#284 
 
Using Relative Supersaturation to 
Support Urinary Tract Health 
Claims for Adult Maintenance Cat 
Food 
 
Guidance for Industry 
 
Draft Guidance 
 
This guidance document is being distributed for comment purposes only.  
 
Submit comments on this draft guidance by the date provided in the Federal Register notice 
announcing the availability of the draft guidance.  Submit electronic comments to 
https://www.regulations.gov.  Submit written comments to the Dockets Management Staff 
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD  
20852.  All comments should be identified with docket number FDA-2023-D-4095.   
 
For further information regarding this document, contact Karen Donnelly, Center for Veterinary 
Medicine (HFV-227), U.S. Food and Drug Administration, 12225 Wilkins Avenue, Rockville 
MD 20852, 240-402-9802, karen.donnelly2@fda.hhs.gov.   
 
Additional copies of this draft guidance document may be requested from the Policy and 
Regulations Staff (HFV-6), Center for Veterinary Medicine, Food and Drug Administration, 
7500 Standish Place, Rockville MD 20855, and may be viewed on the Internet at 
https://www.fda.gov/animal-veterinary, https://www.fda.gov/regulatory-information/search-fda-
guidance-documents, or https://www.regulations.gov.   
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Veterinary Medicine (CVM) 
November 2023 Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
Table of Contents 
 
I.  Introduction ....................................................................................................................... 1 
II.  Background ....................................................................................................................... 1 
A.  Introduction to Urolithiasis in Cats........................................................................... 1 
B.  Relative Supersaturation (RSS) Methodology ......................................................... 2 
C.  Support for Using RSS Methodology in UTH Cat Food ......................................... 3 
III.  Recommended Information to Substantiate RSS-Based UTH Claims ........................ 4 
IV.  Utility .................................................................................................................................. 4 
A.  Target RSS Values ...................................................................................................... 4 
B.  Study Duration and RSS Assessment Schedule ....................................................... 5 
V.  Target Animal Safety ........................................................................................................ 5 
A.  Safety Concerns ........................................................................................................... 5 
B.  RSS Study Design ........................................................................................................ 6 
C.  Combined Safety and Utility Study ........................................................................... 9 
VI.  References .......................................................................................................................... 9 
VII.  Appendix 1  Recommended Combined Safety and Utility Study Flowchart .......... 12 
VIII.  Appendix 2  Glossary of Terms and Acronyms ......................................................... 13 
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Using Relative Supersaturation to Support Urinary Tract Health 
Claims for Adult Maintenance Cat Food 
 
Draft Guidance for Industry 
 
This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
Administration (FDA, we, or Agency) on this topic.  It does not establish any rights for any 
person and is not binding on FDA or the public.  You can use an alternative approach if it 
satisfies the requirements of the applicable statutes and regulations.  To discuss an alternative 
approach, contact the FDA staff responsible for this guidance as listed on the title page. 
 
I.  Introduction  
In response to requests from pet food manufacturers, the FDAs Center for Veterinary Medicine 
(CVM) has evaluated the use of relative supersaturation (RSS) methodology to support urinary 
tract health (UTH) claims for certain adult maintenance cat food.  RSS is a measurement that 
estimates the potential for crystal formation and bladder stone (urolith) growth, which is a 
common affliction in cats.  This guidance provides recommendations for how pet food 
manufacturers can use RSS methodology to substantiate general structure or function claims that 
an adult maintenance cat food supports urinary tract health by promoting a healthy mineral 
content in the urinary tract.   
 
The recommendations we provide in this guidance include:  (1) the wording of UTH claims 
based on RSS methodology for use on adult maintenance cat food labeling; (2) the RSS criteria 
to substantiate UTH claims; and (3) the study data CVM requests from pet food manufacturers 
that demonstrate the utility and target animal safety of the cat food.   
 
For purposes of this guidance, you means the manufacturer of adult maintenance cat food with 
UTH claims (UTH cat food) based on RSS methodology.   
 
In general, FDAs guidance documents do not establish legally enforceable responsibilities. 
Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
the word should in Agency guidance means that something is suggested or recommended, but 
not required.   
 
II.  Background  
A.  Introduction to Urolithiasis in Cats 
Urolithiasis (the presence of uroliths in the bladder) is a fairly common affliction in cats, 
with prevalence estimates from clinical studies ranging from 9-23% (Forester et al. 
2010).  The two most common types of uroliths in cats are magnesium ammonium 
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phosphate (struvite), and calcium oxalate (CaOx), accounting for 50% and 37% of 
analyzed uroliths, respectively (Minnesota Urolith Center Global Data 2022).   
 
In response to concerns about urolithiasis, pet food manufacturers use various 
formulation strategies to make UTH cat food.  Historically, manufacturers of UTH cat 
food restricted the magnesium content and/or formulated their cat food to produce 
slightly acidic urine (pH of 5.9 to 6.4).  The slight acidity and low magnesium content 
create a urinary environment that is unfavorable for struvite crystallization and urolith 
growth but may be favorable for CaOx urolith growth in predisposed cats 
(Lekcharoensuk et al. 2001).  Formulating cat food based on RSS methodology is a more 
recent dietary strategy that some pet food manufacturers use to create UTH cat food.  The 
principles of RSS apply to all urolith types, so UTH cat food based on RSS methodology 
has the potential to help protect cats from both struvite and CaOx urolithiasis.   
 
B.  Relative Supersaturation (RSS) Methodology 
RSS methodology originated in human medicine in the 1960s and is widely used for 
measuring the potential for urolith formation in humans.  Researchers have also validated 
RSS methodology for use in dogs and cats (Robertson et al. 2002).   
 
One of the primary conditions for urolith formation in any species is oversaturation of the 
urine with dissolved substances (solutes) that have the potential to precipitate out of 
solution and form crystals.  These crystals can eventually grow into uroliths.  RSS 
provides a numerical measurement of the degree of saturation of a specific urolith-
forming substance, and thus a quantitative method to evaluate the risk of urolith 
formation.  There is a unique RSS value for each possible urolith type in a urine sample.  
The RSS value for a specific urolith is determined by first measuring the concentration of 
multiple solutes, including magnesium, ammonium, phosphate, calcium, and oxalate, as 
well as the pH in a urine sample collected over at least 24 hours.  These data are entered 
into a computer program that calculates the concentrations of the solutes that remain free 
to interact and form crystals, also known as the activity product (AP).  An RSS value is 
obtained by dividing the AP for a given urolith-forming compound by its known 
thermodynamic solubility product (SP), which represents the maximum concentration at 
which a solute can be completely dissolved in solution.   
RSS = AP  of the urine/SP
urolith urolith 
 
There are three zones of urine saturation that describe the activity of a given crystal in a 
urine sample:   
(1) Undersaturation  crystals will not spontaneously form, and if present, will 
dissolve.   
(2) Metastable supersaturation  crystals will not spontaneously form but may form 
in the presence of solid particles (i.e., a nucleus) such as cells, an existing urolith, 
or other particulate matter.  Existing crystals and uroliths will not dissolve and 
may grow.   
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(3) Labile supersaturation  crystals will spontaneously form and grow.   
The calculated RSS value for a given crystal indicates which zone its concentration is in 
for that urine sample.  An RSS value below the solubility product for a given crystal, i.e., 
RSS less than 1.0, puts it in the undersaturation zone.  The concentration at which 
dissolved urolith material will spontaneously precipitate out of solution to form crystals is 
called the formation product, and the formation product defines the limit between the 
metastable and labile supersaturation zones.  Studies suggest that the formation product 
for struvite uroliths is an RSS of 2.5, and for CaOx uroliths is an RSS of 12 (Houston and 
Elliot 2008; Bartges 2011), and these values are generally accepted and used by the 
veterinary community.  The degree to which an RSS value falls above the solubility 
product and approaches or exceeds the formation product indicates the level of risk for 
urolith formation.   
 
C.  Support for Using RSS Methodology in UTH Cat Food 
We received requests to assess the use of RSS methodology to substantiate UTH claims 
on adult maintenance cat food not restricted to sale through or under the guidance of 
veterinarians.  We therefore reviewed the available literature regarding RSS in cats, and 
we summarize our findings from that literature review below.   
 
1.  RSS and Dietary Factors 
Many studies investigate the relationship between RSS values and various dietary 
factors that possibly influence UTH in cats, such as ingredients that alter urine pH 
(Bartges 2013; Queau et al. 2013; Stevenson et al. 2000; Markwell et al. 1999; Smith 
et al. 1998), dietary moisture (Buckley et al. 2011), and dietary sodium content 
(Queau et al. 2020; Hawthorne and Markwell 2004).  These studies help pet food 
manufacturers, nutritionists, and diet formulators to make cat food that produce the 
desired RSS values.   
 
2.  RSS and Urolith Activity 
There are numerous studies that evaluate the utility of RSS methodology that 
specifically assess the relationship between RSS values and struvite urolithiasis in 
cats.  Several studies demonstrated that cat urine undersaturated for struvite 
(RSS  < 1) successfully dissolved struvite uroliths in-vitro, and the smaller the 
Struvite
RSS value, the faster the dissolution occurred (Tournier et al. 2008; Tournier and 
Biourge 2008; Sagols et al. 2015).  Studies also show that RSS is better than pH for 
predicting struvite urolith activity in-vitro (Van Hoek et al. 2009, Sagols et al. 2015).  
Published in-vivo studies demonstrated that cats that consumed diets formulated to 
induce urine undersaturated for struvite experienced complete struvite urolith 
dissolution after 2 to 10 weeks of feeding (Houston et al. 2004, 2011; Tefft et al. 
2021; Torres-Henderson et al. 2017).   
 
Although researchers cannot perform dissolution studies for CaOx uroliths because 
this urolith is not able to be dissolved, several studies document a positive association 
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between greater RSS  values and CaOx urolith formation in the bladder and/or 
CaOx
kidney in humans (Ferraro et al.  2018; Prochaska et al. 2018; Parks et al. 1997; Thun 
and Schober 1991), rats (Bushinsky et al. 1995), and dogs (Stevenson et al. 2003, 
2004).  We conclude that this information about the relationship between RSS and 
CaOx uroliths in other species and the results from the struvite dissolution studies 
support the use of RSS methodology to substantiate claims that a cat food promotes 
UTH in cats.   
 
III.  Recommended Information to Substantiate RSS-Based UTH Claims 
If you use RSS methodology to substantiate general structure or function claims that an 
adult maintenance cat food supports UTH, we recommend that prior to marketing the 
product, you submit for our review:   
  Empirical data demonstrating the utility and safety of the products mechanism(s) 
for maintaining urinary tract health (See sections IV. Utility and V. Target Animal 
Safety),  
  A complete quantitative ingredient formulation of the product,  
  A complete quantitative nutrient composition of the product, and  
  A complete product label, which can be a pdf-file, printers proof, or an unused 
label.   
If you include an RSS-supported UTH claim on the product label of the adult 
maintenance cat food, you also should include a mechanism of action statement on the 
product label and any additional labeling.  We recommend you use the mechanism of 
action statement:  Formulated to promote a healthy mineral content in the urinary tract.   
 
The submitted information helps CVM ensure the UTH claim is substantiated, and helps 
CVM review the claim in the context of the entire product label and labeling as a whole.   
 
IV.  Utility  
A.  Target RSS Values 
To demonstrate utility of a UTH cat food based on RSS methodology, you should submit 
results to CVM from at least one feeding study that demonstrates cats eating the food 
achieve RSS values below the formation products for struvite and CaOx (2.5 and 12, 
respectively).  The study should evaluate RSS for both struvite and CaOx since they are 
the two most common types of uroliths found in cats and preventing one urolith type 
while potentially promoting formation of the other is not supportive of a general UTH 
claim.  To ensure that cats consuming the food are less likely to develop urinary crystals 
or uroliths, CVMs recommended mean RSS for each urolith type is no greater than the 
midpoint of that uroliths metastable supersaturation range.  In addition, the upper bound 
of the 95% confidence interval (CI) around the mean should be no greater than the value 
of the formation product for the specific urolith.  The values meeting the recommended 
mean RSS and 95% CI limits are:   
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  Struvite: Mean RSS  1.8; Upper bound of 95% CI  2.5  
  CaOx: Mean RSS  6.0; Upper bound of 95% CI  12   
These values allow for some spread in individual cat RSS values and still provide an 
acceptable margin of safety against urolith formation.  If the RSS analysis provides 
separate RSS values for each of the two forms of CaOx crystals  monohydrate and 
dihydrate  rather than providing an RSS value for total CaOx, then the values for 
recommended mean RSS and CI limit apply to each of those forms.   
 
We also recommend you conduct RSS measurements on urine collected over at least 24 
hours, which would likely provide more accurate results because it accounts for possible 
diurnal variation in mineral excretion and other parameters.   
 
B.  Study Duration and RSS Assessment Schedule 
Although we do not define a specific timepoint when a study group of cats should 
achieve the target RSS values, the study should demonstrate that once the cats do achieve 
the RSS targets, the cats continue to meet the RSS targets from that point of the study 
onward.  Data from industry studies measuring RSS submitted to CVM demonstrate that 
RSS is stable from 5 to 26 weeks in cats.  Therefore, we recommend you conduct utility 
studies for a minimum of 40 days with RSS for struvite and CaOx measured at prescribed 
intervals no less than every 10 days during the study.  The first measurement should 
occur between day 10 and 21 of feeding the product.  There should be at least four 
separate RSS measurements, but they need not occur at regularly spaced intervals.  For 
example, the study could run for 40 days with RSS measurements on days 10, 20, 30, and 
40, or the study could run for 120 days with measurements on days 10, 20, 30, 60, and 
120.  Other study durations and schedules are also possible, but we recommend you use 
the guidelines we have described in this paragraph when designing your study.   
 
It is important to note that although we request a minimum of four RSS measurements 
that meet the criteria listed in section IV.A. Target RSS Values to demonstrate utility, this 
does not mean that meeting the utility criteria at any four times out of the total number of 
measurements performed would be acceptable.  The study should demonstrate that cats 
can consistently produce urine that meets the RSS targets, and that consistency should be 
demonstrated by at least four consecutive measurements.  Although it is your decision to 
determine how long a study and how many RSS measurements you wish to perform to 
meet that goal, you should make that decision prior to study initiation and adhere to that 
schedule regardless of the RSS results obtained.   
 
V.  Target Animal Safety 
A.  Safety Concerns 
There may be several methods for formulating a cat food that will produce the desired 
RSS parameters, so safety concerns will vary with the formulation method(s) used.  One 
safety concern is the degree to which the cat food acidifies the urine, because creation of 
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an overly acidic urine can increase the risk of metabolic acidosis.  Although acidification 
may not be the primary mechanism pet food manufacturers employ when formulating 
UTH cat food based on RSS methodology, urinary pH is one of the variables that affects 
RSS values, so adjusting a dietary formula to affect RSS may inherently affect urinary 
pH as well.  Thus, urinary pH measurements are an important safety component for 
manufacturers of UTH cat food when relying on RSS methodology.  Data from studies 
submitted to CVM by pet food manufacturers show a correlation between very low urine 
pH and negative balance of magnesium (Mg) and potassium (K).  Thus, if urinary pH is 
low enough to cause metabolic acidosis, mineral balance data (calcium (Ca), phosphorus 
(P), Mg, and K) are needed to evaluate product safety.  This is addressed in more detail in 
section V.B. RSS Study Design.   
 
Because manufacturers of UTH cat food based on RSS methodology may use various, 
potentially novel, formulation methods to achieve the RSS goals, nutritional adequacy of 
the cat food is another safety concern.  UTH cat food based on RSS methodology should 
therefore meet at least one, and preferably both, of the Association of American Feed 
Control Officials (AAFCO) methods for substantiation of nutritional adequacy (AAFCO, 
2022).  These methods are:  (1) formulate the cat food to meet the AAFCO Cat Food 
Nutrient Profile for Adult Maintenance, and/or (2) successfully complete and pass an 
appropriate AAFCO Protocol Feeding Study that demonstrates the cat food to be 
adequate for maintaining the nutritional status of adult cats.   
 
B.  RSS Study Design 
1.  Duration 
If the cat food is adequate for maintaining the nutritional status of adult cats because 
you formulated the cat food to meet the AAFCO Cat Food Nutrient Profile for Adult 
Maintenance or completed an appropriate AAFCO Protocol Feeding Study, we 
recommend you conduct at least a 40-day feeding study to evaluate product safety.  A 
study of longer duration may be necessary if mineral balance data is needed (see 
section V.B.2. Urinary pH Measurements and Mineral Balance Data).  If the 
nutritional adequacy of the cat food has not been substantiated using either of the 
AAFCO methods, then you should conduct a 26-week adult maintenance feeding 
study as described in the AAFCO Official Publication (AAFCO, 2022) and collect 
safety data during that time.   
 
2.  Urinary pH Measurements and Mineral Balance Data 
We recommend safety studies include measurements of each cats urinary pH at a 
minimum of four timepoints no less than 10 days apart.  Thus, a 40-day study should 
include urine pH measurements on days 10, 20, 30, and 40, but other schedules could 
be acceptable if the study is intended to run longer than 40 days.  You should perform 
urine pH measurements on 24-hour urine samples (rather than on single point-in-time 
urine collections), and then calculate the group mean pH and 95% CI for each time 
point.  The CI values will indicate if the study needs to include collection of mineral 
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balance data (Ca, P, Mg, K), which would necessitate a study of longer duration, or if 
the study can end after 40 days.  We recommend the following guidelines: 
a.  If the lower bound of the 95% CI for the group mean pH is equal to or greater 
than 6.0 for at least three time points, the study can end after a minimum of 40 
days. 
b.  If the lower bound of the 95% CI for the group mean pH is less than 6.0 for 
two or more of the time points, the study should continue with mineral 
balance collections. 
c.  You should start mineral balance collections as soon as they are determined to 
be needed and you should collect mineral balance data at a minimum of three 
timepoints no less than 30 days apart.  A baseline collection prior to feeding 
the test diet is optional.  For this collection to serve as one of the three needed 
timepoints, it should be performed only after all cats have been consuming the 
same complete and balanced diet (e.g., standard colony diet) for a minimum 
of 7 days. 
Additional urinary pH and/or RSS measurements could be made if the study is 
extended to allow for mineral balance collections.  We do not consider these 
additional measurements to be necessary if the study already included the 
recommended four RSS measurements, but the additional pH and RSS data should be 
included in the final study report if they are collected. 
   
3.  Additional Clinical Data 
Regardless of the duration, studies that adequately address target animal safety should 
also include: 
a.  Veterinary physical exams performed at the beginning and end of the study, 
and at the midpoint if the study duration is longer than 40 days,  
b.  Body weights measured weekly and body condition scores determined at least 
monthly,  
c.  Food consumption measured daily,  
d.  Daily stool observations  periodic fecal scoring,  
e.  Morbidity and mortality observations, with any animal that dies being 
necropsied and a cause of death determined, and  
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f.  Serum chemistries,1 hematologies,2 and urinalyses3 performed at the 
beginning and end of the study, and at the midpoint if the study is longer than 
40 days.   
4.  Other Considerations 
a.  You should conduct appropriate statistical comparisons, using suitable 
methodology and numbers of animals to confidently (95%) detect statistically 
significant differences (10%) in safety parameters between baseline and later 
timepoints, should they exist.   
b.  Successful studies should have no more than 25% of the cats starting the study 
removed for non-nutritional reasons or poor food intake, and cats may be 
removed for poor food consumption and their data excluded from the final 
analysis only within the first 14 days of the study.  The reason for any cats 
removal should be recorded and included in the final study report.  A minimum of 
10 cats should complete the study, so we recommend at least 12 cats start the 
study to ensure the minimum number of cats complete the study.   
c.  Any medical treatment provided to cats on study and the reason for it should be 
recorded and included in the final study report.   
d.  The final study report should include all data generated from individual animals 
as well as summary statistics for each day of measurement.  The study report 
should also include a full discussion of the diet formulation, experimental 
methodology, statistical methods used to analyze the data, and interpretation of 
findings.   
e.  If feasible, we recommend you keep animals on study for up to 26 weeks and 
continue to collect blood and urine samples while we review the submitted data, 
as we may request additional data and/or a longer duration of study based on the 
study findings.  Aliquots from collected blood and urine samples should be frozen 
and stored for possible additional testing.   
f.  This guidance document may not address all specifics important for the design of 
the study.  We encourage you to submit protocols to us for review and comment 
prior to study execution.  You should address our questions on details of the 
protocol before the study begins.   
 
1 A serum biochemistry profile should include glucose, albumin, total protein, total bilirubin, conjugated bilirubin, 
blood urea nitrogen, creatinine, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, gamma-
glutamyltransferase, calcium, magnesium, phosphorus, potassium, sodium, chloride, and tCO  or pCO .  
2 2
2 Hematology profile should include a complete blood count and differential white cell count.  
3 Urinalysis should include color, protein, glucose, ketones, bilirubin, specific gravity (by refractometer), and 
microscopic sediment examination to look for crystals, casts, red and white blood cells, and epithelial cells.  
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C.  Combined Safety and Utility Study 
Because we recommend you conduct both target animal safety and utility studies for a 
minimum of 40 days, you may opt to combine both studies in one feeding trial to 
maximize efficiency of time and use of resources.  Appendix 1 contains a flowchart that 
depicts the recommended timeline for a minimum 40-day combined safety and utility 
study.  Please note that this flowchart applies only to cat food for which you have 
substantiated the nutritional adequacy for adult maintenance, as recommended above.  
UTH cat food based on RSS methodology that has not been substantiated for nutritional 
adequacy to maintain adult cats should undergo a 6-month safety study, during which 
nutritional adequacy for adult maintenance can be substantiated according to AAFCO 
protocols along with the other parameters discussed in this guidance.   
 
VI.  References 
1.  Association of American Feed Control Officials. (2022). 2022 Official Publication of the 
Association of American Feed Control Officials. Champaign, IL 61820. 
https://www.aafco.org/publications (accessed October 31, 2023).  
2.  Bartges J. (2011) Urinary saturation testing. In: Bartges, J. W., Polzin, D. J., eds. 
Nephrology and urology of small animals. Chichester, UK: Blackwell Publishing Ltd.: 75-
85.  
3.  Bartges JW, Kirk CA, Cox SK, Moyers TD. (2013) Influence of acidifying or alkalinizing 
diets on bone mineral density and urine relative supersaturation with calcium oxalate and 
struvite in healthy cats. Am J Vet Res 74: 1347-1352.  
4.  Buckley MF, Hawthorne A, Colyer A, Stevenson AE. (2011) Effect of dietary water intake 
on urinary output, specific gravity and relative supersaturation for calcium oxalate and 
struvite in the cat. Br J Nutr 106: S128-S130.  
5.  Bushinsky DA, Grynpas MD, Nilsson EL, Nakagawa Y, Coe FL. (1995) Stone formation 
in genetic hypercalciuric rats. Kidney Int 48: 1705-1713.  
6.  Ferraro PM, Ticinesi A, Meschi T, Rodgers A, Di Maio F, Fulignati P, Borghi L, Gambaro 
G. (2018) Short-term changes in urinary relative supersaturation predict recurrence of 
kidney stones: A tool to guide preventive measures in urolithiasis. J Urology 200: 1082-
1087.  
7.  Forrester SD, Kruger JM, Allen TA. (2010) Feline Lower Urinary Tract Diseases. In: 
Hand.M.S., Thatcher, C.D., Remillard, R. L., et al, eds. in Small Animal Clinical Nutrition. 
5th Ed. Topeka, Kan: Mark Morris Institute: 927-976.  
8.  Hawthorne AJ, Markwell PJ. (2004) Dietary sodium promotes increased water intake and 
urine volume in cats. J Nutr 134: 2128S-2129S.  
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9.  Houston DM, Rinkardt NE, Hilton J. (2004) Evaluation of the efficacy of a commercial 
diet in the dissolution of feline struvite bladder uroliths. Vet Ther 5 (3): 187-201.  
10.  Houston DM, Elliot DA. (2008) Nutritional management of feline lower urinary tract 
disorders, In Encyclopedia of Feline Clinical Nutrition, Pibot et al. eds.: 285-321.  
11.  Houston DM, Weese HE, Evason MD, Biourge V, van Hoek I. (2011) A diet with a 
struvite relative supersaturation less than 1 is effective in dissolving struvite stones in vivo. 
Br J Nutr 106: 90-92.  
12.  Lekcharoensuk C, Osborne CA, Lulich JP, Pusoonthornthum R, Kirk CA, Ulrich LK, 
Koehler LA, Carpenter KA, Swanson LL. (2001) Association between dietary factors and 
calcium oxalate and magnesium ammonium phosphate urolithiasis in cats. J Am Vet Med 
Assoc 219: 1228-1237.  
13.  Markwell PJ, Smith BHE, McCarthy KP. (1999) A non-invasive method for assessing the 
effect of diet on urinary calcium oxalate and struvite relative supersaturation in the cat. An 
Tech 50: 61-67.  
14.  Parks JH, Coward M, Coe FL. (1997) Correspondence between stone composition and 
urine supersaturation in nephrolithiasis. Kidney Int 51: 894-900. 
15.  Prochaska M, Taylor E, Perraro PM, Curhan G. (2018) Relative supersaturation of 24-hour 
urine and likelihood of kidney stones. J Urology 199 (5): 1262-1266.  
16.  Queau Y, Bijsmans ES, Feugier A, Biourge VC. (2020) Increasing dietary sodium chloride 
promotes urine dilution and decreases struvite and calcium oxalate relative supersaturation 
in healthy dogs and cats. J Anim Physiol Anim Nutr 104: 1524-1530.  
17.  Queau Y, Hoek I, Feugier A, Verger L, Soulard Y, Biourge V. (2013) Urinary pH Affects 
Urinary Calcium Excretion but Not Calcium Oxalate Relative Supersaturation in Health 
Cats. ACVIM 2013 (VIN):1.  
18.  Robertson WG, Jones S, Heaton MA, Stevenson AE, Markwell PJ. (2002) Predicting the 
Crystallization Potential of Urine from Cats and Dogs with Respect to Calcium Oxalate and 
Magnesium Ammonium Phosphate (Struvite). J Nutr 132:1637S-1641S.  
19.  Sagols EM, Cuchet-Subsol C, Billy H, Feugier A, Queau Y. (2015) In vitro dissolution of 
feline struvite stones with 2 diets showing different relative supersaturation values. In: 
ESVNU European Society of Veterinary Nephrology and Urology, Proceedings.  
20.  Smith BH, Stevenson AE, Markwell PJ. (1998) Urinary relative supersaturations of 
calcium oxalate and struvite in cats are influenced by diet. J Nutr 128: 2763S-2764S.  
21.  Stevenson AE, Robertson WG, Markwell P. (2003) Risk factor analysis and relative 
supersaturation as tools for identifying calcium oxalate stone-forming dogs. J Sm An Prac 
44: 491-496.  
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22.  Stevenson AE, Blackburn JM, Markwell PJ, Robertson WG. (2004) Nutrient intake and 
urine composition in calcium oxalate stone-forming dogs: comparison with healthy dogs 
and impact on dietary modification. Vet Ther 5: 218-231.  
23.  Stevenson AE, Wrigglesworth DJ, Markwell PJ. (2000) Urine pH and urinary relative 
supersaturation in healthy adult cats. Urolithiasis, 818-820.  
24.  Tefft KM, Byron JK, Hostnik ET, Daristotle L, Carmella V, Frantz NZ. (2021) Effect of a 
struvite dissolution diet in cats with naturally occurring struvite urolithiasis. J Feline Med 
Surg 23 (4): 269-277.  
25.  Thun MJ and Schober S. (1991) Urolithiasis in Tennessee: An occupational window into a 
regional problem. Am J Public Health 81: 587-59.  
26.  Torres-Henderson C, Bunkers J, Contreras ET, Cross E, Lappin MR. (2017) Use of Purina 
Pro Plan Veterinary Diet UR Urinary St/Ox to dissolve struvite cysoliths. Top Companion 
Anim Med 32 (2): 49-54.  
27.  Tournier C, Biourge VC. (2008) Struvite relative supersaturation and dissolution kinetic.  
Investigation using an in vitro method to reproduce cat bladder environment. 
Voorjaarsdagen 253.  
28.  Tournier C, Malandain E, Abouhafs S, Aladenise S, Venet C, Ecochard C, Sergheraert R, 
Biourge V. (2008) Struvite relative supersaturation: a good predictor of struvite stones 
dissolution in vitro. In: Research Abstract Program of the 26th Annual ACVIM Forum. J 
Vet Int Med 22(3): 687-824.  
29.  Van Hoek I, Malandain E, Tournier C. (2009) RSS is a better predictor for struvite 
dissolution than urine pH.  Veterinary Focus 19: 47-48.  
30.  "2022 Minnesota Urolith Center Global Data." generated by Minnesota Urolith Center, 
March 2023. https://z.umn.edu/2022GlobalUrolith (accessed October 31, 2023).  
   
11    Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
VII.  Appendix 1  Recommended Combined Safety and Utility Study Flowchart 
 
+ PE = Physical Exam   
*CBC/Chem/UA = Complete Blood Count, Serum Chemistry, and Urinalysis  
 Not needed if baseline collection performed    
12    Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
VIII.  Appendix 2  Glossary of Terms and Acronyms  
AAFCO  Association of American Feed Control Officials  
Activity Product  A numerical description for the concentration of a solute remaining free in 
solution that is free to interact with other solutes and form crystals  
CaOx  Type of urolith composed of calcium and oxalate  
CI  Confidence Interval  
CVM  Center for Veterinary Medicine  
FDA  Food and Drug Administration  
Formation Product  The concentration at which solute will spontaneously precipitate out of 
solution to form crystals.  Defines the limit between the metastable and labile supersaturation 
zones  
In-Vitro  Describes an experiment or test that takes place in a test tube, culture dish, or 
elsewhere outside a living organism  
In-Vivo  Describes an experiment or test that takes place inside a living organism.  
Labeling  As defined in section 201(m) of the FD&C Act, means all labels and other written, 
printed, or graphic matter (1) upon any article or any of its containers or wrappers, or (2) 
accompanying such article  
Labile Supersaturation  Describes the urinary zone in which crystals will spontaneously form 
and grow  
Metabolic acidosis  The condition in which too much acid accumulates in the body, causing 
serious illness  
Metastable Supersaturation  Describes the urinary zone in which crystals will not 
spontaneously form but may form in the presence of a nucleus (e.g., an existing urolith or other 
particulate matter).  Existing crystals and uroliths will not dissolve and may grow  
RSS  Relative Supersaturation  
Solute  A substance dissolved in solution  
Struvite  Type of urolith composed of magnesium, ammonia, and phosphate  
Thermodynamic Solubility Product  The concentration of a solute at which it completely 
dissolves into solution. Defines the limit between the undersaturation and metastable 
supersaturation zones  
13    Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
Urolith  A bladder stone  
Urolithiasis  The disease condition of having bladder stones  
Undersaturation  Describes the urinary zone in which crystals will not spontaneously form, 
and if present, will dissolve  
UTH  Urinary tract health  
UTH Cat Food  Adult maintenance cat food with UTH claims  
 
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