Serum Creatinine Concentrations and IRIS CKD Stages for Dogs and Cats Serum Creatinine Concentrations (mg/dl) Stage 2 (Mild renal azotemia?

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1 Early Diagnosis of Chronic Kidney Disease (CKD) and Reassessment of Normal Values in Dogs and Cats with CKD Gregory F. Grauer, DVM, MS, Diplomate, ACVIM (Small Animal Internal Medicine) Department of Clinical Sciences, Kansas State University, Manhattan, Kansas Renal damage and disease can be caused by acute or chronic insults to the kidney. The terms renal disease and renal damage are used to denote the presence of renal lesions; these terms however imply nothing about the cause, distribution, or severity of the lesions and importantly nothing about the level of renal function that exists. Chronic kidney disease (CKD) can be caused by diseases/disorders that affect any portion of the nephron, including the glomerulus, the tubule, the vascular supply, and surrounding interstitium. Most definitions of CKD require the lesions to have been present for at least 2-4 months. Early detection of CKD, prior to the onset of renal azotemia/failure, should facilitate appropriate intervention that could stabilize renal function or at least slow its progressive decline. Early diagnosis of CKD: Serum creatinine concentration Early, non-azotemic CKD (IRIS Stage 1) can be diagnosed in dogs and cats with abnormal renal palpation or renal imaging findings, persistent renal proteinuria, or urine concentrating deficits due to renal disease. In most cases however, CKD is diagnosed on the basis of persistent azotemia superimposed on an inability to form hypersthenuric urine (some cats with CKD retain the ability to concentrate urine). Serum creatinine concentrations are commonly used as a marker of glomerular filtration rate (GFR) in dogs and cats. Creatinine is produced from the non-enzymatic degradation of creatine and creatine phosphate in skeletal muscle and therefore serum creatinine concentrations reflect the patient s muscle mass as well as GFR. Interpretation of serum creatinine concentrations can also be influenced by the method of analysis (Jaffe s reaction vs. enzymatic and bench-top vs. reference laboratory). One of the most disconcerting aspects of interpretation of serum creatinine is the relatively large variation in reference intervals between laboratories which can lead to false-positive and false-negative azotemia. Reference ranges need to be individualized to each laboratory but many veterinary nephrologists have suggested that dogs and cats with serum creatinine concentrations lower than most reference ranges (i.e., 1.4 and 1.6 mg/dl in dogs and cats, respectively) have Stage 2 CKD and deserve closer monitoring. Serum Creatinine Concentrations and IRIS CKD Stages for Dogs and Cats Serum Creatinine Concentrations (mg/dl) Stage 1 (Non-azotemic CKD) Stage 2 (Mild renal azotemia?) Stage 3 (Moderate renal azotemia) Stage 4 (Severe renal azotemia) Cats < >5.0 Dogs < >5.0 Serum creatinine concentrations must always be interpreted in light of the patient s muscle mass, urine specific gravity, and physical examination findings in order to rule out pre- and post-renal causes of azotemia. In dogs there can be a large variation in muscle mass (e.g., miniature poodle vs. greyhound) that will tend to increase the breadth of reference ranges. Despite these potential confounding issues, longitudinal assessment of serum creatinine concentrations (analyzed by consistent methodology), is an excellent tool to assess renal function and diagnose early CKD. For example, a serum creatinine concentration that increases from 0.6 to 1.2 mg/dl over several

2 years, without evidence of dehydration or an increase in muscle mass, could indicate at least a 50% reduction in GFR (at least 50% nephron loss because compensatory hypertrophy of remaining nephrons increases the functional capacity of those nephrons). Serum symmetrical dimethylarginine (SDMA) is derived from intranuclear methylation of L-arginine by protein-arginine methyltransferases and released into the circulation after proteolysis. SDMA is eliminated primarily by renal clearance and represents a potential biomarker for diagnosing and monitoring CKD. In two recent longitudinal studies, one in dogs and one in cats that developed CKD, SDMA concentrations increased above normal approximately 17 months prior to serum creatinine concentration increasing above reference range (> 1.8 mg/dl in dogs and > 2.1 mg/dl in cats). Interestingly, if a serum creatinine concentration of > 1.6 mg/dl had been considered abnormal in the feline study, both serum creatinine and SDMA would have identified renal azotemia in these cats at nearly the same time. Serum symmetric dimethylarginine concentration: SDMA is derived from intranuclear methylation of L-arginine by protein-arginine methyltransferases and released into the blood after proteolysis. SDMA is eliminated primarily by glomerular filtration and is not affected by tubular reabsorption or secretion and therefore can be used as an intrinsic GFR marker. Multiple studies in people have documented the utility of serum SDMA concentrations as a biomarker of renal function; a meta-analysis of 18 studies involving over 2100 people documented a high correlation of SDMA to both GFR and scr. Recently SDMA has received attention in veterinary medicine as kidney excretory function biomarker. In one of the first studies involving aged, client-owned cats, an inverse linear relationship between serum SDMA concentration and GFR (Iohexol plasma clearance) was observed (R 2 = , P <.001). In addition to correlating well with GFR, serum SDMA may be a more sensitive biomarker for detection of early CKD compared with scr. In longitudinal studies in dogs and cats that developed CKD, SDMA concentrations increased above normal a mean of 17 months (range of months) prior to scr concentration increasing above reference range ( > 1.8 mg/dl in dogs and > 2.1 mg/dl in cats) (Figure 3). In male dogs with X- linked hereditary nephropathy, using a single cutoff value for serum SDMA identified, on average, a < 20% decrease in GFR as measured by Iohexol plasma clearance. In addition, using a single cutoff value for SDMA, reductions in GFR were detected earlier compared with either a single scr cutoff value or scr trending over time. Another potential advantage to monitoring serum SDMA concentrations for early diagnosis of CKD compared with monitoring scr, SDMA does not appear to be influenced by changes in lean body mass in dogs and cats. Preliminary results also suggest that serum SDMA/creatinine ratios may have prognostic value in dogs and cats with CKD (as long as the SDMA value is > 14 μg/dl); ratios > 10 were associated with mortality within one year. Based on the above studies it appears that compared with scr, SDMA is a more sensitive renal function biomarker. A persistent elevation in SDMA (>14 mg/dl) in a dog or cat with scr <1.4 or <1.6 mg/dl, respectively indicates reduced renal function and indicates Stage 1 CKD. In IRIS Stage 2 patients with low body condition scores and SDMA 25 μg/dl, the scr may have underestimated renal function and IRIS Stage 3 treatment recommendations may need to be considered. Similarly, in IRIS Stage 3 patients with low body condition scores and SDMA 40 μg/dl, the scr may have underestimated renal function and IRIS Stage 4 treatment recommendations may need to be considered. Idexx Laboratories added serum SDMA testing to routine serum biochemistry panels in Serum SDMA concentrations > 14 μg/dl are abnormal in both dogs and cats. Although the effects of dietary arginine are as yet unknown, serum concentrations of SDMA are not correlated to serum arginine concentrations in dogs and cats. In people, dietary arginine has no

3 effect on serum SDMA concentrations. Similar to scr, SDMA must always be interpreted in light of the patient s urine specific gravity and physical examination findings in order to rule out volume-responsive and post-renal causes of azotemia. In addition, longitudinal assessment of serum SDMA concentrations is preferred over one-time assessments. Follow-up: Dogs and cats with borderline scr and/or SDMA concentrations should be retested; initially in approximately 2 weeks to confirm the initial value and then subsequently approximately every 3 months to assess renal function stability. Additional tests that may help further characterize the potential renal disease and/or complications associated with renal disease include a complete urinalysis with urine sediment examination, urine culture, blood pressure, urine protein/creatinine ratio, and urinary tract imaging with radiographs and ultrasound. Early diagnosis of CKD: Urine protein/creatinine ratio Proteinuria in dogs and cats with chronic kidney disease (CKD) can occur due to glomerular and/or tubular lesions. Glomerular proteinuria can be caused by loss of integrity of or damage to the capillary wall (e.g., immune complex disease and x-linked hereditary nephropathy). It is also likely that increases in glomerular capillary pressure increases the amount of filtered plasma protein. Intraglomerular hypertension may result from loss of nephrons (loss of autoregulation) and from systemic hypertension being transmitted into glomerular capillaries. Structural glomerular disease and CKD are often accompanied by systemic hypertension which can exacerbate intraglomerular hypertension and glomerular proteinuria. Tubular proteinuria occurs when tubular reabsorption of protein from the glomerular filtrate is compromised. Tubular proteinuria is typically of lesser magnitude compared with glomerular proteinuria. Reduced tubular reabsorption of protein in dogs and cats with CKD can occur with tubulointerstial injury and decreased numbers of functioning tubules. Whether caused by capillary wall lesions, tubular lesions, or intraglomerular hypertension, excessive quantities of protein in the glomerular filtrate may contribute to additional glomerular and tubulointerstitial lesions leading to loss of more nephrons. Proteinuric renal disease and systemic hypertension are often co-existent and therefore, it is difficult at times to separate the effects of high systemic and intraglomerular pressures and proteinuria. Diagnosis of renal proteinuria in cats and dogs with CKD should be accomplished in a step-wise fashion. In health and in disease, albumin is the major urine protein in dogs and cats. The specificity of the dipstick screening test for albuminuria is poor (especially in cats) and therefore confirmation of traditional dipstick positive proteinuria should be confirmed with a more specific follow-up test such as the sulfosalicylic acid turbidimetric test, UPC, or species specific albuminuria assays. The second step in assessment of proteinuria is to determine its origin (physiologic or benign proteinuria and pre- and post-renal proteinuria need to be ruled out). Renal proteinuria is persistent and associated with a benign or inactive urine sediment (hyaline casts may be observed in the urine sediment in cases of renal proteinuria). Persistent proteinuria is defined as at least two positive tests at two week intervals. Subsequently, via serial monitoring of the UPC, it should be determined if the proteinuria is stable, increasing, or decreasing over time. IRIS Classification of Renal Proteinuria in Dogs and Cats Urine Protein/Creatinine Ratio (UPC) Classification < 0.2 Non-Proteinuric (Cats); (Dogs) Borderline Proteinuric > 0.4 (Cats); > 0.5 (Dogs) Proteinuric

4 Current recommendations suggest that persistent proteinuria of renal origin of a magnitude > UP/C of 0.4 in cats and > 0.5 in dogs with azotemic CKD should be treated with a renal diet and an angiotensin converting-enzyme inhibitor (ACEI). Borderline proteinuria is defined as a UP/C between 0.2 and 0.5 in dogs and 0.2 and 0.4 in cats and warrants increased monitoring. It s interesting to note however that borderline and even normal levels of proteinuria in cats have been associated with poor outcomes. For example, in cats with naturally occurring CKD, relatively mild proteinuria (UPC ) increased the risk for death or euthanasia 2.9 fold compared with cats with UPCs < 0.2. In a prospective, longitudinal cohort study of non-azotemic cats > 9 years, 95 cats (median age = 13) were followed for 12 months or until death or azotemia developed. Azotemia was defined as a serum creatinine concentration > 2.0 mg/dl and 29/95 (30.5%) cats developed azotemia. Proteinuria at presentation (median UPC of 0.19 vs. 0.14) was significantly associated with development of azotemia in these geriatric cats. Finally, when client-owned cats with stable CKD (n=112) were compared with client-owned cats with progressive CKD (n=101), median UPCs in the progressive group were higher when compared with the stable group (0.27 vs. 0.14). A 0.1 increase in UPC was associated with a 24% increase in risk of progression of CKD. Management of CKD: Systolic blood pressure Current recommendations are that blood pressure be measured in a quiet area prior to examining the patient, typically in the presence of the owner and after a 5-10 minute period of acclimation. The ACVIM Panel on Hypertension suggests discarding the first measurement, then obtaining a minimum of 3, preferably 5-7, consecutive measurements with less than 10-20% variability in systolic blood pressure. The animal s disposition, body position, and heart rate, the cuff size and measurement site as well as all measured values should be recorded in the medical record. Many clinicians suggest that hypertension be documented on more than one occasion before accepting the diagnosis (unless ocular lesions compatible with systemic hypertension already exist). IRIS Classification of Systolic Blood Pressure in Dogs and Cats Systolic Blood Pressure (mm Hg) Risk of Target Organ Damage Arterial Pressure (AP) Category <150 Minimal Normotension Low Borderline Hypertension Moderate Hypertension >180 High Severe Hypertension IRIS blood pressure sub-staging for dogs and cats with CKD is based on risk of target organ (ocular, neurologic, cardiac, and renal) damage. Not long ago indirect systolic blood pressure measurements > mmhg were considered the threshold for hypertension. Despite the inherent difficulties with indirect blood pressure measurement in dogs and cats, it may be appropriate to consider systolic hypertension to be present at lower pressures (e.g., > 160 mm Hg). In a recent study, 45 dogs with naturally occurring CKD were divided into three groups based on initial systolic blood pressure were followed for up to 2 years. The blood pressure groups were defined as: High ( mmhg), n = 14; Intermediate ( mmhg), n = 15, and Low ( mmhg), n = 16. The initial high systolic blood pressure group had increased risk of uremic crisis and death when compared with the low pressure group (median survival of < 200

5 days vs. > 400 days). In cats with a remnant kidney-wrap model of CKD, systolic hypertension (mean pressure of 168 vs. 113 mmhg) was associated with reduced GFR (1.34 vs ml/min/kg), increased UPC (1.2 vs. 0.1), and increased glomerulosclerosis. Similarly, in dogs with the remnant kidney-wrap model of CKD, systolic hypertension (> 160 mm Hg) was associated with reduced GFR, increased UP/C ratios, and increased mesangial matrix accumulation, tubular lesions, fibrosis, and cellular infiltrates. Cats with progressive CKD had higher systolic blood pressures than did cats with stable CKD (155 vs. 147 mm Hg). Finally, in 69 cats with naturally occurring CKD, high time-averaged systolic blood pressure (159 vs. 136 mm Hg), was correlated with glomerulosclerosis and hyperplastic arteriolosclerosis. Management of CKD: Serum phosphorus concentrations Similar to serum creatinine reference ranges, there is variability in serum phosphorus reference ranges between laboratories. This variability is likely at least in part due to higher serum phosphorus concentrations observed in healthy, young, growing puppies and kittens. Soft tissue mineralization of the kidney causes irreversible nephron damage and is associated with CKD progression in dogs and cats. Cats with stable CKD had lower serum phosphorus concentrations than did those cats with progressive CKD (4.4 vs. 5.1 mg/dl). Serum phosphorus concentration is a predictor of CKD progression in cats, with a 41% increase in the risk of progression for every 1.0 mg/dl increase in serum phosphorus concentration. In 80 client-owned cats with CKD, serum phosphorus concentrations were correlated with renal interstitial fibrosis. In dogs with CKD, a serum calcium times phosphorus product > 70 mg/dl was a poor prognostic indicator. These findings have prompted closer scrutiny of therapeutic targets for serum phosphorus in dogs and cats with CKD. IRIS treatment guidelines suggest the following targets which are typically well within laboratory reference ranges. IRIS Treatment Recommendations for Serum Phosphorus in Dogs and Cats with CKD IRIS CKD Stage Target Serum Management Options Phosphorus (mg/dl) Renal diet or normal diet with enteric binder Renal diet +/- enteric binder Renal diet with enteric binder Renal diet with enteric binder Summary: Closer monitoring of serum creatinine and UPC may facilitate early diagnosis of CKD in dogs and cats. Longitudinal assessment of these parameters will almost always provide better data than will one-time evaluations. No laboratory test is perfect; trending laboratory data, with the same test methodology, will tend to improve diagnostic sensitivity. Once CKD has been diagnosed, standard of care renoprotective treatment includes a renal diet +/- an enteric phosphate binder for hyperphosphatemia and angiotensin-converting enzyme inhibitors and/or calcium channel blockers for proteinuria and hypertension. Tighter control of hyperphosphatemia, renal proteinuria, and systolic hypertension may improve treatment outcome.

6 Staging and Management of Chronic Kidney Disease Gregory F. Grauer, DVM, MS, Diplomate, ACVIM (Internal Medicine) Department of Clinical Sciences, Kansas State University Chronic kidney disease (CKD) is a major cause of morbidity and mortality in dogs and cats. The prevalence of CKD has been estimated to be % in dogs and 1-3% in cats, but it increases with age, especially in cats. It has been estimated that as many as 30-50% of cats 15 years of age or older have CKD. Nephron damage associated with CKD is usually irreversible and often progressive. In dogs the progressive loss of renal function tends to be common, linear, and relatively rapid compared with cats. Cats may have stable renal for months to years and be relatively unaffected by the CKD or they may have slowly progressive disease over several years. In some cases, cats will be stable for months to years but then experience an abrupt, unpredictable decline in renal function. Soft tissue mineralization, systemic hypertension, intraglomerular hypertension, and proteinuria have been associated with progression of CKD. Although it s usually not possible to improve renal function in CKD, it s logical to assume that early diagnosis of CKD can improve clinical outcomes for dogs and cats. There is firm evidence for dietary treatment and increasing evidence that anti-proteinuric treatments can slow the progressive nature of CKD. Etiology: The cause of canine and feline CKD is usually difficult to determine. Due to the interdependence of the vascular and tubular components of the nephron, the end point of irreversible glomerular or tubular damage is the same. Morphologic heterogeneity between nephrons exists in the chronically diseased kidney with changes ranging from severe atrophy to marked hypertrophy. These histologic changes are not process specific and, therefore, an etiologic diagnosis is frequently not possible. The more common renal diseases that have been associated with the development of CKD in dogs and cats include glomerulonephritis, amyloidosis, tubulointerstitial disease, pyelonephritis, nephrolithiasis, polycystic kidney disease, feline infectious peritonitis, leptospirosis and neoplasia. Progressive diseases that destroy nephrons at a slow rate allow intact nephrons to undergo compensatory hypertrophy which can delay the onset of renal failure. In these cases, when renal failure finally occurs, the nephron hypertrophy can no longer maintain adequate renal function and < 25% of the original nephrons are functional. This demonstrates the need for early diagnosis and intervention. Staging of Canine and Feline CKD: The International Renal Interest Society (IRIS) was created to advance the scientific understanding of kidney disease in small animals at the 8 th Annual Congress of the European Society of Veterinary Internal Medicine in Vienna, Austria in Seventeen independent veterinary nephrologists from eight countries serve on the IRIS Board with the mission of helping practitioners better diagnose, understand, and treat canine and feline renal disease. The following table was developed by the IRIS Board as guide to staging feline CKD. Serum Creatinine Concentration Stage 1 Non-azotemic CKD Stage 2 Mild renal azotemia? Stage 3 Moderate renal azotemia mg/dl (cats) < >5.0 mg/dl (dogs) < >5.0 Stage 4 Severe renal azotemia

7 Serum creatinine concentrations must always be interpreted in light of the patient s urine specific gravity and examination findings in order to rule out pre- and post-renal causes of azotemia. The above stages are further classified by the presence or absence of proteinuria and systemic hypertension as follows: Urine Protein/Creatinine Ratio Classification < 0.2 (cats and dogs) Non-Proteinuric (cats), (dogs) Borderline Proteinuric >0.4 (cats), > 0.5 (dogs) Proteinuric Systolic Blood Pressure (mm Hg) Diastolic Blood Pressure (mm Hg) Risk Level for Target Organ Damage <150 <95 Minimal Low Moderate >180 >120 High Prevalence of Feline CKD: The distribution of staging of 786 cases of CKD in cats was reported by Dr. Jonathan Elliott from the Royal Veterinary college in London at the 2004 ACVIM Forum as follows: Stage 1 = 33.3%, Stage 2 = 37.2%, Stage 3 = 15.4%, and Stage 4 = 14.1%. Similar data has not yet been determined for dogs. Pathophysiology: The pathophysiology of CKD can be considered at both the organ and systemic level. At the level of the kidney, the fundamental pathology of CKD is loss of nephrons and decreased glomerular filtration. Reduced glomerular filtration results in increased plasma concentrations of substances that are normally eliminated from the body by renal excretion. In addition to excretion of metabolic wastes and maintenance of fluid and electrolyte balance, the kidneys also function as endocrine organs and catabolize several peptide hormones. Therefore hormonal disturbances also play a role in the pathogenesis of CKD. For example, decreased production of erythropoietin contributes to the nonregenerative anemia of CKD and decreased metabolism and excretion of parathyroid hormone and gastrin contribute to osteodystrophy and gastritis, respectively. Finally, part of the pathophysiology of CKD is brought about by compensatory mechanisms. For example, the osteodystrophy of CKD occurs secondary to hyperparathyroidism which develops in an attempt to maintain normal plasma calcium and phosphorus concentrations. Similarly, the individual glomerular filtration rate of intact nephrons increases in CKD in an attempt to maintain adequate renal function; however, proteinuria and glomerulosclerosis may be consequences or "trade-offs" of this hyperfiltration. Clinical Signs and Diagnosis: Clinical signs of CKD may not be present in early stages and when present in later stages, are usually nonspecific (lethargy, depression, anorexia, gastroenteritis, and dehydration). Occasionally uremic breath and/or oral ulcers may be observed. Unique signs of CKD (vs. acute renal disease) include a history of weight loss and polydipsia-polyuria, poor body condition, nonregenerative anemia, small and irregular kidneys, and renal secondary hyperparathyroidism. The classic diagnosis of renal failure based on renal azotemia (persistent azotemia superimposed on the inability to concentrate urine) pertains to CKD stages 2-4. Stage 1 CKD (non-azotemic

8 CKD) could be diagnosed in cats and dogs with persistent proteinuria, urine concentrating deficits, increases in serum creatinine over time, even if the values remain in the normal range (e.g., serum creatinine that increases from 0.6 to 1.2 mg/dl could indicate a 50% reduction in GFR), or abnormal renal palpation or renal ultrasound findings. In general, the diagnostic approach to patient once CKD has been identified and staged is focused on three areas: 1) characterization of the renal disease, 2) characterization of the stability of the renal disease and function, and 3) characterization of the patient s problems associated with the decreased renal function. Further definition of the renal disease (beyond a standard minimum data base) could include for example, quantitation of proteinuria, measurement of blood pressure, urine culture, kidney imaging, and possibly kidney biopsy. The stability of the renal function would be assessed by serial monitoring of abnormalities identified during the initial characterization of the renal disease. This monitoring should always include serum biochemistry profiles, urinalyses, quantitation of proteinuria, and measurement of blood pressure but may also include follow-up urine cultures and ultrasound examinations. Characterization of the renal disease and its stability is most important in the earlier stages of CKD when appropriate treatment has the greatest potential to improve or stabilize renal function. Characterization of patient problems becomes more important in the later stages of CKD when clinical signs tend to be more severe. In the later stages of CKD, diagnostic (and subsequent therapeutic) efforts should directed at assessing anorexia, vomiting, acidosis, potassium depletion, hypertension, anemia, etc. Management: Similar to the diagnostic approach to CKD, the therapeutic approach should also be tailored to fit the patient s stage of disease. For example, disease specific treatments for nephroliths and bacterial pyelonephritis as well as treatments designed to slow the progression of renal disease (so called renoprotective treatments) will be of most value in the earlier stages of CKD. Renoprotective treatments include dietary change designed to reduce serum phosphorus concentrations and angiotensin-converting enzyme inhibitors designed to normalize systemic and intraglomerular blood pressures and reduce proteinuria. In the later stages of CKD, treatment tends to be focused on decreasing the patient s clinical signs associated with the decreased renal function. Hypertension: Systemic hypertension is relatively common in cats and dogs with CKD. Although the exact mechanism of the hypertension is not known, a combination of glomerular capillary and arteriolar scarring, decreased production of renal vasodilatory prostaglandins, increased responsiveness to normal pressor mechanisms, and activation of the renin-angiotensin system may be involved. Gradual reduction of dietary salt intake is often recommended as the first line of treatment; however, there are no studies that document the efficacy of dietary salt reduction in lowering blood pressure. In many cases vasodilators (angiotensin converting enzyme inhibitors [ACEI] and calcium channel antagonists [CCA]) may be necessary to control hypertension. Systemic hypertension may contribute to progressive nephron loss by causing irreversible glomerular damage via increased intraglomerular pressures and glomerulosclerosis. Although ACEI will normalize intraglomerular pressures via efferent arteriole vasodilatation, CCA (e.g., amlodipine) may be necessary in addition to control systemic hypertension, especially in cats. In cats with reduced renal mass and concurrent hypertension, amlodipine had an antihypertensive effect and reduced the risk of ocular injury and neurologic complications induced by hypertension. In another study of cats with reduced renal mass, treatment with benazepril sustained single nephron GFR and increased whole kidney GFR, while reducing the degree of

9 systemic hypertension. Similar results have been observed in dogs with naturally-occurring CKD treated with enalapril. Based on these studies, angiotensin-converting enzyme inhibition may be an effective treatment to slow the rate of progression of renal failure in dogs and cats with renal disease. Dietary Management: Reduction of dietary phosphorus and protein intake is the cornerstone of management of CKD. Dietary management may not only allow the animal to live more comfortably with decreased renal function but may also significantly prolong survival. Ideally, dietary protein reduction allows all essential amino acid requirements to be met without excesses. This is accomplished by feeding lowered quantities of high biological value protein and results in decreased need for renal clearance of urea and other nitrogenous metabolites. It is important to keep in mind when feeding reduced protein diets, that the energy requirements of the body have a higher priority than does protein anabolism, and therefore, if the available carbohydrates and fats are insufficient to meet caloric requirements, endogenous proteins will often be broken down as a source of energy. Catabolism of endogenous proteins for energy increases the nitrogenous waste the kidney must excrete and exacerbates the clinical signs of renal failure. Researchers postulate that protein requirements for patients with CKD are higher than those of normal animals. Ideally, dogs and cats with CKD should receive a minimum of and g protein/kg/day, respectively. Twenty percent of the 70 to 80 Kcal/kg/day in cats should be high quality protein. A good recommendation for dietary protein reduction is to feed the maximum amount of high biological value, highly digestible protein that the animal can tolerate at his/her level of renal function. (Dietary protein reduction refers to decreased protein intake compared to normal protein intake. Most commercial pet foods contain relatively high levels of protein. Dietary protein should never be restricted, that is fed at a level that is less than the patient's dietary requirements.) A favorable response to therapy is a stable body weight and serum creatinine and albumin concentrations with decreasing serum urea nitrogen and phosphorus concentrations. Moderate dietary protein reduction should be employed early in the course of renal failure and use of more severely reduced protein diets should be reserved for patients that are refractory to moderate dietary protein reduction. Management of the hyperphosphatemia that occurs in CKD is closely related to dietary protein reduction inasmuch as protein reduced diets are also phosphorus reduced. An increase in plasma phosphorus concentration occurs in CKD as a result of decreased renal excretion. Concurrently, decreased renal production of the active form of vitamin D3 decreases intestinal absorption of calcium which, in conjunction with impaired renal reabsorption of calcium, decreases plasma ionized calcium concentrations. Decreased vitamin D3 and serum calcium concentrations stimulate parathyroid hormone (PTH) secretion which facilitates renal excretion of phosphorus and increases serum calcium concentrations by increasing renal calcium reabsorption and calcium absorption from bones and the gastrointestinal tract. The "trade-offs" for this hyperparathyroidism, however, can be severe and include osteodystrophy, bone marrow suppression, and soft tissue mineralization. Soft tissue mineralization occurs predominately in damaged tissue and if mineralization occurs in renal tissue the result may be a progressive decline in renal function. If the product of the serum calcium and phosphorus concentrations is greater than mg/dl, the patient is at risk for soft tissue mineralization. Studies in cats with remnant kidney CKD have shown that normal dietary phosphorus intake is associated with microscopic renal mineralization and fibrosis and these changes were prevented by reducing dietary phosphorus. Similarly in both cats and dogs with naturally occurring CKD, feeding a diet specifically formulated to meet the needs of cats with CKD, together with phosphate binding

10 drugs if required, controls hyperphosphatemia and secondary renal hyperparathyroidism, and is associated with an increased survival time. In addition to feeding a phosphorus-restricted diet, administration of enteric phosphate binders will help combat hyperphosphatemia. Enteric phosphate binders do not directly lower plasma phosphorus but bind phosphorus in the intestinal tract and prevent absorption. Enteric phosphate binders are generally ineffective if dietary phosphorus intake is not restricted. In many cases of canine CKD, low dosages of 1, 25-dihdroxycholecalciferol (calcitriol) have been associated with decreased PTH concentrations and decreased renal mortality. Conversely, preliminary studies in cats with CKD have not demonstrated a benefit to calcitriol treatment. Calorie Malnutrition: Vomiting and anorexia are common in dogs and cats with CKD and can often result in decreased caloric intake. Causes of vomiting and anorexia include: 1) stimulation of chemoreceptor trigger zone by uremic toxins, 2) decreased excretion of gastrin and increased gastric acid secretion (plasma gastrin concentrations in dogs and cats with advanced CKD may be as high as 20 times the normal concentrations), and 3) gastrointestinal irritation secondary to uremia. Vomiting may be treated with metoclopramide, which blocks the chemoreceptor trigger zone. Metoclopramide also increases gastric motility and emptying without causing gastric acid secretion and is the drug of choice for vomiting associated with renal failure. H2 receptor blockers and proton pump blockers (e.g., famotidine and omeprazole) have been shown to effectively decrease gastric acid secretion, which may attenuate vomiting in cats with CKD. Oral ulcers, stomatitis, and glossitis may occur as a result of gastritis and vomiting or the effect of uremic toxins on mucosal membranes and will often also result in anorexia. If vomiting has been controlled but anorexia persists, placement of a gastrostomy tube (especially in cats) will often facilitate the maintenance of caloric intake and hydration status.

11 Hypertension and Proteinuria in Chronic Kidney Disease Gregory F. Grauer, DVM, MS, Diplomate, ACVIM (Internal Medicine) Department of Clinical Sciences, Kansas State University, Manhattan, Kansas Introduction: Chronic kidney disease (CKD) is a common problem that adversely affects both quality of life and survival time. Although the prevalence of CKD in the general small animal population is ill defined, CKD may affect up to 10% of dogs and 35% of cats in referral hospital populations (Polzin and Osborne 1986; Krawiec and Gelberg, 1989). Nephron damage associated with CKD is usually irreversible and can be progressive. Renal failure results when three-quarters or more of the nephrons of both kidneys are not functioning. Whether the underlying CKD primarily affects glomeruli, tubules, interstitial tissue, or renal vasculature, irreversible damage to any portion of the nephron renders the entire nephron nonfunctional. Healing of irreversibly damaged nephrons occurs by replacement fibrosis and therefore a specific etiology is often not determined. Chronic kidney disease occurs over a period of weeks, months, or years and since it is often not possible to improve renal function in CKD, treatment is aimed at stabilizing renal function. In addition to dietary therapy, there is increasing evidence that treatment with ACE inhibitors can decrease the progressive nature of CKD by attenuating systemic hypertension, intraglomerular hypertension, and proteinuria. By altering pre-glomerular resistance, healthy kidneys can maintain relatively stable glomerular capillary pressures despite variations in systemic blood pressure. This pressure regulatory process is termed renal autoregulation. Autoregulation can be reduced when renal disease results in loss of nephrons. Compromised autoregulation allows high systemic blood pressure to be transmitted to glomerular capillaries. This glomerular hypertension has been documented by micropuncture studies in dogs and cats with surgically reduced renal mass. In these models, glomerular hypertension was associated with glomerular hypertrophy, sclerosis, and proteinuria. Systemic hypertension is relatively common in dogs with renal disease. In a recent study of dogs with spontaneous chronic kidney disease (CKD), 29/45 (64%) had systolic blood pressure > 144 mm Hg and 14/45 (31%) had systolic blood pressure > 161 mm Hg. In cats with naturally-occurring CKD, systemic hypertension has been observed in 19-65% of cases depending on the definition of hypertension. Renal proteinuria can result from glomerular and/or tubular abnormalities in dogs and cats with CKD. Glomerular proteinuria may arise from immune complex disease or structural abnormalities involving the glomerular capillary wall (e.g., amyloidosis and x-linked hereditary nephropathy). Protein-losing nephropathy caused by glomerular capillary wall lesions is often accompanied by systemic hypertension and glomerular proteinuria can be exacerbated by intraglomerular glomerular hypertension that can result from systemic hypertension. Tubular proteinuria occurs when tubular reabsorption of protein from the glomerular filtrate is compromised. Whether caused by capillary wall lesions, tubular lesions, or intraglomerular hypertension, excessive quantities of protein in the glomerular filtrate may contribute to additional glomerular and tubulointerstitial lesions leading to loss of more nephrons. Diagnosis of hypertension and proteinuria: Current recommendations are that blood pressure be measured in a quiet area prior to examining the patient, typically in the presence of the owner and after a 5-10 minute period of acclimation. The ACVIM Panel on Hypertension suggests discarding the first measurement,

12 then obtaining a minimum of 3, preferably 5-7, consecutive measurements with less than 10-20% variability in systolic blood pressure. The animal s disposition, body position, and heart rate, the cuff size and measurement site as well as all measured values should be recorded in the medical record. Many clinicians suggest that hypertension be documented on more than one occasion before accepting the diagnosis (unless ocular lesions compatible with systemic hypertension already exist). Diagnosis and management of proteinuria in cats and dogs with CKD should be accomplished in a step-wise fashion. The specificity of the dipstick screening test for proteinuria is poor and therefore confirmation of traditional dipstick positive proteinuria should be accomplished with a more specific follow-up test such as the sulfosalicylic acid (SSA) turbidimetric test, UP/C, or species specific albuminuria assay. The second step is assessment of proteinuria is to determine its origin. Renal proteinuria can adversely affect the prognosis of dogs and cats with CKD and therefore, physiologic or benign proteinuria and pre- and post-renal proteinuria should be ruled out. Subsequently, via serial monitoring, it should be determined if the proteinuria is persistent or transient and if persistent is the magnitude stable or increasing or decreasing over time? Persistent proteinuria is defined as at least two positive tests at two week intervals. Relatively mild proteinuria in dogs and cats with spontaneous/naturally-occurring CKD appears to be a negative predictor of survival. In dogs and cats with the remnant kidney model of CKD, proteinuria is associated with nephron hypertrophy and increased intraglomerular pressures. Persistent proteinuria of renal origin of a magnitude > UP/C of 0.4 in cats and > 0.5 in dogs with azotemic CKD should be treated with an ACEI and/or dietary protein reduction. Borderline proteinuria is defined as a UP/C between 0.2 and 0.5 in dogs and 0.2 and 0.4 in cats. What evidence exists that systemic hypertension and/or proteinuria are detrimental to canine and feline kidneys? 1. In dogs with the page/remnant kidney model of chronic renal failure (CRF), systemic hypertension had adverse effects on renal function and morphology. Finco DR. J Vet Intern Med 2004;18: In dogs with remnant kidneys, mmhg increases in systolic blood pressure over baseline resulted in enhanced renal damage. Brown SA, et al. J Vet Intern Med 2000;14: In dogs with spontaneous chronic renal failure, initial high systolic blood pressure was associated with increased risk of developing a uremic crisis and of dying. Jacob F, et al. J Am Vet Med Assoc 2003;222: Angiotensin-converting enzyme inhibition (ACEI) treatment that lowered systolic blood pressure and decreased proteinuria was associated with improved outcome in dogs with spontaneous glomerulonephritis. Grauer GF, et al. J Vet Intern Med 2000;14: ACEI treatment in dogs with remnant kidney CRF was effective in modulating progressive renal injury, which was associated with a reduction in glomerular and systemic hypertension. Brown SA, et al. Am J Vet Res 2003;64: Glomerular capillary hypertension, glomerular enlargement, and proteinuria have been documented in dogs with the remnant kidney model of renal failure. Brown SA, et al. Am J Physiol 1990;258:F In cats with the remnant kidney model of CKD, increases in single nephron GFR occur in association with glomerular hypertrophy, increasing intraglomerular pressures,

13 hyperfiltration, mesangial matrix expansion, and proteinuria. Brown SA, et al. Am J Physiol 1995;269:R In dogs with naturally occurring CKD, the relative risk of uremic crises and mortality was approximately three time greater in dogs with UP/C s > 1.0 (n=25) compared with dogs with UP/C s < 1.0 (n=20). In this study the risk of an adverse outcome was approximately 1.5 times greater for every 1 unit increase in UP/C and the decline in renal function was greater in dogs with higher UP/C s. Jacob F, et al. Am J Vet Res 2005;226: In cats with naturally occurring CKD, relatively mild proteinuria (UP/C s > 0.4) appear to be negative predictors of survival. Increasing proteinuria was associated with increasing serum creatinine concentrations and increasing systolic blood pressure (presumably related to glomerular hyperfiltration). UP/C, age, and serum creatinine concentration (but not blood pressure) were independently associated with mortality. Syme HM, et al. J Vet Intern Med 2006;20: Proteinuria has been associated with increased risk of mortality due to all causes in cats that have normal renal function when their proteinuria is first detected. Walker D, et al. J Vet Intern Med 2004;18: In 141 client-owned cats with naturally-occurring systemic hypertension, amlodipine treatment decreased both blood pressure and proteinuria. Proteinuria (UP/C) (before and after treatment as well as the change in UP/C was the only variable related to survival in these cats. Jepson RE, et al. J Vet intern Med 2007;21: In cats with naturally-occurring CKD, shorter survival time was associated with an increased UP/C as an independent risk factor. King JN, et al. J Vet Intern Med 2007;21: In 61 cats with naturally-occurring CKD, treatment with benazepril decreased proteinuria (UP/C) and decreased progression of the CKD to advanced stages. Mizutani H, et al. J Vet Intern Med 2006;20: In a prospective, longitudinal cohort study of non-azotemic cats > 9 years, 95 cats (median age = 13) were followed for 12 months or until death or azotemia developed. 29/95 (30.5%) developed azotemia (Sr Cr > 2.0 mg/dl). Proteinuria at presentation (median UP/C of 0.19 vs. 0.14) was significantly associated with development of azotemia. Jepson RE, et al. JVIM 2009; 23: In cats with the remnant kidney model of CKD, hypertension was associated with more severe glomerular histologic lesions. Mathur, et al, AJVR 2004;65: In 59 cats with CKD (serum creatinine concentrations > 2.0 mg/dl, USG < 1.035, and history and clinical signs compatible with CKD vs. AKI) with postmortem data and biochemistry and urine protein data (obtained during the last 2 months of life) the UP/C was positively correlated with both renal interstitial fibrosis score and maximal glomerular volume. 34 of the 59 cats (58%) were classified as proteinuric. Chakrabarti, et al. Diagnostic Pathol 2013;50: When cats with CKD surviving for more than one month (surviving group, n = 34) were compared with cats with CKD surviving less than one month (non-surviving group, n = 16), UP/C was significantly higher in the non-surviving group. In the surviving group, UP/C was the only clinicopathologic variable that exhibited a consistent alteration (increase) in relation to first visit data and was most likely to be associated with mortality. Kuwahara, et al. J Small Anim Pract 2006;47:

14 18. When client-owned cats with stable CKD (n=112) were compared with client-owned cats with progressive CKD (n=101), median UP/Cs in the progressive group were higher than the stable group (0.27 vs. 0.14). A 0.1 increase in UP/C was associated with a 24% increase in risk of progression of CKD. Chakrabarti, et al. J Vet Intern Med 2012; 26: In 69 cats with CKD (serum creatinine concentrations > 2.0 mg/dl, USG < 1.035, and history and clinical signs compatible with CKD vs. AKI) with postmortem data and timeaveraged systolic blood pressure (SBPOT) (obtained over a mean of 284 days) the SBPOT was positively correlated with maximal glomerular volume, hyperplastic arteriolosclerosis, and glomeruloscerosis. 34 of the 69 cats (49%) were classified as hypertensive (SBPOT of 159 mm Hg vs 136 mm Hg in normotensive cats). Chakrabarti, et al. Diagnostic Pathol 2013;50: In 26 client-owned dogs with CKD, treatment with benazepril (vs. placebo) decreased UP/C and increased GFR (plasma clearance of iohexol) and health status score over a 6 month study. Tenhundfeld J, et al. J Am Vet Med Assoc 2009; 234: ACE-Inhibitors and CKD: The Good, Bad, and Ugly Introduction: By altering pre-glomerular resistance, healthy kidneys can maintain relatively stable glomerular capillary pressures despite variations in systemic blood pressure. This pressure regulatory process is termed renal autoregulation. Autoregulation can be reduced when renal disease results in loss of nephrons. Compromised autoregulation allows high systemic blood pressure to be transmitted to glomerular capillaries. This glomerular hypertension has been documented by micropuncture studies in dogs and cats with surgically reduced renal mass. In these models, glomerular hypertension was associated with glomerular hypertrophy and sclerosis and proteinuria. Systemic hypertension is relatively common in dogs and cats with renal disease. In a recent study of dogs with spontaneous chronic kidney disease (CKD), 29/45 (64%) had systolic blood pressure > 144 mm Hg and 14/45 (31%) had systolic blood pressure > 161 mm Hg. In cats with naturally-occurring CKD, systemic hypertension has been observed in 19-65% of cases depending on the definition of hypertension. Renal proteinuria can result from glomerular and/or tubular abnormalities in dogs and cats with CKD. Glomerular proteinuria may arise from immune complex disease or structural abnormalities involving the glomerular capillary wall (more common in dogs e.g., amyloidosis and x-linked hereditary nephropathy). Protein-losing nephropathy caused by glomerular capillary wall lesions is often accompanied by systemic hypertension and glomerular proteinuria can be exacerbated by intraglomerular glomerular hypertension that can result from systemic hypertension. Tubular proteinuria occurs when tubular reabsorption of protein from the glomerular filtrate is compromised. Whether caused by capillary wall lesions, tubular lesions, or intraglomerular hypertension, excessive quantities of protein in the glomerular filtrate may contribute to additional glomerular and tubulointerstitial lesions leading to loss of more nephrons. Indirect systolic blood pressure greater than 160 mmhg is often listed as the threshold for systemic hypertension in dogs and cats. Hypertension:

15 Systemic hypertension in animals has largely been thought to be secondary to another disease (e.g., renal disease and endocrinopathies), as opposed to idiopathic (primary or essential). This has recently been called into question. For example, in a report of 69 hypertensive cats, seen at North Carolina State University for ocular disease, revealed that at least 17%, and possibly as many as 50%, of cats had no identifiable cause for their systemic hypertension. Elliott and associates at the Royal Veterinary College in London have documented that approximately 20% of hypertensive cats, diagnosed in primary-care practices, were idiopathic. Another retrospective study, which used very strict criteria for the diagnosis of primary (essential, idiopathic) hypertension, revealed a prevalence of 11% in cats. Described and potential etiologies of secondary hypertension include acute and chronic renal disease, hyperthyroidism, hypothyroidism, hyperadrenocorticism, hyperaldosteronism, pheochromocytoma, diabetes mellitus, and obesity. Chronic kidney disease has the greatest association with hypertension and may often be causal. A recent report suggested approximately 29% of elderly cats with CKD were hypertensive, with the range reported in 4 studies being 19-65%. In dogs with CKD, approximately one-third will be normotensive, one-third will have borderline hypertension, and one-third will be hypertensive. Systemic hypertension may contribute to progressive nephron loss by causing irreversible glomerular damage via increased intraglomerular pressures and glomerulosclerosis. By altering pre-glomerular resistance, healthy kidneys can maintain relatively static glomerular capillary pressures despite variations in systemic blood pressure via autoregulation. Inappropriate dilation of the afferent glomerular arteriole occurs in dogs and cats with CKD and diminishes the ability of the afferent arteriole to protect the glomerulus from variations in systemic blood pressure. Although the exact mechanism of the CKD-associated hypertension is not known, a combination of glomerular capillary and arteriolar scarring, decreased production of renal vasodilatory prostaglandins, increased responsiveness to normal pressor mechanisms, and activation of the renin-angiotensin-aldosterone system (RAAS) may be involved. The increased renin secretion leads to increased production of angiotensin II and aldosterone. In addition to its direct pressor effects, angiotensin II also has a stimulatory effect on the sympathetic nervous system, increasing vascular tone, and, in CKD vasoconstriction of the efferent arteriole which further contributes to the intraglomerular hypertension. Finally, angiotensin and aldosterone may also stimulate renal tissue remodeling via increased matrix production and fibrosis. The consequences of systemic hypertension are usually dependent on the magnitude and duration of the blood pressure elevations. Acute ocular and central nervous system abnormalities can occur associated with hemorrhage or edema formation. Renal damage associated with hypertension tends to be more chronic and characterized by glomerular lesions (e.g., glomerulosclerosis) and proteinuria. Finally, functional/adaptive changes like ventricular hypertrophy can occur due to increased after-load in patients with hypertension. Diagnosis and treatment of hypertension in dogs and cats with CKD may prevent development of retinal and CNS lesions or may limit or slow progression of renal and cardiac lesions. Proteinuria: Renal proteinuria is a diagnostic marker of the severity of renal disease and potentially a mediator of glomerular and tubular injury. Recent findings have demonstrated that proteinuria is