Following this presentation, the attendee should be able to

• Define IRIS CKD stage 1
• Describe methods for diagnosis of patients with IRIS CKD stage 1
• Compare and contrast evidence for medical intervention of patients with IRIS CKD stage 1

What Is IRIS Staging for CKD?

Chronic kidney disease (CKD) implies irreversible failure that remains stable for a period of time, but is ultimately progressive over some period of time. CKD may occur at any age, but incidence increases with increasing age.¹ The kidneys are involved with homeostasis; therefore, CKD affects many organ systems. Clinical signs involve primarily change in water balance (polyuria and polydipsia), gastrointestinal signs (anorexia, hyporexia, halitosis, vomiting), and evidence of chronicity (weight loss, loss of body condition and muscle mass, unkempt appearance). Physical examination may reveal oral ulceration and halitosis, decreased muscle mass and body weight, dehydration, and small, irregular kidneys. Laboratory evaluation may reveal azotemia, inappropriately dilute urine, hyperphosphatemia, metabolic acidosis, and possibly hypokalemia, nonregenerative anemia, and calcium imbalance. Bacterial urinary tract infection may be present but is often not associated with active urine sediment. Systemic arterial hypertension occurs in 65–80% of patients. The International Renal Insufficiency Society (www.IRIS-kidney.com) has developed staging system for animals with CKD and treatment based on staging.² A diagnosis of CKD is made first and staging is accomplished by evaluating creatinine when patient is well hydrated, urine protein:creatinine ratios (UPC), and indirect arterial blood pressure determinations. CKD is staged by magnitude of renal dysfunction and further modified (substaged) by presence or absence of proteinuria and/or hypertension. Proteinuria only refers to renal proteinuria and not prerenal or postrenal, based on UPC.

IRIS CKD staging is based currently on fasting blood creatinine concentrations, but there are indications that SDMA concentrations in blood plasma or serum may be a more sensitive biomarker of renal function. Accordingly, if blood SDMA concentrations are known, some modification to the guidelines might be considered, as follows:

• A persistent increase in SDMA above 14 µg/dl suggests reduced renal function and may be a reason to consider a dog or cat with creatinine values in IRIS CKD Stage 1 range
• In IRIS CKD2 patients with low body condition scores, SDMA ≥25 µg/dl may indicate degree of renal dysfunction has been underestimated. Consider treatment recommendations for IRIS CK D3.
• In IRIS CKD3 patients with low body condition scores, SDMA ≥45 µg/dl may indicate degree of renal dysfunction has been underestimated. Consider treatment for IRIS CKD4.

How Is IRIS CKD Stage 1 Diagnosed?

IRIS CKD1 is a non-azotemic dog or cat with kidney disease. There are several potential types of patient:

• Patients with proteinuria consistent with primary glomerular disease
• Patients without proteinuria that is consistent with primary glomerular disease such as bilateral renal disease, but no biochemical abnormalities (e.g., renal infarcts, nephroliths) or patients with unilateral renal disease that may or may not be serious (e.g., unilateral renal lymphoma, unilateral renal agenesis, unilateral nephrolithiasis)

The diagnosis of CKD1 disease is, therefore, dependent on finding renal disease that is chronic in nature but associated with a normal creatinine concentration. The urine may or may not be concentrated. The use of SDMA determination may help; however, SDMA may be normal with serious unilateral renal disease (e.g., unilateral renal lymphoma) as with creatinine, BUN, and USG. Additionally, comorbidities complicate patients with CKD including those in stage 1 (e.g., feline hyperthyroidism, urinary tract infections, etc.).

Tests of Glomerular Function

Glomerular filtration rate (GFR) can be estimated using both clearance methods and "spot" or single time point tests. Renal or plasma clearance of an injected substance (e.g., iohexol, creatinine) is most accurate estimate of GFR. It is a more sensitive means for detecting early CKD than spot methods of GFR estimation. Determining plasma clearance can be a relatively expensive and time-consuming procedure. It is most often performed to establish a decrease in GFR when clinical parameters (e.g., poorly concentrated urine) create suspicion for CKD but cannot confirm its presence, and to determine dosage regimens for therapeutic agents whose excretion is primarily renal in patients with CKD. Measuring reduction of an injected substance in the blood over time can be used to estimate renal clearance and therefore GFR. Most common exogenous substances used in veterinary medicine for estimation of GFR are iohexol and creatinine. Other substances and techniques can be used, such as inulin, radiolabeled markers, and contrast-enhanced computed tomography (CT). A novel fluorescent tracer has been evaluated as a rapid, non-invasive bedside test in dogs. Ultimately, choice in method used depends on availability of the injected substance and method of measurement as well as the experience. In some cases, estimation of individual kidney GFR (vs. global GFR) is necessary, as is possible with scintigraphy or CT. Iohexol clearance and exogenous creatinine clearance give a measure of total GFR; DTPA (a radiolabeled marker) gives estimate of total as well as individual kidney GFR. One of the main limitations with clearance methods is need for serial, precisely timed blood draws. An accurate clearance calculation requires as many as 8 post-injection blood samples over 6 hours or longer, although reasonable estimates can be obtained with limited sampling (i.e., 2 or 3 post-injection samples). Timing of these limited sample collections varies depending on the substance used. Some studies have found that calculation of plasma clearance based on a single post-injection sample is strongly correlated with 3-sample techniques, as long as an estimated volume of distribution can be determined. This is especially important in cats, where multiple collections can prove difficult. Another limitation with plasma clearance is the large amount of variability in what is considered to be "normal" in dogs and cats. In one study of 118 healthy dogs, iohexol clearance ranged from 0.95–4.25 mL/min/kg. In previously published studies in healthy dogs and cats, the range for various clearance estimates was as wide as 2.45–6.64 mL/min/kg (dogs) and 2.19–3.49 mL/min/kg (cats), although most weighted reference intervals were around 3–4 mL/min/kg (dogs) and 2.5–3.5 mL/min/kg (cats). Therefore, it is difficult to define a normal GFR in a particular animal without a baseline for that patient, and it limits ability of plasma clearance to detect early reductions in GFR. Week-to­week and month-to-month biological variability must also be considered when monitoring plasma clearance in a particular patient. Based on the week-to-week variability of iohexol clearance in a cohort of dogs with mild but stable renal disease, a subsequent measurement must increase or decrease by up to 20% in order to be 95% confident that a true change in clearance has occurred. Interestingly, despite using more measurements, each with its own inherent variability, iohexol clearance variability was similar to that for serum creatinine (sCr) in these dogs. In addition to biological considerations, analytical considerations in plasma clearance calculations are important. When using a limited sampling technique, a correction formula must be applied to correct for the initial distribution phase in order to avoid overestimation of the GFR. Correction formulas for both dogs and cats are available when using iohexol. Normalization to body weight, surface area, or extracellular volume has been recommended, but it is not clear which normalization technique should be used in dogs and cats.

In patients with CKD1 disease, azotemia is not present and a spot test such as urine specific gravity (USG) may not reflect renal function because it is influenced by non-renal factors. Most adult cats have a USG>1.035 regardless of time of day, whereas adult dogs have variable USG throughout the day. Persistently dilute USG may indicate loss of renal function but other non-renal diseases (e.g., hyperadrenocorticism, diabetes mellitus, hyperthyroidism, etc.) must be ruled out first. Other biomarkers are being evaluated. Symmetric dimethylarginine (SDMA) test is now provided on all biochemical panel testing through IDEXX Laboratories: www.idexx.com/corporate/home.html. SDMA is a small molecule that originates from hydrolysis of methylated proteins. This molecule has shown great promise as an endogenous marker of GFR as it appears to be exclusively eliminated by glomerular filtration, and significant extrarenal influences on its production and elimination have not yet been identified. It is stable in whole blood, serum, and plasma at 4°C and room temperature for up to 7 days, and it is not altered with freezing in serum or plasma.³ In dogs with rapidly progressing CKD, SDMA correlated strongly with GFR estimated using iohexol clearance. Notably, when using reference intervals, SDMA identified a decrease in GFR earlier than sCr; however, when both were trended over time, no major differences in identification of declining GFR were noted. SDMA changed approximately 9 months earlier than sCr. These results support that trending of sCr is necessary for sensitive detection of decreasing GFR and that SDMA might be a useful adjunct to sCr in identification of renal disease, particularly given the tendency to classify a dog as azotemic or not based on a reference interval. SDMA is not influenced by muscle mass, but any non­renal change in GFR will impact it. For example, with dehydration there is a decrease in GFR and therefore SDMA will also be influenced. It might prove especially useful in the initial diagnosis of CKD in those patients for which sCr will not provide a reliable estimate of GFR. In cats with CKD, SDMA correlates with sCr; while data suggest that SDMA might increase beyond its reference interval before sCr in cats and that a higher SDMA:creatinine ratio might indicate a worse prognosis. Similar to dogs, it is not influenced by lean body mass; however, non-renal factors affecting GFR will impact SDMA. SDMA changed approximately 17 months earlier than sCr.

Should Dogs and Cats with IRIS CKD Stage 1 Be Treated?

Most publications discuss management of IRIS CKD2–4, where therapy has been shown to improve survival and quality of life in dogs and cats. There is minimal information on prognosis and management of patients diagnosed with IRIS CKD1, and most information applies to patients with proteinuric CKD1 disease.

Proteinuric Patients

Overt glomerular proteinuria occurs more commonly in dogs than in cats and is defined as a urine protein:creatinine ratio (UPC) >2.0 that is renal in origin. Approximately 50% of dogs with glomerular proteinuria have an immune-mediated disease either as a primary process or secondary to chronic antigenic stimulation (e.g., infections, inflammatory, or neoplastic disease).⁴ Treatment involves achieving a diagnosis of the underlying cause, if possible, and treating it, if possible. Other treatment involves feeding a protein-restricted diet (therapeutic renal diet), giving omega-3 fatty acids (300 mg of sum of EPA [eicosapentaenoic acid] and DHA [docosahexaenoic acid] per 10 pounds of body weight per day), and pharmacologic agents that inhibit the renin-angiotensin-aldosterone system (RAAS).⁵ Conventionally, an angiotensin-converting enzyme inhibitor (ACEI) is often used and has the most, albeit, limited data. Enalapril has been evaluated in dogs with glomerular proteinuria and was shown to decrease the degree of proteinuria and increase the serum albumin concentration. Benazepril is often used instead of enalapril; however, there is one study in dogs comparing enalapril with benazepril in dogs with CKD and proteinuria and enalapril gave a more sustained anti­proteinuric effect over 5 months. Angiotensin-receptor blockers (ARB) may be used in combination with or instead of ACEI although there is minimal information available. In human beings, use of an ACEI with an ARB provides better proteinuria-lowering response than either alone. This has not been evaluated in dogs. While losartan is the oldest of the ARBs, newer ARBs, such as telmisartan and irbesartan, have more selectivity for the angiotensin receptor and may have a greater effect. With any RAAS inhibitor potential adverse events include azotemia, hyperkalemia, and GI disturbances. ACEI are usually administered every 12 hours while ARB are usually administered every 24 hours. Dogs with glomerular proteinuria are often administered drugs that inhibit platelet aggregation (e.g., aspirin or clopidogrel). In dogs with a diagnosis of an immune-mediated disease by renal biopsy, in dogs with suspected immune-mediated glomerulonephritis, or in dogs that do not respond well to conventional therapy, immunosuppression should be undertaken. Which immunosuppressive drug is best is not known. None have been shown to be effective in controlled studies, although there are sporadic case reports of response. Studies in dogs have shown that in most cases of proteinuria, glucocorticoid administration is not beneficial and is often associated with a worsening of the proteinuria. Glucocorticoids appear to promote glomerulosclerosis and intraglomerular hypertension. Therefore, glucocorticoids are not recommended unless the proteinuria is secondary to glucocorticoid-responsive systemic disease. Often glucocorticoids are given with severe glomerular proteinuria in order to achieve quicker control while other immunosuppressive drugs are initiated. Cyclosporine was not found to be effective in dogs with idiopathic GN in a controlled, blinded study. Other immunosuppressive drugs that may show benefit, but that have not been evaluated in placebo-controlled, blinded studies are azathioprine (2 mg/kg PO q24h x 2 weeks, then 1 mg/kg PO q24h, then 1 mg/kg PO q48h), cyclophosphamide (50 mg/m² PO q48h), and chlorambucil (2–6 mg/m² PO q24–48h). The most promising is mycophenolate (20 mg/kg PO q12h for 3–4 weeks, then 10 mg/kg PO q12h).⁶ The decision to use immunosuppressive therapy should be based on the likelihood of an immune-mediated cause of proteinuria, the patient's overall condition, and the ability to monitor the patient. Consider diuretics to decrease sodium retention and edema/ascites. In human beings with nephrotic syndrome, diuretics are often used to decrease ascites/edema. Commonly a combination of a loop diuretic (such as furosemide) and a thiazide diuretic (such as hydrochlorothiazide) are used. Furosemide is often used in veterinary medicine to decrease fluid retention and should be considered in dogs or cats that have nephrotic syndrome. Combination diuretic therapy may be considered in animals that are refractory to single-agent therapy.

Nonproteinuric Patients

Management of patients with CKD1 without proteinuria is less clear. A decrease in renal function without a progressive underlying disease may not warrant intervention. At present there is no means of predicting progression of CKD1 disease other than monitoring trends and/or identifying and treating the underlying cause if possible. Dogs and cats with congenital renal disease may or may not have progressive disease. For example, dogs with unilateral renal agenesis may not experience progressive CKD if the solitary kidney is otherwise structurally and functionally normal. On the other hand, patients with unilateral renal lymphoma often develop it in both kidneys and so CKD is progressive. Dogs and cats with Fanconi syndrome are often diagnosed as CKD1; however, this is usually progressive disease. The question is in patients without identifiable specific diseases does a diagnosis of CKD1 warrant intervention? There are 3 studies in dogs^7-9 and 2 studies in cats^10,11 that have been published. In a study of 210 client-owned dogs with normal creatinine concentrations, 18 dogs had an increased SDMA at baseline or during a 6-month crossover dietary study.¹⁰ Feeding a heat-processed dry food containing fruits and vegetables, egg protein, wet chicken meat, lipoic acid, α-tocopherol, vitamin C, carnitine, and omega-3 fatty acids compared with a control was associated with a decrease in SDMA in 8 of 9 dogs compared with 4 of 9 dogs when consuming the control diet. A study of 81 geriatric research dogs were compared with 30 mature adult research dogs consuming a control diet and 2 foods that were similar to the aforementioned diet; however, one of the test diets contained additional fruits and vegetables and egg protein and did not contain corn gluten meal.⁹ The geriatric dogs had lower GFR than the mature dogs. GFR increased and SDMA decreased in geriatric dogs when fed the test foods; however, the effect was greater in the geriatric dogs eating the second test diet. None of the dogs had GFR or SDMA values outside of the normal range, however. A longitudinal study of 36 client-owned dogs with CKD1 diagnosed by having abnormal kidneys, dilute urine of renal origin, proteinuria of renal origin, or combinations evaluated the influence of consuming a therapeutic renal diet over a 3- to 12-month period.⁷ Of the 36 dogs, 20 had dilute urine, 6 had persistent proteinuria, and 10 had both; 50% had an elevated SDMA at baseline. Serum creatinine, BUN, and SDMA decreased from baseline to 3 months and remained decreased from baseline in the 20 dogs that completed the 12-month study. Proteinuria was reduced in 12 of 16 dogs with proteinuria. Thirty-two geriatric research cats were fed two diets containing low phosphorus and protein with added omega-3 fatty acids, and L-carnitine; the second test diet contained median-chain triglycerides.¹² Over a 6-month feeding period, SDMA decreased slightly, but not significantly, and GFR increased in cats fed the second test diet but decreased in the cats fed the first test diet; however, results were not significantly different from baseline. A study of client-owned cats has also been published.¹⁰ Cats consuming owner's choice foods showed significant increase in SDMA at 3 and 6 months whereas in cats consuming a test diet (described above), SDMA did not change. During the study 23 cats had an increased SDMA including 17 cats in the owner's choice food group and 6 in the test diet group. In the 6 cats fed the test food, SDMA decreased or remained stable in 4 cats, and increased in 2 cats, whereas in the 17 cats in the owner's choice food group, SDMA increased in 13 cats and decreased or remained stable in 4 cats. Results of these studies suggest that nutritional intervention may be beneficial in some older dogs and cats with CKD1 and that SDMA is a useful biomarker; however, there is variability in SDMA and trends in changes in SDMA may be more important in managing patients with CKD.

References

1.  Bartges JW. Chronic kidney disease in dogs and cats. Vet Clin North Am Small Anim Pract. 2012;42(4):669–92, vi.

2.  Elliott J, Watson ADJ. Chronic kidney disease: staging and management. In: Bonagura JD, Twedt DC, eds. Kirk's Current Veterinary Therapy XIV. St. Louis, MO: Saunders Elsevier; 2008:883–92.

3.  Hokamp JA, Nabity MB. Renal biomarkers in domestic species. Vet Clin Pathol. 2016;45(1):28–56.

4.  Schneider SM, Cianciolo RE, Nabity MB, Clubb FJ, Jr., Brown CA, Lees GE. Prevalence of immune-complex glomerulonephritides in dogs biopsied for suspected glomerular disease: 501 cases (2007–2012). J Vet Intern Med. 2013;27(Suppl 1):S67–75.

5.  Brown S, Elliott J, Francey T, Polzin D, Vaden S. Consensus recommendations for standard therapy of glomerular disease in dogs. J Vet Intern Med. 2013;27(Suppl 1):S27–43.

6.  Pressler B, Vaden S, Gerber B, Langston C, Polzin D. Consensus guidelines for immunosuppressive treatment of dogs with glomerular disease absent a pathologic diagnosis. J Vet Intern Med. 2013;27(Suppl 1):S55–9.

7.  Hall JA, Fritsch DA, Yerramilli M, Obare E, Yerramilli M, Jewell DE. A longitudinal study on the acceptance and effects of a therapeutic renal food in pet dogs with IRIS-Stage 1 chronic kidney disease. J Anim Physiol Anim Nutr (Berl). 2017.

8.  Hall JA, MacLeay J, Yerramilli M, Obare E, Yerramilli M, Schiefelbein H, el al. Positive impact of nutritional interventions on serum symmetric dimethylarginine and creatinine concentrations in client-owned geriatric dogs. PLoS One. 2016;11(4):e0153653.

9.  Hall JA, Yerramilli M, Obare E, Yerramilli M, Panickar KS, Bobe G, et al. Nutritional interventions that slow the age-associated decline in renal function in a canine geriatric model for elderly humans. J Nutr Health Aging. 2016;20(10):1010–23.

10.  Hall JA, MacLeay J, Yerramilli M, Obare E, Yerramilli M, Schiefelbein H, et al. Positive impact of nutritional interventions on serum symmetric dimethylarginine and creatinine concentrations in client-owned geriatric cats. PLoS One. 2016;11(4):e0153654.

11.  Hall JA, Yerramilli M, Obare E, Yerramilli M, Yu S, Jewell DE. Comparison of serum concentrations of symmetric dimethylarginine and creatinine as kidney function biomarkers in healthy geriatric cats fed reduced protein foods enriched with fish oil, L-carnitine, and medium-chain triglycerides. Vet J. 2014;202(3):588–96.

12.  Half JA, Yerramilli M, Obare E, Yerramilli M, Jewell DE. Comparison of serum concentrations of symmetric dimethylarginine and creatinine as kidney function biomarkers in cats with chronic kidney disease. J Vet Intern Med. 2014;28(6):1676–83.