Abstract

Chronic kidney disease is a commonly encountered problem in cats and dogs as well as many other species. Because of the frequency of disease in small animal medicine, much interest and research has been given to the topic in recent years. Staging guidelines have been developed by the International Renal Interest Society (IRIS) to help direct diagnosis, treatment, and monitoring of patients. Therapies that have been anecdotal in the past are now being explored via evidence-based medicine. Prognostic factors have been identified which can assist owners in decision-making. This lecture will cover the current management of chronic kidney disease in dogs and cats and how these strategies might apply to zoological species.

Introduction

Chronic kidney disease is a common entity in cats and dogs. Much has changed over the years in our understanding of kidney disease in these species resulting in changes in terminology, diagnosis, and treatment. In addition, markers of prognosis and effect of treatment have been identified. The goal of this lecture is to provide an update on approach to chronic kidney disease from the perspective of small animal medicine.

Terminology

For years, terms such as renal insufficiency or renal failure were used to describe patients with chronic kidney disease. These terms were difficult to define (e.g., when does disease go from insufficiency to failure?) and centered on only specific functions of the kidney. The term chronic kidney disease (CKD) is more encompassing of the primary disease processes that can occur. Additionally, owners are more likely to understand the term “kidney” than “renal.” CKD is defined as the presence of functional or structural abnormalities in one or both kidneys that result in reduced function or tissue damage. Damage may be microscopic (e.g., glomerular injury) or macroscopic (e.g., renal infarcts with fibrosis).

The International Renal Interest Society (IRIS) was originally formed in 1998 and has established guidelines for staging CKD based on creatinine concentration and presence or absence of proteinuria or hypertension (www.iris-kidney.com). The staging provides a system to categorize different degrees of CKD and provide guidelines for diagnosis and treatment depending on the stage of disease. Recently, guidelines for the diagnosis and management of canine proteinuria have also been published.

Diagnosis

CKD is most often defined by the loss of renal concentrating ability with or without the presence of azotemia. As it requires 66% loss of renal function before concentrating ability is affected and 75% loss of function prior to azotemia developing, there can be disease present long before we are able to detect it. This is in part due to the poor sensitivity of creatinine and BUN to detect significant changes in glomerular filtration rate.

Evaluation of other biomarkers is underway to find a more sensitive indicator of renal dysfunction and includes cystatin C and neutrophil gelatinase-associated lipocalin (NGAL). In people, serum cystatin C is considered better than creatinine in detecting renal dysfunction. Studies in cats and dogs are limited and currently hindered by variable cross-reactivity with a human assay. In addition, the effects of non-renal disease on serum cystatin C concentrations need to be established. Measurement of urine cystatin C (as a ratio with creatinine) may be of benefit to detect tubular disease.

NGAL is used in people as a marker of acute kidney injury (AKI). Studies in dogs have evaluated serum and urinary NGAL in both AKI and CKD. It appears to be a sensitive marker of AKI but may not differentiate AKI from CKD. Serum NGAL may be a useful prognostic indicator, but further studies are needed.

Proteinuria is often the earliest sign of CKD in dogs due to the higher rate of glomerular versus tubular disease, and this may occur in other species. Patients with proteinuria and an inactive urinary sediment should have a urine protein:creatinine ratio (UPC) performed to establish the severity of the proteinuria.

Imaging such as radiographs, ultrasound or CT should be considered in all patients newly diagnosed with CKD. Imaging will allow assessment for stones or tumors that may be causing obstructive disease or be a nidus of chronic infections. Contrast studies should be performed with caution as further renal damage could occur.

Renal biopsy is important in evaluating patients with suspected glomerular disease. Some forms of glomerular disease may be responsive to immunosuppressive therapy, but biopsy diagnosis is recommended before starting immunosuppressive therapies. Ideally, samples are collected for standard H&E stain, immunohistochemistry, and electron microscopy. A renal biopsy kit can be obtained in advance that contains materials and instructions (International Veterinary Renal Pathology Service, The Ohio State University or Utrecht Veterinary Nephropathology Service, Utrecht University).

Treatment

Treatment of CKD centers on 1) removing any primary causes such as drugs/toxins, infections, or obstruction; 2) symptomatic therapy to address fluid, electrolyte, acid-base, endocrine, and nutritional deficiencies; and 3) minimizing clinical and pathophysiological consequences of disease. Symptomatic therapy is instigated based on the IRIS stage of CKD and the clinical signs of the patient. Recently, evidence-based recommendations for treatment of CKD in cats and dogs were reviewed.¹¹

Fluid Therapy

The goal of fluid therapy is to maintain hydration. Most patients with stages 1 and 2 CKD are able to maintain hydration on their own and do not typically require fluid supplementation. Patients with stage 3 or 4 disease are more likely to benefit. Traditionally, fluid therapy has involved the SQ administration of a balanced electrolyte solution such as lactated Ringer’s solution or 0.9% NaCl. These fluids have a high sodium content which does not match the free water losses that are usually occurring in patients with CKD and could contribute to hypertension or fluid retention. From a physiological standpoint, administration of water enterally (via a feeding tube) would be more appropriate but not possible in all patients.

Hyperphosphatemia

Phosphorus is primarily excreted by the kidneys. As kidney function declines, phosphorus is retained, leading to renal secondary hyperparathyroidism. This can result in mineralization of tissues and progression of CKD. Patients with renal secondary hyperparathyroidism may have high total calcium, but the ionized calcium is typically normal or low despite a high PTH. First-line therapy for hyperphosphatemia is dietary phosphorus restriction, usually by feeding a “kidney” diet. If diet alone is not effective, the addition of phosphate-binding agents such as aluminum hydroxide, salts of calcium, or lanthanum should be considered. It is important that these are given at the time of feeding as they only bind phosphorus present in the GI tract.

Calcitriol Therapy

The kidneys are responsible for converting 25-hydroxycholecalciferol to its active form, 1,25-dihydroxycholecalciferol (also known as calcitriol). As kidney disease progresses, calcitriol concentrations decrease, which may be a factor in the development of renal secondary hyperparathyroidism. Subsequently, PTH concentrations increase, and PTH is thought to be an important uremic toxin. Calcitriol therapy in dogs has shown a survival benefit by decreasing the progression of CKD, but this has not been demonstrated in cats. Prior to therapy, phosphorus concentrations should be normalized, and ionized calcium should be normal (or low). Starting dose of calcitriol in dogs is 2.0–2.5 ng/kg q 24 h, and ionized calcium and PTH concentrations are monitored. Calcitriol dose is then adjusted to minimize PTH concentrations without causing hypercalcemia.

Anemia

Anemia in CKD is usually due to lack of erythropoietin production by the kidney, though other causes such as hemorrhage (GI or other), poor nutrition, concurrent diseases, or decreased red cell lifespan may play a role. Erythropoietin deficiency can be treated with hormone replacement. The most frequently used product in cats and dogs has been human recombinant erythropoietin (EPO, Epogen or Procrit). EPO results in a dose-dependent rise in hematocrit but has been associated with the development of antibodies that target the endogenous hormone, resulting in transfusion dependent anemia. Darbepoetin (DBO, Aranesp) is a newer, longer acting form of erythropoietin. Based on anecdotal reports, DBO may be less likely to induce antibodies. The initial dose is 1.0 µg/kg SQ once a week until the target PCV is reached, then every 2–3 weeks. Iron supplementation is recommended when initiating therapy and can be accomplished with iron dextran administration.

Antihypertensive Therapy

Systemic hypertension is a common sequela of CKD in dogs and cats and may contribute to progression of disease. Ideally, hypertension is confirmed based on three separate measurements prior to treatment. Exceptions would be severe hypertension (>200 mm Hg) in a patient with evidence of target organ damage (retinal lesions, neurological signs), in which case therapy may be started after a single measurement. Options for therapy include ACE inhibitors (ACEI) and calcium channel blockers (amlodipine). Generally, ACEI do not have a great effect on lowering blood pressure. However, they may have renoprotective effects by reducing intraglomerular pressure, reducing proteinuria, and altering the profibrotic effects of the intrarenal renin-angiotensin system. Amlodipine is often the treatment of choice for hypertension in cats and in dogs with severe hypertension.

Dietary Therapy

Diet therapy remains an important component of therapy for patients with CKD. Renal diets are currently recommended for dogs with IRIS stage 3 and 4 and cats with stage 2–4 disease based on studies that show increased survival time compared to maintenance diets. Renal diets are typically formulated to be restricted in protein, phosphorus, and sodium. They have increased B vitamins, caloric density, omega-3 fatty acids, antioxidants, and sometimes potassium. Simply feeding a lower-protein diet is not likely to give the same benefit as a true renal diet. Diet changes should not be done when the patient is clinically ill as this can result in food aversion. If needed, pharmacological interventions can be used to address uremic gastritis, nausea/vomiting, and appetite stimulation. If patients are not consuming adequate nutrition with these efforts, placement of a feeding tube should be considered. A feeding tube also allows easy administration of medications and free water for hydration.

Hemodialysis

Hemodialysis is being used with increasing frequency in small animal medicine. This modality is best suited for patients with AKI that need support until renal function improves. Patients with CKD may be treated with hemodialysis, but this becomes a lifelong treatment. Currently there are limited centers offering this therapy.

Obstructive Therapies

CKD may be the result of, or complicated by, renal pelvic or ureteral obstruction. The obstruction may be partial or complete and causes include uroliths, blood clots, strictures, or tumors. Therapy to relieve obstruction can be beneficial to prevent nephron loss and preserve renal function. Early intervention is ideal, but treatment of chronic obstructions may be of benefit. A number of options are currently available to relieve obstructions including surgery (urolith removal, ureteral reimplantation), ureteral stenting, and subcutaneous ureteral bypass.

Prognostic Factors

IRIS staging of CKD is prognostic for survival times in cats and dogs. Patients with stage 3 or 4 disease have a shorter survival than patient with lower stage disease. Proteinuria has also been shown to be of prognostic value. Cats with a UPC >0.4 and dogs with a UPC >0.5 have shorter survival times and more uremic crises. As noted above NGAL may be useful as a prognostic factor, but further studies are needed.

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