International Congress of the Italian Association of Companion Animal Veterinarians

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1 Close this window to return to IVIS International Congress of the Italian Association of Companion Animal Veterinarians May, 2010 Rimini, Italy Next Congress : SCIVAC International Congress May 27-29, Rimini, Italy Reprinted in IVIS with the permission of the Congress Organizers

2 65 CONGRESSO INTERNAZIONALE MULTISALA SCIVAC RIMINI MAGGIO 2010 Effective management of familial renal diseases in dogs and cats (Part 1-2) Shelly L. Vaden DVM, PhD, Dipl ACVIM, North Carolina, USA Management of a primary disease process is paramount in the management of kidney diseases. Some of the diseases have specific treatment guidelines (e.g., antiproteinuric drugs for hereditary nephritis; the Gonto protocol for Fanconi syndrome). Unfortunately there is no cure for the familial renal diseases of dogs and cats and most will progress to having advanced chronic kidney disease (CKD) and uremia, often over a fairly compressed time period (i.e., most before 3 years of age). As with all animals with CKD, controlling those factors that are believed to slow the progression of CKD in dogs and cats is important in animals with familial renal disease. These factors are feeding a diet formulated for animals with renal disease as well as adequate control of hypertension, proteinuria and renal secondary hyperparathyroidism. In addition, early recognition and treatment of urinary tract infections, dehydration, and hypokalemia and specific treatment of the components of uremia may reduce the progression and the morbidity associated with familial renal diseases. STAGING OF DOGS AND CATS WITH CHRONIC KIDNEY DISEASE The International Renal Interest Society (IRIS) formulated a staging system for dogs and cats with CKD (Table 1), which would also apply for dogs and cats whose CKD developed because a familial disease. This staging is intended to facilitate application of appropriate clinical practice guidelines for diagnosis, prognosis and treatment of CKD. The stage of CKD should be assigned based on stable serum creatinine measured at a time when prerenal and postrenal contributions to the azotemia have been eliminated. Typically, patients in stage 1 or 2 CKD do not have clinical signs of renal disease with the exception of polyuria and polydipsia. Dogs and cats in these stages may have clinical signs related to their kidney lesions (e.g., acute pyelonephritis) or other aspects of their kidney disease (e.g., proteinuria, hypertension). Nonproteinuric, nonhypertensive dogs and cats with stages 1 and 2 CKD may have stable renal function for an extended period of time. Evaluation of patients with stage 1 or 2 CKD should be aimed at identifying and providing specific treatment for their primary disease process. Renal function should be monitored for disease progression. Animals with stage 3 CKD may have clinical signs but typically do not have signs of uremia. Progression during this stage may be due to both inherent mechanisms of progression and the primary disease process. Treatment of stage TABLE 1 - IRIS Classification System for Chronic Kidney Disease Stage 1 (Nonazotemic) Markers of renal disease present Creatinine Dogs <1.4 mg/dl, <125 umol/l; Cats <1.6 mg/dl, <140 umol/l * ** Stage 2 (Mild Renal Azotemia) Markers of renal disease present Creatinine Dogs mg/dl, umol/l; Cats mg/dl, umol/l Stage 3 (Moderate Renal Azotemia) Creatinine Dogs mg/dl, umol/l; Cats mg/dl, umol/l Stage 4 (Severe Renal Azotemia) Creatinine Dogs and Cats >5 mg/dl, >440 umol/l *P, proteinuria = Dogs UPC >0.5; Cats UPC >0.4. BP, borderline proteinuria = Dogs UPC ; Cats UPC NP, nonproteinuria = Dogs and Cats UPC <0.2. **Hypertension Stages: Stage 0 = <150/<95 mmhg (systolic/diastolic); minimal risk of organ damage Stage 1 = /95-99 mmhg; low risk of organ damage Stage 2 = / mmhg; moderate risk of organ damage Stage 3 = 180/ 120 mmhg; high risk of organ damage 3 CKD includes specific treatment for the primary disease process and treatment designed to slow the progression of renal disease. Dogs and cats with stage 4 CKD have severe azotemia and often have uremia. In addition to treatment provided to stage 3 CKD patients, patients with stage 4 CKD will require therapy to prevent or alleviate signs of uremia. 236

3 SPECIFIC TREATMENT OF FAMILIAL RENAL DISEASES IN DOGS AND CATS Hereditary Nephritis: There is no specific treatment for affected dogs. Feeding a diet formulated for renal failure and administering angiotensin-converting enzyme inhibitors (ACEi) have proven beneficial. If proteinuria is not sufficiently decreased after an ACEi has been administered for a period of several months, additional drugs such as angiotensin receptor blockers (ARB) can be administered (see proteinuria section below). Early detection of HN by screening dogs of relevant breeds for microalbuminuria will allow early therapeutic intervention, which may slow disease progression. Amyloidosis: The beta-pleated sheet configuration of amyloid fibrils leads to their insolubility and resistance to proteolysis, making specific treatment historically ineffectual. In people with Familial Mediterranean Fever, for which Shar Peis affected with amyloidosis may be a model, colchicine prevents or delays renal amyloidosis, even in patients who continued to have recurrent febrile episodes. Colchicine has been recommended in Shar Peis with renal amyloidosis. This drug should be administered to Shar Peis shortly after recurrent fevers and swollen hocks are noted. Colchicine administration may lead to remission of proteinuria even after the appearance of amyloid deposits. There is no evidence to support that colchicine is effective once renal failure is present. Investigations into the use of this drug in other forms of amyloidosis are in their infancy. Polycystic Kidney Disease: No specific treatment exists for PKD although many potential treatments are being explored in people with PKD. Affected animals are treated for their CKD. Cats and dogs that are exhibiting signs of pain associated with cysts may have control of their pain following ultrasound-guided drainage and alcoholization of the incriminating cysts. Fanconi Syndrome: Dogs affected with this syndrome eventually progress to CKD and need to have therapeutic regimens designed that limit disease progression and manage clinical signs. However, additional care is needed to restore losses of bicarbonate, electrolytes, proteins, vitamins and minerals per the Gonto protocol ( This protocol recommends feeding affected dogs a meat-based maintenance dog food, unless they have advanced renal failure when they are fed a diet formulated for dogs in renal failure that is supplemented with amino acids. In addition, dogs are given calcium, phosphorus, multi-vitamin, and potassium supplements, and sodium bicarbonate. Renal dysplasia and other miscellaneous familial renal diseases: Goals of treatment of affected animals include limiting progression and control of clinical signs of uremia. NUTRITIONAL MANAGEMENT The nutritional management of dogs and cats with stage 3 or 4 CKD of all causes has been documented to be important in reducing the signs of uremia, preventing malnutrition and slowing the progression of disease. This would be expected to also be true in animals that have CKD secondary to a familiar disorder. Renal diets are modified as follows: restricted quantity of high quality protein, phosphorous, and sodium, enhanced omega-3: omega-6 polyunsaturated fatty acid ratio, and increased caloric density and fiber content. Dogs with stage 3 CKD that were fed a renal diet had a 70% reduction in the relative risk of developing a uremic crisis, remained free of uremic signs almost 2.5 times longer, had a slower decline in renal function and had a median survival that was three times longer than dogs with stage 3 CKD that were fed a maintenance diet. Likewise, cats fed a renal diet had a median survival time that was 2.4 times longer than cats fed a maintenance diet. Whereas renal diets are generally recommended for adult dogs and cats with stage 3 or 4 CKD, they may not be ideal for supporting growth. We generally recommend feeding a geriatric diet to dogs and cats that develop stage 3 or 4 CKD before reaching skeletal maturity. PROTEINURIA Persistent renal proteinuria is associated with a greater frequency of morbidity and mortality from renal disease as well as all cause mortality in dogs and cats. Renal proteinuria can occur secondary to any renal disease in which there is functional or structural alteration of the glomeruli, tubules, or interstitium. Dogs and cats with glomerular proteinuria may eventually progress to have a urine protein: creatinine ratio >2.0 although in the early stages of disease the magnitude of proteinuria may be lower than this. Glomerular disease can develop secondary to any persistent noninfectious inflammatory, infectious or neoplastic disease. Because there of similarities between acquired glomerular disease and some of the familial glomerular diseases, persistent not renal disease that may be leading to immunecomplex formation may need to be excluded before confirming a familial disease is present in some breeds (e.g., soft coated wheaten terriers, Bernese mountain dogs). Marked proteinuria can occur in animals with familial glomerular diseases. When dogs and cats with marked renal proteinuria are treated with ACEi, the reduction in the magnitude of proteinuria is believed to be renoprotective. ACEi may reduce proteinuria and preserve renal function by several possible mechanisms. The decreased efferent glomerular arteriolar resistance effected by ACEi leads to decreased glomerular transcapillary hydraulic pressure and decreased proteinuria. Other proposed mechanisms include reduced loss of glomerular heparan sulfate, decreased size of the glomerular capillary endothelial pores, improved lipoprotein metabolism, slowed glomerular mesangial growth and proliferation, and inhibition of bradykinin degradation. ACEi therapy and appropriate monitoring are currently recommended for: 1) Dogs with CKD causing azotemia and UPC >0.5; 2) Cats with CKD causing azotemia and UPC >0.4; 3) Nonazotemic dogs or cats with persistent renal proteinuria and UPC >1.0. More study is needed to determine if there is a benefit to administering ACEi to non-azotemic animals with lower magnitudes of proteinuria. If severe hyperkalemia develops or if proteinuria is not adequately controlled with an ACEi, ARB can be substituted or added. 237

4 Combination therapy with an ACEi and an ARB may lead to a greater reduction in proteinuria than monotherapy with either an ACEi or an ARB. Losartan is the ARB that we have used most often. If an ACEi is not tolerated, an ARB can be used instead of the ACEi. HYPERTENSION Hypertension is common in dogs and cats with CKD from all causes and systolic pressures in excess of mmhg carry a greater risk of organ damage, including more rapid rate of progressive decline in renal function. Blood pressure control should be considered a cornerstone to appropriate management of animals with familial renal disease and hypertension. While guidelines are still being developed, the current recommendation is to use ACEi as the first line antihypertensive agents for dogs and cats with a calcium channel blocker (e.g., amlodipine besylate) as a second agent, when needed. Animals presenting with systolic pressures > 200 mmhg or with evidence of target organ damage (e.g., choroidopathy) should be given both drugs because monotherapy with an ACEi is unlikely to provide adequate blood pressure control. Both of these agents are vasodilators and can cause a decrease in GFR. If renal function worsens after initiating treatment with one of these agents, the drug should be temporarily withdrawn and reinstituted at a lower starting dose. RENAL SECONDARY HYPERPARATHYROIDSM Animals with CKD are less able to excrete phosphates through the kidney. Phosphate retention may contribute to progression of CKD through the development of renal secondary hyperparathyroidism, nephrocalcinosis, or both. Parathyroid hormone has been described as a uremic toxin that contributes to the progression of CKD. However, increased concentrations of parathyroid hormone may simply be a marker of vitamin D deficiency, which may be a in uremia. Diet alone is unlikely to control hyperphosphatemia in many animals with stage 3 and 4 CKD. Aluminum hydroxide has been the phosphate binder of choice for many years. Calcium carbonate and calcium acetate are alternatives but both carry the risk of causing hypercalcemia; this risk may be greater with calcium carbonate. Calcium containing phosphate binders should be used with caution in dogs or cats that have a serum calcium and phosphorous product in excess of 60. Epakitin, an intestinal phosphate binder that contains chitosan, derived from crab and shrimp shells, and calcium carbonate. Epakitin appears to be effective at reducing phosphate absorption from the gut and reducing serum phosphorous concentrations. However, it has the potential to increase the calcium x phosphorous product of the patient. Furthermore, chitosan is also marketed as an intestinal fat absorber, leading to weight loss in people. The weight of any patient receiving this medication should be closely monitored. Sevelamer HCl (RenaGel, Genzyme Corporation, Cambridge, MA) is an intestinal phosphate binder used in people with CKD. Sevelamer is a polymer that is not absorbed systemically when given to people and does not promote hypercalcemia. Dogs given sevelamer at 100x the recommended dosage did not develop any apparent toxicity. However, the use of this agent in dogs and cats has not been studied and recommended doses have not been established. The agent is hygroscopic and cannot be crushed or broken before ingestion because an intact gelatinous matrix is needed for efficient phosphate binding. This raises concerns about compounding this drug. Furthermore, when exposed to moisture it expands to up to 8 times it size; administration through a feeding tube should be avoided. Low doses of calcitriol administered orally will reduce parathyroid hormone concentrations in dog with CKD. Preliminary results of a controlled clinical study suggest that calcitriol is effective in prolonging survival in dogs with stages 3 and 4 CKD; results of ongoing studies in cats have not been released. Calcitriol should not be given until hyperphosphatemia is controlled and the calcium x phosphorous product is less than 60. Parathyroid hormone concentrations should be monitored to document that renal secondary hyperparathyroidism is adequately controlled during calcitriol administration. The efficacy of calcitriol in cats with CKD has not been clearly established. Guidelines have not been established for effective management of renal secondary hyperparathyroidism in animals that have not reached skeletal maturity. This subset of patients is more likely to develop renal osteodystrophy; therefore, it would seem as though special attention for these animals is warranted. Skeletally immature animals have higher reference range for serum phosphate and the target for control of hyperphosphatemia is unclear. Furthermore, it has been suggested that they would require a higher dose of calcitriol to achieve the same effect as seen in mature animals and that they would benefit for concurrent calcium carbonate administration but neither of these hypotheses have been studied. MANAGEMENT OF ANEMIA Moderate to severe anemia may lead to weakness, lethargy, anorexia and cold intolerance. Sources of ongoing blood loss (e.g., gastrointestinal hemorrhage), infection or inflammation should be eliminated, iron deficiencies should be corrected and blood sample collection should be minimized in animals with CKD and anemia. Transfusions of whole blood or packed red blood cells may be used for short-term control of anemia but are less suited for long-term control. Animals requiring repeat transfusions in order to maintain a PCV above 20-25% may benefit from administration of recombinant human erythropoietin (rhuepo) or darbepoetin, a synthetic form of erythropoietin. Because systemic hypertension may be exacerbated by this therapy, blood pressure should be adequately controlled before instituting therapy. Oral iron supplementation is needed to prevent the development of iron deficiency during treatment with either agent. Clinically relevant anti-rhuepo antibodies develop in approximately 25-30% of dogs and cats weeks to months after starting rhuepo therapy. Darbepoetin may be less antigenic and can be given less often than rhuepo. Increased PCV from these therapies results in increased appetite, energy, weight gain, playfulness, strength and alertness. 238

5 FLUID THERAPY The goals of fluid therapy should be to restore the patient to euvolemia and alleviate clinical signs of uremia. There is no magic number for serum urea nitrogen or creatinine that should be targeted during fluid therapy; rather attention should be given to the well being of the patient. The patient s volume status needs to be assessed prior to initiating and during administration of fluid therapy. Volume depletion should be rapidly corrected because ongoing hypovolemia may exacerbate clinical signs and contribute to further renal damage. Some animals with stage 4 CKD, and some with advanced stage 3 CKD, subjectively appear to have fewer uremic episodes and improved appetites when given subcutaneous fluid intermittently although others do not appear to benefit from this therapy. The owners can give these fluids at home. However, fluids should be administered in the smallest volume and the lowest frequency that is needed to help the animals feel better. Because chronic sodium administration may activate the renin-angiotensin-aldosterone system, exacerbate hypertension and be harmful to the kidneys, fluids formulated for maintenance therapy should be used to minimize the amount of sodium given to these patients. MANAGEMENT OF ACID BASE AND POTASSIUM DISTURBANCES Metabolic acidosis may be associated with progressive renal injury, loss of lean muscle mass and the development of osteodystrophy that can occur in association with CKD. Metabolic acidosis contributes to nausea, anorexia and lethargy in patients with CKD. Alkalinization therapy should be considered if the animal is consuming a renal diet and the TCO 2 is <15 meq/l. Sodium bicarbonate is commonly used for alkalinization therapy. However, potassium citrate may have an added advantage in cats with CKD or dogs with Fanconi syndrome that have concurrent hypokalemia. CONTROL OF UREMIC GASTROPATHY Vomiting, nausea and anorexia in dogs and cats with CKD may be signs of uremic gastropathy. The frequency of these signs may decrease when the patient consumes a renal diet. When these signs are not controlled by diet alone, histamine type 2 (H 2 ) receptor antagonists (i.e., cimetidine, ranitidine, famotidine) are often used to reduce gastric acid secretion. Proton pump inhibitors (e.g., omeprazole) are more effective at reducing gastric acid secretion than are the H 2 receptor antagonists but are also more expensive. Proton pump inhibitors should be tried in dogs and cats that have persistent signs of uremic gastropathy despite appropriate administration of a H 2 receptor antagonist. If gastric ulceration is suspected, sucralfate should also be given. Centrally acting antiemetics (e.g., metoclopromide) may be needed to control vomiting during a uremic crisis. Suggested reading 1. Lees GE, Brown SA, Elliot J, et al. Assessment and management of proteinuria in dogs and cats: 2004 ACVIM forum consensus statement (small animal). J Vet Intern Med 2005; 19: Lees, GE. Familial Renal Disease in Dogs. In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine. 7th ed. St. Louis: Saunders Elsevier, 2010; Polzin DJ, Osborne CA, Ross S. Chronic Kidney Disease. In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine, 7th ed. St. Louis: Elsevier Saunders, 2010; Zatelli A, D Ippolito P, Bonfati U, and Zini E. Ultrasound-assisted drainage and alcoholization of hepatic and renal cysts: 22 cases. J Am Anim Hosp Assoc 2007; 43: Address for correspondence: North Carolina State University College of Veterinary Medicine Raleigh, NC, USA 239