The term kidney disease, or nephropathy, identifies a disease that affects one or both kidneys and can cause renal failure. Renal failure is the condition that follows the reduction of renal function and is associated with the accumulation of toxins in the body (the most common are represented by the creatinine and urea). A dog or a cat may be suffering from a kidney disease regardless of levels of uremic toxins detected in their body and will be considered in renal failure only when the quantities of blood uremic toxins (e.g. creatinine and urea) increase over the normal range.
Kidney disease is considered chronic (Chronic Kidney Disease-CKD), when it has been present for at least 3 months.
The possibility of having a patient suffering from CKD, but not in renal failure, is due to the ability of the kidneys to compensate for the loss of part of their functionality; for this reason, a dog or a cat can lose up to 70% -80% of their kidney function, before an increase in creatinine values and therefore the accumulation of uremic toxins may be seen. When the reduction of the renal function overtakes the 70% -80%, uremic toxins begin to accumulate within the body, there is an increase in creatinine values, and the patient develops renal failure. Over time, the kidney disease advances and there is a reduction in functionality, with increase of uremic toxins accumulating within the organism and deterioration in clinical status of the patient; for these reasons, a patient suffering from chronic kidney disease may have mild symptoms or even absent at an early stage of the disease and a progressive worsening of the medical conditions with the onset of polyuria and polydipsia (often present from the earliest stages of the disease), gastrointestinal symptoms (vomiting the most frequent), depression, reduced physical activity and weight loss (especially there is a reduction in muscle mass).
Both therapeutic and monitoring directions of patients with CKD are meant to slow the progression of the disease, giving the patient the longest survival period with the best possible quality of life.
In 2006, the International Renal Interest Society (IRIS) presented a staging system dedicated to dogs and cats with CKD (www.iris-kidney.com). The IRIS staging system is based on the current veterinary literature and on the expertise of the members who constitute the IRIS board. After its presentation, the IRIS staging system has been accepted by either the American and the European Society of Veterinary Nephrology and Urology. The IRIS staging system is a useful tool for diagnosis, staging, treatment and management of patients with CKD and can be applied to a large number of cases, although only the Veterinarian can decide for the therapeutic indication and follow-up that the individual clinical case requires. The IRIS staging is based on the initial determination of creatinine, which will identify the stage of the disease. Once the patient has been staged based on creatinine, substage shall be provided by the protein content in urines (proteinuria) and the blood pressure. Based on creatinine, proteinuria and blood pressure, both therapeutic and monitoring suggestions can be obtained to assess the effectiveness of an established therapy and monitor patients affected by CKD. Here are best described the clinical and laboratory parameters used to stage a dog or a cat suffering from CKD: creatinine, proteinuria and arterial pressure.
Blood Creatinine –creatinine determination allows to stage the patient and classify it as not-affected (IRIS Stage 1) or affected (stages 2 to 4 IRIS) from kidney failure. Creatinine should be determined in a clinically stable patient (e.g. not dehydrated), which has a normal capacity of urination (no obstructions of the urinary excretory system) and fasted for at least 12 hours. The fasting period is important in all cats and dogs, but in some breeds its non-observance may cause increased blood creatinine. In Greyhounds, a fasting period lower than 12 hours can cause a rise in blood creatinine also equal to or greater than 50% compared to values obtained in the same patient with the corrected time of fasting. Some dogs with particular development of muscle mass, even with normal renal function, can show creatinine values higher than normal (accordingly with the IRIS staging). In particular canine breeds, such as Dogue de Bordeaux, Rottweiler, Mastiff, Bull Mastiff, Great Dane, Caucasian Shepherd Dog, Greater Swiss Mountain Dog, Bernese Mountain dog and others, can be advisable the animal undergoes a clinical examination, urinalysis and creatinine determination between the 12th and the 18th month of age. If either the clinical examination and the laboratory tests will not reveal abnormalities or will not be suspicious for kidney disease, the creatinine value found will be considered the normal baseline value for that patient (even if above the IRIS 1 normal values). Also a muscle mass loss can determine a reduction in the creatinine value, and can lead to assume a clinical improvement while, on the contrary, the loss of muscle mass in patients with CKD is a negative prognostic factor and a result, in many cases, of the deterioration of the patient's condition. It is then clear the utility of using body weight and also a table for determining the nutritional status (Body Condition Score), while monitoring dogs and cats affected CKD.
Based on creatinine values, the IRIS staging system recognizes 4 stages of CKD.
SDMA - since the end of 2015, the International Interest Society includes symmetric dimethylarginine (SDMA) to stage patients with CKD, intended to be run alongside plasma creatinine as a marker of renal function. SDMA is a methylated form of the amino acid arginine, which is released into the bloodstream after proteolysis and then excreted by the kidneys. The increase in the SDMA plasma concentration seems capable to identify, earlier than plasma creatinine, a renal impairment. The SDMA can then be used, together with the creatinine and urea levels and the urinalysis, to identify a patient with kidney disease. Unlike plasma creatinine, SDMA is not affected by the patient's muscle mass and provides a more accurate assessment of renal function in dogs and cats with a low body condition score. A reduction of muscle mass, commonly found in older animals and in patients with CKD in advanced stages, can decrease plasma creatinine levels then leading to an incorrect staging of the nephropatic patient. The International Renal Interest Society (www.iris-kidney.com) proposes SDMA to stage patients with CKD according to the following scheme (expanded by the author):
1. A cat or a dog with creatinine level < 1.6 and 1.4 mg / dl, respectively, but with SDMA persistently > 14 µg / dl - should be considered as suffering from CKD, particularly if the patient has a reduced muscle mass. To date, we have no evidence demonstrating therapy is useful in these patients, but early identification of CKD can justify to seek for an underlying cause (and specific therapy when possible) as well as helping to improve monitoring (eg during the administration of potentially nephrotoxic drugs).
2. A cat or a dog in IRIS stage 2, but with SDMA ≥25 µg / dl and a poor nutritional status - the reduction in renal function may have been underestimated, then these patients should receive therapeutic and monitoring suggestions listed under IRIS stage 3.
3. A cat or a dog in IRIS stage 3, but with SDMA ≥45 µg / dl and a poor nutritional status - the reduction in renal function may have been underestimated, then these patients should receive therapeutic and monitoring suggestions listed under IRIS stage 4.
Proteinuria - the term proteinuria refers to the abnormal presence of protein in urine; in CKD, proteinuria of clinical interest is that of renal origin. Proteinuria can be measured through various tests; in clinical practice, the most commonly used are the Urinary Protein/Creatinine ratio of urine (UP/C) and the dipstick. In dogs, but not in cats, dispstick can be used as screening tests and a negative result allows to classify the patient as non proteinuric with reasonable certainty.; in cats, determination of UP/C is needed to identify or exclude proteinuria. The IRIS staging system uses UP/C to quantify proteinuria; the test can be performed on a urine sample first evaluated under a microscope to be sure of the absence of bacteria and/or inflammatory cells as well as of red blood cells. Based on UP/C, dogs and cats are then substaged as:
Blood pressure and hypertension – often, dogs and cats with CKD are hypertensive and, as in humans, hypertension might damage various organs and apparatus including the kidney itself. Both dogs and cats can measure the blood pressure. The IRIS recognizes 4 substages, based on the risk of organ damage, identifying as target organs for high pressure damage the kidney, eye, nervous system and the heart: the acronyms AP0, AP1, AP2 and AP3 are used to substage. AP means Arterial Pressure and numbers 0 to 3 refer to 4 substages, with growing potential risk. Dogs and cats in AP2 and AP3 substages get directions for antihypertensive therapy. If blood pressure was not determined, the system uses the acronym RND (Risk Not Determined).
Hyperphosphatemia - blood phosphorus concentration (serum phosphorus) depends primarily on the amount taken with food then absorbed in the intestine and excreted with urines. The intestinal absorption of phosphorus increases with Vitamin D and when diets with a very low phosphorus content are administered. Disorders in phosphorus metabolism begin by early stages of chronic kidney disease and tend to worsen as the disease progresses. To diagnose hyperphosphatemia, the Veterinarian must relate the value of blood phosphorus to the IRIS stage of that patient (serum creatinine value). Hyperphosphatemic patients should be treated to reduce the progression of renal disease and prevent systemic complications.
Anemia – anemia is seldom detected in stages 3 and 4. Many factors can cause anemia, including the lower production of the hormone erythropoietin (stimulates the generation of red blood cells), the reduced sensitivity to erythropoietin of cells producing new red blood cells, the inhibition of the production of red blood cells caused by uremic toxins, the low life-time of red blood cells, bleeding from the gastroenteric tract and nutritional deficiencies. Monitoring anemia is important to improve tissue oxygenation and the quality of life of patients.
Metabolic Acidosis– often detected in IRIS stage 3 (advanced) and 4 and it is characterized by increased acidity of the blood. Metabolic acidosis causes nausea, vomiting, decreased appetite, malnourishment and can obviously influence the patient's quality of life; a particular exam called hemogasanalysis allows identification and treatment of acidotic conditions.
Main aims of the therapy of dogs and cats with CKD are improving the quality of life of the patients and the prolongation of survival time while slowing the progression of kidney disease. In the initial phase, the therapeutic approach will include identification and treatment of any underlying conditions which may affect the renal function or cause renal damage. Even the administration of drugs and/or substances with known or potential renal toxicity should be discontinued or, if needed, continued under strict medical control.
The therapeutic approach to the patient with CKD should include the treatment of underlying causes (when they are identified) and of azotemia, therapy of proteinuria, hypertension, hyperphosphatemia, anemia and metabolic acidosis and of the other pathological conditions that may be encountered. It is, therefore, to set a symptomatic and support therapy, while minimizing the consequences that the renal impairment has on the whole body. It should be underlined that many patients benefit and show a marked improvement in their quality of life thanks to the symptomatic treatment started although, frequently, creatinine values are not changed significantly from the therapeutic approach. When managing a patient with CKD, a proper monitoring is fundamental, allowing early identification and appropriate treatment of alterations and complications which can gradually occur as a result of reduced kidney function.
Diet - dietary approach is extremely important both in dogs and cats suffering from CKD; diets formulated for nephropatic patients have important changes to their composition, compared to maintanance diets. Among these changes are an appropriate reduction of the amount of proteins (represented by high-quality proteins), a low sodium and phosphorus content, an increase in soluble fiber, supplementation of omega-3 fatty acids (PUFA) and antioxidants. In addition, diets for nephropatic cats are often supplemented with potassium, being quite common in felines (in a later stage of CKD) a condition of hypokalemia . It would be therefore wrong to think that diets addressed to nephropatic patients are mainly low protein content as products showing protein levels even lower have no reasonable use in CKD. Clinical evidence: numerous clinical studies have demonstrated the efficacy of renal diet in improving the quality of life, the survival time and reduce the risk of uremic crisis in dogs and cats with chronic renal failure. In addition, all patients affected by proteinuric CKD benefit from administration of a diet with a controlled protein content.
Therapy of proteinuria – both dogs and cats, if proteinuric, are treated with diet and pharmacological therapy. Renal diets are usually combined with supplementation with omega-3 (EPA) and therapy with ACE-inhibitors (see Terminology) or sartans. The efficacy of the antiproteinuric therapy is evaluated through the UP/C (see Terminology) that is usually re-evaluated after 1 month of treatment. If therapy was found to be effective and there are no complications, the patient remains in treatment for a lifetime. Clinical evidence: numerous clinical studies have demonstrated the efficacy of antiproteinuric therapy in slowing the progression of kidney disease and reducing the risk of uremic crisis in proteinuric dogs and cats.
Therapy of hypertension – all dogs and cats in IRIS substage AP2 and AP3 require medical treatment. Lowering the sodium content in the diet can be helpful in improving some hypertensive states and most renal diets have a low sodium content. If a drug therapy is needed, the most used drugs are ACE-inhibitors and calcium channel blockers; the Veterinarian will choose the most appropriate treatment depending on the severity of hypertension.
Therapy of hyperphosphatemia – renal diets have a low phosphorus content and this modification has been proved as useful in reducing hyperphosphatemia. In most dogs and cats in IRIS stage 2 renal diet alone allows to achieve and maintain a proper serum phosphorus after 2 to 4 weeks of dietary therapy. Patients in IRIS stage 3 and 4, instead, often require to associate a phosphate binder to the diet, in order to further reduce the intestinal absorption of phosphorus. All phosphate binders should be administered with food and their being odourless, tasteless, easily administrable and mixable to food are important aspects. Phosphate binders are used at different doses and they vary with the patient and the serum phosphorus values to achieve. Therapy should be started at the highest dosage; then, the dose is gradually reduced in order to identify the minimum effective dose useful to mantain the serum phosphorus within the reference range. Most frequently used phosphorus binders are aluminum hydroxide, calcium carbonate and lanthanum carbonate. Clinical evidence: support the recommendation of diets with a low phosphorus content for both dogs and cats in IRIS stage 2, 3, and 4. The use of phosphorus binders is not supported by clinical trials and studies that can clearly demonstrate their efficacy and usefulness, even if there is an unanimous consensus for their use whereas the renal diet alone is not effective in controlling hyperphosphatemia.
Omega-3 fatty acids and antioxidants – dietary supplementation with omega-3 fatty acids proved its efficacy in maintaining stable renal function, reducing proteinuria and blood cholesterol and increasing survival times. In dogs and cats affected by CKD it seems a greater effectiveness is associated with a particular type of omega-3 fatty acids (EPA) found mainly in oils obtained from some fish; the efficacy of the EPA, was only noticeable respecting minimum daily quantities and when fatty acids were administered together with a renal diet. Clinical evidence: currently, there is an unanimous consensus for the recommendation of daily supplementation with omega-3 fatty acids in dogs with proteinuric CKD. Clinical trials showing the efficacy of omega-3 fatty acids in cats, are not available at the moment even if a retrospective study on the efficacy of different renal diets in cats, proved a higher survival time in cats receiving the highest daily content in omega-3.
Dehydration in patients with CKD - patients affected by CKD can develop dehydration for several reasons, even though malnourishment and a low content in fat other than vomit and diarrhea, which are often associated to uremia, should be considered the most frequent factors causing dehydration in both dogs and cats. Based on clinical and laboratory exams, the Veterinarian will suggest to hospitalize the patient to treat dehydration or, alternatively, will suggest house medical management to mantain the correct hydration of dogs and cats with CKD. Clinical Evidence: maintaining the proper hydration, associated with an adequate nutritional status, reduces the risk of hospitalization and uremic crisis in cats and dogs affected by CKD.
Hypokalemia – hypokalemia is not so common in cats with CKD in IRIS stage 2 and 3, most frequently observed in stage 4. Contrary to what happens in felines, hypokalemia is difficult to notice in dogs affected by CKD. Insufficient potassium intake with food and increased urine loss may be determinant in the development of hypokalemia. The symptoms most commonly associated with hypokalemia in cats are represented by muscle weakness which usually manifests as ventroflexion of the neck and plantigrade stance, with the patient walking resting on the tarsus. In these cases, oral supplementation with potassium leads to resolution of the symptomatology. Clinical evidence: in cats, treatment of hypokalemia is effective in improving quality of life, physical activity and intake of food.
Metabolic Acidosis– it worses quality of life in patients affected by CKD and its treatment plays an important role in the management of renal disease. Metabolic acidosis (see Terminology) causes depression, muscle weakness, fatigue, nausea and muscle mass loss in either dogs and cats with CKD. Renal diets contain alkalizing useful in controlling mild conditions of metabolic acidosis. Based on clinical and laboratory exams, the Veterinarian will suggest to hospitalize the patient to treat the acidotic condition or, alternatively, will suggest oral therapy to be administered at home. Sodium bicarbonate and potassium citrate are the products most used to treat metabolic acidosis.
Anemia – main causes of anemia are deficiencies associated with an improper diet and bleeding from the ulcers of the gastrointestinal tract, often associated to uremia; the reduced survival in the circulating blood of the red blood cells and the erythropoietin hormone deficiency also contribute to the anemic state. When controlling the above factors is not sufficient, the Veterinarian might prescribe specific therapies (recombinant human erythropoietin or its synthetic derivatives) to stimulate the production of new red blood cells by the bone marrow. Clinical evidence: there is unanimous consensus that treatment of anemia in the course of CKD is effective in improving the quality of life and patients' survival times.
Monitoring – monitoring a patient affected by CKD reveals extremely important in the early recognition of the clinical signs and laboratory abnormalities that justify changes to the ongoing therapy. The owner has a key role in monitoring some parameters as body weight, nutritional status, vomit, polyuria and polydipsia (see Terminology); any new alterations should be quickly reported to the Veterinarian. In principle, a patient with CKD which is clinically stable, properly hydrated and with a good nutritional status, should be visited once a year if in IRIS stage 1, twice a year if in stage 2, every 3 months if in stage 3 and every 6 weeks in stage 4.