Folks: Every once in a while, I get an email that demonstrates such
extreme clarity of mind that it cannot be ignored.  This morning, I
received such a letter and I wish I could post it in its entirety.  The
letter was not exactly in my favor, but the writer really thought about
what I said and subsequently asked some delightfully difficult questions.
Even for someone as longwinded as myself, I simply cannot respond to her
entire letter here, so I will pick out what I think are the two hardest
hitting questions and answer them.  Before I make another comment,
however, I want to say that I cannot tell you how much I appreciate such
insightful questions.  The questions made me think, which is the greatest
gift you can ever give to a person.  Well, except for beer and tacos.
 
Q: "And a gene that caused kidney problems when the animal was confronted
with too much protein would not have selection pressure against it if the
situation never arose in which that level of protein was habitually being
given."
 
Good idea, however, cystinuria is not actually a kidney problem.  It is
a COLA amino acid transport problem.  The problem exists whether or not
you make stones, so the only ferrets that would have selection pressure
on them would be the ones with the stones.  Also, the high protein
requirement of ferrets is not because they need it for growth and
maintenance, but for energy, so those proteins are converted by the liver
into blood sugar via gluconeogenesis and are never excreted into the
urine to become a problem, so again, no selection pressure.  Kibble, on
the other hand, has lots of carbohydrates, so rather than excess protein
being converted into energy as it should be, the protein is just floats
around to be excreted into the urine.
 
Here's the thing about cystinuria.  The creation of the stones is a
function of four variables.
1) You need to have the trait.  It is a recessive genetic trait, so you
will not form the stones unless you have the disease.
2) Regardless of the level of protein you are eating, it is the
concentration of cystine (and the other COLA amino acids) in the urine
that leads to stone formation.  Because the kidney is a distilling organ,
low protein levels can result in stones just like high protein levels;
perhaps not at the same frequency, but they nonetheless form.  More than
60 breeds of dogs, consuming a lower percentage of protein in their
kibble than ferrets, routinely form cystine stones, so stones can form
even though protein levels are well below "ferret kibble levels".
3) The amino acid cystine is not as soluble as its other happy family
members, especially in acidic environments.  The pH of the urine is
therefore as important, or more, than any other factor.  Ferret kibbles
are purposely balanced to be acidic to prevent the formation of mineral
stones and can therefore exacerbate the problem.
4) The first treatment for any species is to increase water consumption
in an attempt to double urinary output.  For species with cystinuria,
water is a drug and will not only help prevent stones, but help dissolve
existing ones.  Kibble is not more than 10% moisture; kiln-dried lumber
is about 18%, a fresh bone contains about 15% moisture, hardwood flooring
staves are 10-12% moisture, and gypsum board (sheet rock, drywall) is
about 5% moisture.  This means kibble has a moisture content somewhere
between hardwood flooring staves and drywall.  To digest kibble, the GI
tract pulls moisture from the body and the kidneys react by pulling
moisture from the urine (within the kidney, not in the bladder).  This
concentrates the urine, making stones more likely.  This is why vets
generally place dogs with cystinuria on a wet diet, such as canine u/d.
Meat, on the other hand, is nearly three-quarters moisture, so the impact
on the ferret's body moisture is considerably less.
 
Cystinuria has NOTHING to do with the protein requirements of a species.
It is a recessive genetic defect that makes it hard for cystine and the
other COLA amino acids to transport across cell membranes.  If an animal
has 10%, 25%, or 50% protein requirements, cystinuria doesn't change that
a single iota.  They are two distinctly separate things.  If an animal
that requires 10%, 25%, or 50% protein for a healthy life was born with
cystinuria, it STILL has a 10%, 25%, or 50% protein requirement.
 
The hypothesis that suggests ferrets may have had cystinuria for a long
time and it never showed up because they were consuming a diet containing
30-35% protein, requires one thing to be true: the disease will never
show in ferrets eating those levels of protein, only showing up in
ferrets eating higher levels.  Can this hypothesis be falsified; that it,
can it be shown to be untrue?
 
We have to ask ourselves, what requirements are necessary if the
hypothesis WAS true (cystinuria being widespread in ferrets, but masked
because of a low-protein diet)?  First, ferrets consuming the current
kibbled diets (30-35% protein) should NOT form stones.  It fails here,
because they do, and it has been documented that they did in the past,
in the few cases having made it into the literature.  This would not be
unexpected, because as mentioned before, cystine stones forms in species
eating considerably lower levels of protein.  As pointed out, the
precipitation cascade of cystine is dependent on cystine levels, but it
is just as dependent upon urine acidity and hydration.
 
A second requirement would be that ferrets consuming high-protein foods
would develop cystine stones in a rate well above those of ferrets
consuming low-protein foods.  It fails here also, because there is no
increase in the numbers of ferrets consuming a high protein diet that
show symptoms of the disease compared to those consuming a low-protein
diet.  Granted, the actual number of reports of the disease is extremely
small (that says something in itself, doesn't it?), but even so, there
should be differences.  The use of Bob's Chicken Gravy is widespread.  On
a dry matter basis, BCG is about 45-55% protein and it has been widely
used for 6 to 7 years or so, yet the ferrets consuming it do not develop
cystine stones.  If the disease was widespread in the ferret gene pool,
statistically at least some of them would have consumed BCG, various
other chicken-based foods (baby food, soups, and alternative gravies),
yet none of these ferrets grow cystine stones.
[Posted in FML issue 4789]