Chronic Kidney Disease Early Diagnosis is Key. Bill Saxon DACVIM, DACVECC

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1 Chronic Kidney Disease Early Diagnosis is Key Bill Saxon DACVIM, DACVECC Chronic kidney disease can be defined as an abnormality in kidney function that persists for 3 months or longer or imaging findings suggestive of chronic disease. It is critical that practicing veterinarians not equate azotemia with CKD. When identified, azotemia must be categorized as prerenal, renal/intrinsic, or post renal. The goal is to find a potentially reversible cause of the azotemia such as dehydration (prerenal), leptospirosis (renal/intrinsic), or urethral or ureteral obstruction (post renal) to prevent development of CKD. Realizing that CKD is irreversible the importance of prevention is clear. Further, some patients with early or mild (IRIS stage 1) CKD show no clinical signs and are not azotemic. In such patients persistent renal proteinuria and/or structural renal abnormalities on imaging studies provide the diagnosis. All patients diagnosed with stable CKD should be staged using the International Renal Interest Society guidelines. These guidelines are often misapplied in patients at first diagnosis of azotemia (see above). The IRIS guidelines are periodically updated thus practicing veterinarians are encouraged to visit the website on a regular basis. The purpose of the guidelines is to provide a standard approach to the staging and treatment of CKD in dogs and cats. Patients are placed into one of four stages primarily based on serum creatinine concentration and are then substaged based on proteinuria and blood pressure. Serum SDMA (see below) is used to refine staging. Once staging of CKD is complete stagespecific therapeutic and monitoring guidelines are followed. The overriding theme is that given the irreversible progressive nature of CKD early diagnosis and intervention is critical and has been shown in controlled studies to prolong survival. Symmetric dimethyl arginine is a sensitive and specific biomarker for GFR. It is a byproduct of cellular protein turnover and once in serum is excreted by the kidneys and is neither reabsorbed or secreted. Increases in SDMA are not specific for CKD. As with creatinine, any cause of decreased GFR may result in elevated SDMA concentration. However, SDMA is a more sensitive and specific marker of GFR than creatinine making it possible to identify CKD earlier and more accurately assess severity. SDMA increases when GFR decreases by only 25-40% versus 75% before creatinine increases. Unlike creatinine, a muscle breakdown product, SDMA is not affected by lean muscle mass. It is understood that creatinine underestimates the degree of CKD in cachectic patients (older cats) due to decreased production. In these patients SDMA is a more reliable indicator of kidney function. Thus, SDMA enables earlier detection of CKD and more accurate staging compared to other currently available renal biomarkers. Elevations in SDMA (25-40% GFR loss) will precede loss of urine concentrating ability (66% GFR loss) and increases in creatinine (75% GFR loss). Thus, SDMA may be the only laboratory abnormality supporting renal dysfunction in clinically normal patients. It is important to understand that this indeed may represent early or mild kidney disease and not be considered laboratory error. A reasonable approach is to complete the minimum data base including urinalysis if not already performed. If the elevated SDMA is persistent on reevaluation a thorough investigation for an underlying cause is indicated. This might consist of urine culture and susceptibility testing, urine protein to creatinine ratio, screening for leptospirosis, imaging studies, etc. Treatment should be aimed at any identified disease. If none is

2 found and the abnormality in SDMA persists for 3 months or longer, IRIS staging and treatment guidelines should be followed.

3 The Complete Urinalysis An Important Part of the Minimum Data Base Bill Saxon DACVIM, DACVECC A complete urinalysis consists of assessment of physical characteristics (color, clarity), specific gravity, urine chemistries (dipstick), and urine sediment and can be considered part of the minimum data base along with CBC and biochemical profile. Urine collection method is important and determines appropriate use of the sample. Cystocentesis is preferred if bacterial culture and susceptibility testing and/or urine protein to creatinine ratio is indicated. Free catch samples are acceptable for UPC determination provided the urine sediment is inactive. Free catch samples are not suitable for urine culture. Midstream urine samples collected by asceptic catheterization may be suitable for culture in patients in whom cystocentesis is contraindicated, eg, bladder neoplasia, coagulopathy, though introduction of bacteria into the bladder (contamination) by this method can occur. A useful clinical maxim is any sample is better than no sample meaning that even a few drops of a dirty sample (table top or floor) can be used for specific gravity and dip stick. Such samples should never be cultured and a complete urinalysis is indicated as soon as an appropriate sample can be obtained. Discolored urine can provide clues to underlying disease. Red or red brown urine may indicate hematuria, hemoglobinuria, or myoglobinuria. Hematuria is confirmed if the supernatant clears after centrifugation and red cells are seen on sediment examination. Hemoglobinuria is diagnosed if the supernatant remains discolored, serum is discolored (hemolysis), and/or hematocrit is decreased. Myoglobinuria can be differentiated from hemoglobinuria by evaluating serum (clear with myoglobinuria) and creatine kinase (increased with moderate to severe muscle injury). Urine specific gravity obtained prior to fluid administration aids in characterizing azotemia as prerenal, renal/intrinsic, or post renal and in assessing concentrating ability. In azotemic patients USG <1.030 in dogs and <1.035 in cats indicates renal azotemia. In non azotemic patients, persistently decreased USG with signs of pu/pd indicate impaired concentrating ability form numerous causes including kidney disease, endocrine disease, leptospirosis or other infection, and medications (glucocorticoids). It is important for clinicians to keep in mind that a one time decreased USG in the absence of pu/pd may be physiologic (time of day, recent water consumption) not pathologic. Urine chemistries are quickly and accurately determined using urine dipsticks. It is important to follow insert guidelines regarding timing of assessing color changes if an automated reader is not used. Proteinuria has diagnostic, therapeutic, and prognostic importance. Urine dipsticks detect primarily albumin at levels of 30 gm/dl or higher. A useful clinical guideline is to perform a UPC on all urine samples with any degree of proteinuria regardless of USG as long as the urine sediment is inactive. The clinical significance/prognostic value of urine microalbuminuria has not been established. Persistent increased renal proteinuria defined as 3 or more elevated UPCs over 2 or more weeks warrants further investigation and therapy (follow IRIS guidelines). Avoid overinterpreting or treating isolated abnormal urine ph in clinical normal patients as factors including exposure of sample to air can alter results. Glucosuria is most often due to diabetes mellitus. Persistent glucosuria without hypoglycemia indicates renal tubular disease due to inborn error of metabolism (renal tubular glucosuria, Fanconi syndrome) or

4 tubular injury due to infection, ischemia, or toxin exposure. A false positive urine glucose can be caused by some cleaning solutions if voided urine samples are collected off a table top or into a container. Ketonuria is most often seen with diabetes mellitus. Persistent ketonuria as an isolated finding is indicates severe malnutrition or high protein/low carbohydrate diets. Bilirubinuria may be a normal finding in dogs; especially male dogs who can conjugate bilirubin in renal tubular cells. In dogs or cats persistent bilirubinuria especially in dilute urine samples should prompt evaluation of serum bilirubin and liver enzymes as bilirubinuria precedes bilirubinemia. Ignore the specific gravity, nitrite, ph, and urobilinogen pads on the dipstick as these are of no benefit in small animals. The urine sediment allows detection of cellular elements, organisms, crystals, and casts. Unstained samples should be evaluated initially to eliminate confusion caused by precipitates or bacterial contamination of stains. The sediment should be evaluated within 30 minutes of collection as crystals may form and changes in cellular morphology will occur with delayed assessment. Clinical pathologist review of epithelial cells should not be performed on urine samples more than a few hours old. Instead, obtain fresh urine, centrifuge, pour off the supernatant, make an air dried slide of the pellet which preserves cellular morphology, and submit to the reference lab for review. Culture should be recommended on all samples in which organisms are seen, collecting fresh urine by cystocentesis if necessary. Struvite or oxalate crystals seen in concentrated urine with no other sediment abnormalities in a clinical normal patient may be artifact if urinalysis was delayed, ie, sent to a reference laboratory. An in clinic sediment examination of a fresh sample within 30 minutes of collection should be performed. Urate crystals are never normal and may be the only abnormality seen in some young animals with portosystemic shunts. This underscores the importance of complete urinalysis including sediment evaluation even in young animals as part of preanesthetic screening for neutering.

5 Feline Hyperthyroidism What s New? Bill Saxon DACVIM, DACVECC Hyperthyroidism is the most common endocrine disorder of cats with a steadily increasing prevalence since first reported in the s. The incidence in the US is up to 10% in cats over 10 years of age. It is caused by excess production of thyroid hormone most commonly from adenomatous hyperplasia of one or most often both thyroid glands. Thyroid carcinoma is rare cause of hyperthyroidism in cats accounting for less than 2% of cases. Hyperthyroidism is a disease of older cats (mean years, range 3-22 years) with no breed or sex predilection. Clinical signs due to excess circulating thyroid hormone include weight loss, polyphagia, hyperactivity, pu/pd, vomiting, diarrhea, unkempt hair coat, panting/dyspnea, and congestive heart failure. Subclinical and apathetic (lethargy, weakness, inappetence) forms exist underscoring the importance of screening all middle age to older cats. An enlarged thyroid gland is palpable in most cases. Diagnosis is usually straight forward based on history, clinical findings including enlarged thyroid gland, and elevated total T4. Additional laboratory abnormalities may include mild erythrocytosis, stress leukogram, increased liver enzymes especially ALT, and hyperglycemia. Normal serum T4 concentration, however, does not definitively rule out hyperthyroidism. As in dogs, nonthyroidal illness will lower T4 values. Cats with early or mild hyperthyroidism may have T4 concentration in the normal range, or that fluctuate. A T4 value in the upper half of the normal range in a cat >8-10 years old raises the suspicion for hyperthyroidism. In these cats free T4 should be measured. Elevated freet4 concentration in a cat with high normal total T4 is consistent with hyperthyroidism. Free T4 may be elevated in up to 15% of cats with nonthyroidal illness for reasons as yet unknown. In these cats, total T4 is low to low-normal, however. For this reason, freet4 is not recommended as a screening test (low specificity when used alone) for feline hyperthyroidism. Rarely, definitive diagnosis requires thyroid scintigraphy. Radioactive iodine is the treatment of choice for feline hyperthyroidism as it is effective, relatively free of complications, and curative. Bilateral thyroidectomy is another curative option though not commonly performed. Medical treatment consists of methimazole (or Felimazole) which blocks thyroid hormone production (inhibits thyroid peroxidase) but not release of preformed hormone which explains the 2-4 weeks required to reach effect after beginning therapy. Methimazole is used at mg BID. Twice daily administration is more effective than once daily administration. Higher doses are usually not necessary and may increase the risk of renal decompensation.

6 Chronic kidney disease is another common disease of older cats (up to 80% of cats >15 years of age) and often occurs with hyperthyroidism. Hyperthyroidism increases renal blood flow and GFR and may mask renal disease. With correction of hyperthyroidism renal function may deteriorate. It must be underscored that treatment for hyperthyroidism does not cause kidney disease; both diseases are present and both require treatment. In fact, untreated hyperthyroidism may cause further deterioration of kidney function due to local activation of renal renin-angiotensin system and nephron hyperfiltration. It is difficult to predict which hyperthyroid cats have underlying kidney disease. Symmetric dimethylarginine (SDMA) is a more reliable indicator of kidney disease in hyperthyroid cats than creatinine (diagnosing 6 times as many cats) and should be part of the pretreatment evaluation. In cats with known or highly suspected renal disease a conservative approach using methimazole at 1.25 mg SID-BID aiming for a T4 value in the middle to upper normal range is indicated. Renal values often increase slightly but stabilize with no adverse effect on long term survival if stage specific therapy for CKD is administered. Based on response to methimazole, curative treatment using radioactive iodine can be considered. To avoid adverse renal affects iatrogenic hypothyroidism should be avoided when treating hyperthyroidism. Measurement of serum TSH concentration will allow differentiating iatrogenic hypothyroidism (TSH increased) which must be corrected by administering thyroid supplementation and/or decreasing methimazole dose from sick euthyroid (TSH normal) in which thyroid supplementation is contraindicated. The American Association of Feline Practitioners published updated guidelines for managing feline hyperthyroidism in This is a valuable resource for all small animal practitioners.

7 ProBNP When to Use It and How Bill Saxon DACVIM, DACVECC The lecture will cover diagnosing and treating cardiac disease in dogs and cats. The notes will focus on indications for using the cardiac biomarker probnp. B-type natriuretic peptide (BNP) is produced under normal conditions by atrial myocardial cells and aids in controlling vascular tone (vasodilator) and volume (natriuresis). It is stored as the prohormone probnp. In heart disease, ventricular stress or stretch (pressure of volume overload) leads to increased production of BNP primarily by the left ventricle. The probnp is cleaved into equal amounts of active BNP and inactive NT-proBNP. In circulation BNP counteracts the conditions that caused it s release sodium retention and volume/pressure overload. NT-proBNP is the stable metabolite that can be measured in plasma or serum or whole blood using an in-house test in cats. The primary indications probnp in dogs are: 1. Differentiating cardiac from respiratory disease in coughing dogs. A normal probnp rules out cardiac disease. A probnp >1800 pmol/l supports that the clinical signs are due to cardiac disease. 2. Determining onset of congestive heart failure in dogs with valvular heart disease. The rate of progression of valvular heart disease in small breed dogs is variable. A probnp value of >1500 pmol/l in conjunction with a VHS >12 is predictive of CHF within 3-6 months. These dogs should undergo more frequent monitoring including thoracic radiographs and owner monitoring of resting respiratory rate (normal <30 breaths per minute). 3. Detecting occult dilated cardiomyopathy in Doberman pinschers. A probnp > 735 pmol/l was 92% sensitive and 92% specific for identifying those Dobermans at greatest risk for occult DCM and requiring follow-up diagnostics (Holter/Echo). The primary indications for probnp in cats are: 1. Differentiating cardiac from respiratory disease in symptomatic cats (respiratory signs). A normal BNP rules out cardiac disease. 2. Screening asymptomatic cats with risk factors for heart disease such as murmur, gallop sound, or breed predisposition. A normal BNP rules out heart disease. An increased BNP should be followed by ECG, radiographs, and echocardiogram (the gold standard for evaluation feline cardiac disease). 3. Differentiating cardiac from respiratory disease as the cause of pleural effusion. A BNP >322 pmol/l on pleural fluid supports cardiac disease.

8 Levels of BNP can also be increased from pulmonary hypertension, arrhythmia, and severe azotemia (undergoes renal excretion), and systemic hypertension (independent of renal disease). Therefore, the test must be interpreted considering concurrent clinical abnormalities and in conjunction with ECG and imaging results.

9 Practitioner s Challenge: Managing the Challenging Senior Patient Bill Saxon, DACVIM, DACVECC IDEXX This session will consist of case-based discussion of senior patients with challenging and/or multiple diseases. The emphasis will be on the diagnostic workup and new information on managing liver and endocrine diseases.

10 Diagnostic Update for Practitioners Parts 1 & 2 Bill Saxon DACVIM, DACVECC Case-based discussion of the complicated patient using updated published guidelines and novel interpretation of laboratory and other diagnostics to improve outcomes. Enodcrine diseases (adrenal/thyroid), cardiorespiratory problems, the hyperthyroid/chronic kidney disease cat, coagulopathies, and others as time permits will be covered.