotion. Its called the autonomic nervous system and it has two branches. One, the sympathetic branch, is quite active during times of stress. Veterinarians call that an increase in its “tone”. When its tone increases, as it does in stress and exercise, blood vessels in the kidneys contract and less blood passes through their tiny filtering units, the glomeruli. The increased sympathetic tone of stress and exercise also has a negative effect on the blood vessel endothelial cells I mentioned earlier. The ones that line your pets blood vessels and heart - the ones that are capable of releasing SDMA. (ref) Under conditions of stress and exercise, less blood is getting filtered by your pet’s kidneys (ref), so they are performing similarly to the way they would perform if they had early kidney disease (their GFR is down). That could, theoretically, raise your pet’s SDMA levels. It does in humans. (ref scroll down to P3353 | BEDSIDE).

There is a strange tie-in between SDMA levels and muscles activity. Within a week of producing severe muscle loss in mice, their SDMA blood levels had increased 1.3-1.9 fold. (ref)

Infections

There are many reports of SDMA levels going up in infections. In some of those reports, the patients had confirmed kidney problems (ref) In others, they did not. These were generally quite severe infections. It would be quite rare for tests as complicated as SDMA testing used to be to have been run in non-life-threatening situations. So no one really knows the effects of less serious bacterial or viral infections on SDMA levels (ref1, ref2, ref3, ref4 ref5) Even if some, or even if all, of these cases had co-exiting kidney issues caused by bacterial toxemia, the solution would have been antibiotics, not kidney diets or medications aimed at improving kidney function.

Hemorrhage And Trauma

When one experiences substantial bleeding or trauma, the lining of blood vessels is always affected. Again, no one has measured SDMA levels in our dogs and cats and attempted to tie SDMA levels to those events. But in humans, SDMA blood levels rise after both types of strokes – the kind where blood vessels are blocked by clots and the kind where blood vessels hemorrhage. (rptref1, ref2)

How Can So Many Different Things Influence Blood SDMA Levels ?

Enlarge the fanciful image above. There is a specific group of enzymes that are required to turn L-arginine amino acids into SDMA (ie, methylate it). Those enzymes are called PRMT enzymes (protein arginine methyltransferases). There are between 7 and 9 of them depending on which biochemist you talk to. Through 2009, they weren’t even sure if PRMT-Type II really belonged in the PRMT family at all. (ref1, ref2) Of the Type II group of methyltransferases, , it is PRMT 5 that is thought to generates SDMA and PRMT 1 that is thought to generates ADMA. SDMA and ADMA can’t be all bad because a genetic lack of the ability to produce either of them is lethal – at least to mice. (ref)

Anything that increases the activity (upregulates) the PRMT type II family will increase the production of SDMA. Many things have been suggested to do that. Insufficient oxygen (hypoxia) at the tissue level. (ref) Chronic inflammation. (ref) Cancer. (ref, ref2) Creating SDMA is only one of these enzymes’ functions. It gets involved in other aspects of inflammation and chats with the immune system as well. (ref)

When these enzymes are activated, more SDMA will be produced at the front door, when they are less active, less SDMA will be produced. That occurs independently of your pet’s kidney’s ability to excrete the SDMA that is waiting to leave through back door - your pet's kidneys.

So - On The Whole - What Do You Think Of The Value Of The SDMA Test ?

I do not believe that SDMA tests perform any better than the nest of other tests veterinarians have experience with – the tried and true tests: blood creatinine, microalbuminuria, BUN, urine specific gravity, blood phosphorus, albumin, anemia and body weight. At best, the SDMA test will confirm them, at worst, it will sow confusion and cause needless worry for pet owners and veterinarians alike. Sure, we could use better tests than the traditional ones (less confounders). Sure, SDMA goes up in kidney disease. But its specificity for kidney disease is insufficient. Too many other factors can influence SDMA levels in your pet’s blood stream. There is just too much background “noise” to decide the meaning of elevated SDMA levels when they occur. Like a rock concert amplifier turned up too loud, everyone's going to hear it; the SDMA test is not going to miss many pets with kidney issues. But it’s going to cry wolf an unacceptable number of times. It will also generate a lot of pointless specialty dog and cat food sales.

In demonstrating the ability of the SDMA test to detect kidney disease earlier than other tests (ref), Idexx set the value for normal creatinine levels too high. Higher than current IRIS standards. If one adjusts their experiment to today's standards, I believe the presumed superiority of the SDMA test over sCr (blood creatinine) disappears. Kidney decline (decreased GFR) is also a normal part of aging. According to Idexx, elderly dogs and up to 90% of elderly cats have kidney issues. So using the SDMA test to find kidney disease in these pets is a bit like using a divining rod to find water in a Louisiana swamp.

Central labs like Idexx and Antech need to improve their interpretation of blood creatinine normals to factor in breed, body size, age and anything else that turns out to be statically significant in determining what is normal for one dog and abnormal for another. That will take some effort, but it quite doable. It is also not patentable.

That said, the Idexx SDMA Test is probably going to be around for a long time. The company has invested a lot of money to insure that. In late February 2018, they and Hills Pet Nutrition launched a media campaign to make the SDMA test a routine part of veterinary hospitals' in-house blood panels. (ref) At its best, persistently high SDMA results, accompanied by normal creatinine levels, suggest that further tests on your dog or cat are in order: Have you vet check the pet's blood pressure for signs of elevation. Check elderly cats for hyperthyroidism. Check the pet’s heart for enlargement or valve disease. Check for all the non-kidney issues I listed that are accompanied by elevated SDMA levels.

Be sure your pet is well hydrated before a standard kidney panel and SDMA tests. Dehydration, insufficient water intake, diarrhea or vomiting decrease blood flow through the kidneys and raises blood laboratory markers of kidney disease through (blood) volume depletion.

Why Did You Write This Article ?

If one is clever and has deep pockets, it is quite simple to control the narrative – at least for a while. Instead of renting a billboard, journal covers are for sale - no questions asked. (ref) Deep pockets give you control of the media, the message and the microphone. One can pick and choose between research article when presenting your case - that applies to me as well as everyone else. But if you let whoever is playing this game pick his cards unsupervised, he is going to show you a royal flush every time. o.

I am not a biochemist. I treat sick animals. This information probably could have been presented to you better by a veterinary scholar. If you want a more accurate description, talk to an enzyme biochemist or veterinary scholar. Preferably talk to one who is not associated or supported by a company attempting to sell you something - be it their services, a product or a test. People write me when they worry about their pet's health. This site gets about 240,000 dog and cat-owners visits/month. (ref) The AVMA does not allow me to answer any of those people. I am tired of getting emails like this one that I am not allowed to answer. So I will send them a link to this article instead. Best wishes to you and your pets, RSH

Cat & Dog Owner Feedback On The SDMA Test