Chronic Kidney Disease - The Merck Veterinary Manual

Chronic Kidney Disease

This disease process involves a loss of functional renal tissue due to a prolonged (≥3 mo), usually progressive process. Dramatic changes in renal structure may be seen, although structural and functional changes in the kidney are only loosely correlated. Chronic kidney disease often smolders for many months or years before it becomes clinically apparent, and is invariably irreversible and progressive. Although congenital disease results in a transient increase in prevalence in animals <3 yr old, the prevalence increases with advancing age from 5-6 yr. In geriatric populations at referral institutions, chronic kidney disease affects up to 10% of dogs and 35% of cats. The prevalence in the general small animal population is likely to be lower. Several breeds of dogs and cats are afflicted with heritable chronic kidney disease (see congenital and inherited anomalies of the urinary system, Congenital and Inherited Anomalies of the Urinary System: Introduction). There is no apparent breed or sex predisposition for nonheritable chronic kidney disease in dogs or cats.

Chronic kidney disease is generally classified into various stages (Table:International Renal Interest Society Classification of Stages of Kidney Disease) based on laboratory tests and clinical signs. In Stage I, a process is damaging the kidneys but azotemia and clinical signs have not developed. Unfortunately, renal disease is uncommonly detected at this stage. In Stage II, the disease has progressed, GFR has fallen to <25% of normal, and azotemia is present, but clinical signs are not yet observed. However, this stage may be associated with impaired urine-concentrating ability and increased urine volume. Stage III occurs when GFR has declined further and both azotemia and clinical signs are often present. Stage IV reflects further progression and severe azotemia, with clinical signs present. This staging system applies to both chronic and acute kidney disease.

Etiology:

Attempting to identify the primary process causing the kidney disease, especially in Stages I and II, is important to form a prognosis and treatment plan. Known causes of chronic kidney disease include diseases of the macrovascular compartment (eg, systemic hypertension, coagulopathies, chronic hypoperfusion), microvascular compartment (eg, systemic and glomerular hypertension, glomerulonephritis, developmental disorders, congenital collagen defects, amyloidosis), interstitial compartment (eg, pyelonephritis, neoplasia, obstructive uropathy, allergic and immune-mediated nephritis), and tubular compartment (eg, tubular reabsorptive defects, chronic low-grade nephrotoxicity, obstructive uropathy). Many causes of chronic, generalized renal disease are associated with progressive interstitial fibrosis. The severity of interstitial fibrosis is positively correlated to the magnitude of decline of GFR and negatively correlated with the prognosis. The glomerular, tubulointerstitial, and vascular lesions found in animals with generalized, chronic renal disease are often similar, regardless of the initiating cause. At this point, renal histology may show only marked interstitial fibrosis, which may be called chronic interstitial nephritis. This term describes the morphologic appearance of kidneys with end-stage chronic disease of any cause. Because acute kidney disease may progress to a chronic condition, any cause of acute kidney disease is also a possible cause of chronic kidney disease.

Clinical Findings:

Chronic intersitial nephritis, pig

Generally, no clinical signs are observed as a direct result of disease until ≥75% of nephron function has been impaired (Stages III and IV). Exceptions are chronic kidney diseases that develop as part of a systemic disease with clinical signs referable to involvement of other body tissues (eg, systemic lupus erythematosus, systemic hypertension) or those associated with marked renal inflammation and capsular swelling leading to flank pain and occasionally to vomiting. Clinical evaluation may identify systemic hypertension and proteinuria with the nephrotic syndrome in any stage. Usually, the earliest clinical signs commonly attributable to renal dysfunction are polydipsia and polyuria, which are not observed until the function of approximately two-thirds of the nephrons has been impaired (late Stage II or early Stage III). Further destruction of renal tissue leads to azotemia without new clinical signs in Stage II, and finally to the clinically apparent uremic syndrome in Stage IV. Initially, uremia is associated with occasional vomiting and lethargy. As disease progresses within Stages III and IV over months (dogs) to years (cats), anorexia, weight loss, dehydration, oral ulceration, vomiting, and diarrhea become fully manifest. Loose teeth, deformable maxilla and mandible, or pathologic fractures may be seen with renal secondary osteodystrophy ( Renal Secondary Hyperparathyroidism), but these are uncommon and generally observed only in young dogs with end-stage congenital renal disease. Physical examination and imaging studies of animals in Stages III and IV usually reveal small, irregular kidneys, although normal to large kidneys can be observed in animals with neoplasms, hydronephrosis, or glomerulonephritis. Mucous membranes are pale in late Stage III and Stage IV, due to the presence of a nonregenerative, normocytic, normochromic anemia.

Diagnosis:

In Stages I and II, diagnosis is often missed or made incidentally during imaging studies or urinalyses conducted for other purposes. In Stages III and IV, the BUN, serum creatinine, and inorganic phosphorus concentrations are increased. Potassium depletion, due to renal potassium wasting combined with inadequate intake and the kaliuretic effects of acidosis, is frequently seen in cats and occasionally seen in dogs. Hyperkalemia associated with oliguria and anuria may be noted in terminal Stage IV or whenever marked prerenal azotemia is superimposed on chronic kidney disease. Systemic hypertension and associated complications develop in ~20% of affected cats and dogs and can occur at any stage. Osteoporosis may be seen radiographically, although this late finding is generally not helpful for diagnosis. In healthy dogs and cats, urine specific gravity generally ranges from 1.001-1.070, depending on body needs for water homeostasis; the normal range overlaps the abnormal or inappropriate range. In dogs and cats with dehydration and normal renal function, urine specific gravity should be >1.035. The inability to produce concentrated urine when challenged by dehydration is an early sign of chronic kidney disease; however, dogs with primary glomerular disease, and some cats, may become azotemic while retaining the ability to concentrate urine to a specific gravity >1.035. Even so, concentrated urine is rarely observed when the serum creatinine is >4 mg/dL in an animal with azotemia of renal origin.

The polydipsia and polyuria of chronic kidney disease must be differentiated from diseases that cause primary polydipsia (eg, psychogenic polydipsia, hyperthyroidism) or interfere directly with the urine-concentrating mechanism. This includes conditions that lead to retention of solute in tubular fluid (eg, diuretic administration, diabetes mellitus), central diabetes insipidus, and nephrogenic diabetes insipidus (eg, hyperadrenocorticism, hypercalcemia, pyometra, diseases causing septicemia). Adrenal insufficiency leads to a urine-concentrating defect and may thus be confused with Stage II and III oliguric renal disease because prerenal azotemia may be caused by the vomiting, diarrhea, and polydipsia associated with hypoadrenocorticism. Hyperkalemia, hyponatremia, and/or reduced plasma Na+/K+ ratio is most helpful in establishing a tentative diagnosis of adrenal insufficiency, which must be confirmed by hormonal assay(s). Also, animals with hypoadrenocorticism improve rapidly in response to proper therapy.

Combinations of survey radiography, abdominal ultrasonography, serial clinical pathology tests including urinalyses and urine cultures, and blood pressure measurements should be performed to evaluate the severity of disease, establish a prognosis, monitor the response to therapy, and identify complicating factors. Specific renal function tests and renal biopsy may be helpful to identify the exact cause in Stages I-III, but the presence of advanced pathologic changes in Stage IV is nonspecific and often precludes identification of an underlying cause by histologic studies. This condition in late Stage IV is often described as end-stage renal failure clinically and as chronic, generalized nephritis pathologically. Chronic kidney disease should be distinguished from the more readily reversible acute disease. Frequently, differentiation may be accomplished with an appropriate history, physical examination, and laboratory findings, although a renal biopsy may be required (see below). However, therapy for chronic renal failure caused by a range of morphologic lesions is similar, so renal biopies may not be warranted.

Treatment:

With appropriate therapy, animals can survive for long periods with only a small fraction of functional renal tissue, perhaps 5-8% in dogs and cats. Recommended treatment varies with the stage of the disease. In Stages I and II, animals usually have minimal clinical abnormalities. Efforts to identify and treat the primary cause of the disease should be thorough. The identification and supportive treatment of developing complications (eg, systemic hypertension, potassium homeostasis disorders, metabolic acidosis, bacterial urinary tract infection) should be aggressively pursued. The systemic hypertension seen in ~20% of animals with chronic kidney disease may be observed at any stage and is not effectively controlled by feeding a low-salt diet. The usual antihypertensive medications are a calcium-channel blocker such as amlodipine besylate (0.1-0.25 mg/kg, PO, sid) or an angiotensin-converting enzyme (ACE) inhibitor such as enalapril (0.5 mg/kg, sid-bid). While these may be administered together, a calcium-channel blocker is usually recommended as initial therapy in cats and an ACE inhibitor in dogs. In addition to providing a continual supply of fresh drinking water and encouraging (and documenting) adequate dietary intake, body condition scoring should be used routinely to assess adequacy of intake. Animals in this stage should be fed standard, commercially available maintenance diets, unless they are markedly proteinuric (see below). All affected animals should be reevaluated every 3-6 mo, or sooner if problems develop.

In Stages II and III, the principles for management of complications are the same, except that the animal should be evaluated every 2-3 mo. These evaluations should include hematology, serum biochemistries, and urinalysis. Because dogs and cats with chronic kidney disease are prone to the development of bacterial urinary tract infections, urine culture should be performed twice annually or if urinalysis suggests infection. The progressive nature of this disease produces a vicious cycle of progressive renal destruction. Measures that may slow this progression include dietary phosphorus restriction (dogs and cats), dietary fish oil supplementation (dogs), antihypertensive agents (hypertensive dogs and cats), and administration of ACE inhibitors. Dietary restriction of phosphate and acid load is essential in this stage, and specialized diets for management of kidney disease should be fed. Potassium citrate or sodium bicarbonate, given PO, may be indicated if the animal is severely acidotic (plasma bicarbonate <15 mEq/L) or remains acidotic 2-3 wk after diet change. If dietary restriction of phosphorus is unsuccessful in maintaining a normal level of serum phosphorus within 2-3 mo, phosphate-binding gels containing calcium acetate, calcium carbonate, or aluminum hydroxide should be administered with meals to achieve the desired effect. In dogs only, there is a clear rationale for the inclusion of dietary n-3 polyunsaturated fatty acids in these stages.

In late Stage III and Stage IV, all of the principles of managing the preceding stages apply, except that the animal should be evaluated every 1-2 mo. Dietary restriction of protein may relieve some of the signs of uremia. High-quality protein (eg, egg protein) should be fed at a level of 2.0-2.8 g/kg/day for dogs and 2.8-3.8 g/kg/day for cats. Commercial diets formulated for cats and dogs with chronic kidney disease generally meet this recommendation. Administration of an H₂-receptor antagonist such as famotidine (5 mg/kg, PO, tid-qid) decreases gastric acidity and vomiting. Anabolic steroids, such as oxymethalone or nandrolone, have been administered to stimulate RBC production in anemic animals, but this is not effective. Recombinant erythropoietin is effective in stimulating RBC production, but antierythropoietin antibodies develop in ~50% of animals and may result in refractory anemia; until species-specific products become generally available, erythropoietin administration is now recommended only for animals showing clinically apparent signs of anemia (eg, weakness, marked lethargy not attributable to other factors), which generally occurs at a hematocrit <20%. Fluid therapy with polyionic solutions, given IV or SC in the hospital or SC by owners at home, is often beneficial in animals with intermittent signs of uremia. Although controversial, oral vitamin D administration may reduce uremic signs. However, vitamin D administration requires prior resolution of hyperphosphatemia and it may induce hypercalcemia. Feeding tubes may help manage chronic anorexia. Euthanasia or renal replacement therapy (renal transplantation and/or dialysis) should be carefully considered if therapy does not improve renal function and alleviate signs of uremia.