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Renal Disease David J. Polzin, DVM, PhD, DipACVIM Professor, U of MN, Twin Cities Visiting Professor, U of CA, Davis Chronic Kidney Disease OVERVIEW Chronic kidney disease (CKD) is the most common kidney disease in dogs and cats. Regardless of the cause(s) of nephron loss, irreversible structural lesions characterize CKD. After correcting reversible primary diseases and/or prerenal or postrenal components of renal dysfunction, further improvement in kidney function should not be expected in patients with CKD, because compensatory and adaptive changes designed to sustain kidney function have largely already occurred. However, unless additional kidney injury occurs or CKD is very advanced, rapid deterioration of intrinsic kidney function is also unusual. The magnitude of kidney dysfunction typically remains stable or slowly declines over months to years.1,2 However, it may not be necessary for the disease process responsible for the initial kidney injury to persist for progressive dysfunction to occur. Therefore, irrespective of underlying etiopathogenesis, CKD is often described as irreversible and progressive. Patients with CKD often survive for many months to years with a good quality of life. Although as yet no treatment can correct existing irreversible kidney lesions of CKD, the clinical and biochemical consequences of reduced kidney function can often be ameliorated by supportive and symptomatic therapy. In addition, therapy may be designed to interrupt mechanisms that contribute to the self-perpetuation of progressive CKD. Chronic Kidney Disease - Defining the Syndrome Kidney disease is the presence of functional or structural abnormalities in one or both kidneys. It is recognized by reduced kidney function or the presence of kidney damage. Kidney damage is defined as either: 1) microscopic or macroscopic renal pathology detected by kidney biopsy or direct visualization of the kidneys or 2) markers of renal damage detected by blood or urine tests or imaging studies (table 1).3 The severity and clinical implication of kidney disease varies greatly depending on the magnitude of kidney involvement. Kidney disease is staged (described below) to reflect these variations. Table 1 - Markers of kidney damage*
*Markers must be confirmed to be of renal origin to be evidence of kidney damage. Chronic kidney disease (CKD) is defined as: 1) kidney damage that has existed for at least three months, with or without decreased glomerular filtration rate (GFR), or 2) a reduction in GFR by more than 50% from normal persisting for at least three months. A duration of at least 3 months is used as the benchmark criterion for confirming the diagnosis of CKD based on the observation that renal compensatory hypertrophy and improvement in renal function may continue for up to Terms and Concepts Related to Kidney Disease, Kidney Failure, and Uremia Use of the terms kidney disease, kidney insufficiency, kidney failure, azotemia, and uremia as synonyms may result in misdiagnosis and formulation of inappropriate or even contraindicated therapy. It is recommended that the term kidney be used in preference to the term renal, because clients know what a kidney is, but may not know what a "renal" is. The descriptors kidney insufficiency and kidney failure have not been uniformly and adequately defined; therefore have been replaced by a CKD staging system proposed by the International Renal Interest Society (IRIS; www.iris-kidney.com). Kidney disease may affect glomeruli, tubules, interstitial tissue, and/or vessels. Some kidney diseases may be associated with dysfunction (e.g., some forms of nephrogenic diabetes insipidus and some forms of renal tubular acidosis) or biochemical abnormalities (e.g. cystinuria) without detectable morphologic alterations. Others may be associated with morphologic kidney disease (anomalies, infections, endogenous or exogenous toxin-induced lesions, immune-mediated lesions, damage caused by hypercalcemia and other mineral imbalances, traumatic lesions) that affects one or both kidneys with variable effects on kidney function. The specific cause(s) of kidney disease(s) may or may not be known; however, quantitative information about kidney function (or dysfunction) is not defined or implied by the term kidney disease; the extent of functional derangement is defined by the staging system. Azotemia is defined as an abnormal concentration of urea, creatinine, and other nonprotein nitrogenous substances in blood, plasma, or serum. Azotemia is a laboratory finding with several fundamentally different causes. Since nonprotein nitrogenous compounds (including urea and creatinine) are endogenous substances, abnormally elevated concentrations in serum may be caused by an increased rate of production (by the liver for urea; by muscles for creatinine), or by a decreased rate of loss (primarily by the kidneys). Because azotemia may be caused by factors that are not directly related to the urinary system and by abnormalities of the lower urinary tract not directly related to the kidney, azotemia should not be used as a synonym for kidney failure or uremia. Although the concentrations of serum urea nitrogen and creatinine are commonly used as crude indices of glomerular filtration rate, meaningful interpretation of these parameters depends on recognition and evaluation of prerenal, primary renal, and postrenal factors that may reduce glomerular filtration rate. Uremia is defined as (1) abnormal quantities of urine constituents in blood caused by primary generalized kidney disease and (2) the polysystemic toxic syndrome which occurs as a result of abnormal kidney function. When the structural and functional integrity of both kidneys has been compromised to such a degree that polysystemic signs of kidney failure are clinically manifested, the relatively predictable symptom complex called uremia appears, regardless of underlying cause. In some instances, uremic crises may suddenly be precipitated by prerenal disorders or, less commonly, postrenal disorders in patients with previously compensated primary kidney failure. Uremia is characterized by multiple physiologic and metabolic alterations that result from impaired kidney function. Staging Chronic Kidney Disease Patients with CKD can be categorized into stages along a continuum of progressive CKD.4 The value of staging CKD is to facilitate application of appropriate clinical practice guidelines for diagnosis, prognosis and treatment. The International Renal Interest Society (IRIS) has proposed a 4 tier system for staging CKD in dogs and cats (tables 2 and 3). Although the specific values used to categorize patients with CKD into these stages are inherently arbitrary, staging is nonetheless useful for establishing prognosis and managing patients with CKD. Table 2 - Stages of Chronic Kidney Disease in Dogs and Cats
Table 3 - Relationship Between Clinical Abnormalities and CKD Stage
The stage of CKD is assigned based on the level of kidney function. While not the only kidney function, the level of GFR is accepted as the best measure of overall kidney function in health and disease.3 Unfortunately, limitations on specificity and sensitivity of serum creatinine concentration as an estimate of GFR can lead to misclassification. Ideally, two or more serum creatinine values obtained when the patient is fasted and well hydrated should be determined over several weeks to stage CKD. Further, variations between laboratories, patient-specific characteristics (e.g. breed, age, gender, body condition and lean body mass) and transient prerenal and postrenal events may influence serum creatinine values. Reduced muscle mass, a common manifestation of advanced CKD, may result in a substantial reduction in serum creatinine concentration relative to true GFR. Greyhounds reportedly have higher serum creatinine concentrations, presumably due to their athletic nature.5 Because of these variations, published reference ranges for serum creatinine are often exceedingly broad. Using the staging system described here, some patients classified as having mild renal azotemia (stage 2) may have serum creatinine values within published reference ranges. As a consequence, the patient's overall clinical status should be considered when interpreting serum creatinine concentration and other laboratory tests and when planning patient management. By stating that stage 2 CKD in dogs begins at a serum creatinine concentration of 1.4 mg/dl and in cats 1.6 mg/dl, we have essentially increased the sensitivity of serum creatinine as a diagnostic tool for CKD; however, the specificity of the test is somewhat reduced. Stage 1 CKD includes dogs and cats with CKD that are not azotemic, while stage 2 CKD includes dogs and cats that are mildly azotemic (tables 2 and 3). Patients in these stages of CKD typically do not have clinical signs of kidney dysfunction with the exception of polyuria and polydipsia. Occasionally cats with stage 2 CKD may have weight loss or selective appetites. However, patients may have clinical signs resulting from their kidney lesions (e.g. acute pyelonephritis, nephrolithiasis). Patients with marked proteinuria or systemic hypertension due to CKD may have clinical signs related to these aspects of CKD. Renal function is often stable or only very slowly progressive for an extended period in non-proteinuric, non-hypertensive dogs and cats with stages 1 and 2 CKD. However, when progression does occur in this group of patients, it may occur largely as a consequence of their primary CKD.4 Patients with stages 1 and 2 CKD should be evaluated with the goals of identifying and providing specific treatment for their primary CKD. In addition, renal function should be monitored to assess for possible progression of their CKD. Patients with moderate azotemia are classified as stage 3 CKD. Patients in this stage may have clinical signs referable to their loss of kidney function; however, with appropriate treatment, they typically do not have clinical signs of overt uremia. Patients with stage 3 CKD may progress due to inherent mechanisms of spontaneous progression as well as their underlying CKD. Therefore, in addition to identifying and treating primary CKD, therapy designed to modify factors promoting progression of renal disease may be of benefit to these patients. Stage 4 CKD includes dogs and cats with severe azotemia (serum creatinine values greater than 5.0 mg/dl). This stage is also called chronic kidney failure and is frequently associated with clinical signs that occur as a consequence of loss of kidney function. Diagnostic and therapeutic initiatives in this stage include those appropriate for stage 3 patients as well as therapy designed to prevent or ameliorate signs of uremia. Table 4 - Classification of Proteinuria by Urine Protein:Creatinine Ratio*
* Based on ACVIM Consensus Statement on Proteinuria (Lees, 2005) It is useful therapeutically and prognostically to further subclassify patients according to their urine protein loss and systemic blood pressure. Proteinuria and hypertension may influence prognosis and may be amenable to therapeutic intervention. Classification of patients as proteinuric necessitates eliminating hemorrhage and/or inflammation as the cause for proteinuria and determination of the urine protein-to-creatinine ratio. Further, proteinuria should be shown to be persistent by reexamining the UPC ratio 2 to3 times over at least one or two months. For both dogs and cats, patients are classified as proteinuric (P) when their protein-to-creatinine ratio exceeds 0.5 and 0.4, respectively (table 4). Patients with borderline proteinuria should be re-evaluated after two months to reassess classification. In some patients, classification of proteinuria may change due to the natural course of their disease or in response to therapy. The lack of consensus as to what blood pressure values constitute hypertension in dogs and cats obfuscates any classification of patients as to their hypertension status. It is likely that "normal" blood pressure values for dogs and cats will change as more data becomes available. A 2003 ACVIM Hypertension Consensus Group has proposed the following hypertension classification system for dogs and cats. The same system is advocated by IRIS. Table 5 - Blood Pressure Risk Groups for Dogs and Cats*
* The designator complicated (c) is added to the risk level designator when evidence of end-organ hypertensive injury is present in the patient; the designator non-complicated (nc) is added to the risk level designator when no evidence of hypertensive injury is evident in the patient. Causes of Chronic Kidney Disease Chronic kidney disease may be initiated by a variety of different familial, congenital, or acquired diseases. In a study of biopsy findings in 37 dogs with primary renal azotemia, chronic tubulointerstitial nephritis was observed in 58%, glomerulonephropathy occurred in 28%, and amyloidosis was observed in 6%.11 In cats, tubulointerstitial nephritis was observed in 70%, glomerulonephropathy occurred in 15%, and lymphoma was observed in 11%, and amyloidosis occurred in 2%. Unfortunately, the initiating cause(s) of CKD often cannot be identified at the time of diagnosis. The initiating causes of diseases thought to originate in the tubulointerstitium have been especially elusive. Although bacteria can cause tubulointerstitial lesions, in our experience bacterial UTI appears more often to be a sequela of the immunocompromised condition associated with CKD than the cause. In one retrospective study of CKD cats, bacterial UTI was detected in 20% of the patients.9 Glomerulonephropathies have been linked to a variety of neoplastic, metabolic, and infectious and noninfectious inflammatory processes.12 Periodontal disease has been linked to microscopic renal lesions in dogs, but a cause and effect relationship has not been established.13 Feline immunodeficiency virus (FIV) has been linked to renal disease in cats, although few cats with CKD are FIV positive.14,15 Subcutaneous administration of feline herpesvirus 1, calicivirus, and panleukopenia virus vaccines grown in feline tissue culture systems to kittens have been shown to induce production of anti-feline renal tissue antibodies in serum (Lappin et al). This observation prompts the question as to whether repeated vaccinations play a role in development of chronic renal disease. Difficulty in detecting the inciting cause of CKD is associated with three phenomena related to the evolution of progressive renal diseases. First, various components of nephrons (glomeruli, peritubular capillaries, tubules, and interstitial tissue) are functionally interdependent. Second, the functional and morphologic responses of tissues comprising the kidneys to different etiologic agents is limited number. Third, after maturation of nephrons, which occurs at approximately one month of age, new nephrons cannot be formed to replace others irreversibly destroyed by disease. Progressive irreversible lesions initially localized to one portion of the nephron are eventually responsible for development of lesions in the remaining but initially unaffected portions of nephrons. For example, progressive lesions (such as amyloid or immune complex disease) confined initially to glomeruli will subsequently decrease peritubular capillary perfusion. Reduced peritubular capillary perfusion will in turn result in tubular epithelial cell atrophy, degeneration, and necrosis. Recent studies suggest that tubular epithelial cells may also be damaged as a consequence of glomerular proteinuria. Secondary tubular damage may be related, at least in part, to excessive tubular cell uptake of filtered proteins or protein-bound substances.16 Studies showing that the rate of disease progression correlates with the amount of proteinuria, and that therapy designed to reduce proteinuria retards progression, support the concept that glomerular proteinuria damages tubules. These processes are amplified by the secondary processes of inflammation and fibrosis. An influx of T-cells and macrophages into the interstitium may cause further tubular injury, and macrophages in particular produce profibrotic substances. Ultimately nephron destruction initiated by glomerular disease will simulate repair by substitution of functioning nephrons with nonfunctional connective tissue. Similarly, generalized progressive interstitial disease initially caused by bacteria eventually destroys tubules and glomeruli and stimulates inflammation and fibrosis. Thus, irrespective of the initiating cause, replacement of the majority of the damaged nephrons with collagenous connective tissue results in overall reduction in kidney size and impaired renal function. Because of the structural and functional interdependence of various components of nephrons, differentiation of different progressive renal diseases that have reached an advance stage is often difficult. Functional and structural changes prominent during earlier phases of progressive generalized renal diseases may permit identification of a specific cause and/or localization of the initial lesion to glomeruli, tubules, interstitium, or vessels. With time, however, destructive changes of varying severity (atrophy, inflammation, fibrosis, and mineralization of diseased nephrons), superimposed on compensatory and adaptive morphologic and functional of remaining partially and totally viable nephrons, provide a functional and morphologic similarity to the findings associated with these diseases. Despite the irreversibility of generalized renal lesions associated with CKD, it is important to formulate diagnostic plans to try to identify the underlying cause and to determine if it is still active. Although specific therapy directed at eliminating or controlling the primary cause will not substantially alter existing renal lesions, it is important in context of minimizing further nephron damage. Renal diseases potentially amenable to specific therapy include bacterial pyelonephritis, chronic urine outflow obstruction, nephrolithiasis, renal lymphoma (particularly in cats), hypercalcemic nephropathy, and some immune-mediated diseases. Acute onset of nonurinary disorders, especially those that interfere with compensatory polydipsia, may precipitate a uremic crisis may in patients with asymptomatic CKD ( so-called "acute-on-chronic" kidney disease). However, if acute decompensation of CKD has been caused by reversible factors, correction of them will often result in recompensation of the CKD. Prognosis of CKD With appropriate therapy, cats with stages 2 and 3 CKD commonly survive 1 to 3 years, while dogs with stage 3 CKD typically survive about 1 to 2 years. However, many survive much longer. A host of factors influence prognosis of CKD, both favorably and unfavorably. Included among these factors are the quality of medical care provided to the patient, the degree of interaction between the veterinarian and pet owner, and the level of owner commitment. The estimate of prognosis often influences the owner's decisions about treatment options in complying with recommendations for management of the patient. A comprehensive evaluation of the patient is the best way to establish a reasonably accurate prognosis. Prognosis for patients with CKD is usually subcategorized according to the probability of immediate survival (short-term prognosis) and survival over the subsequent months to years (long-term prognosis). A guarded prognosis indicates that the chances for recovery are unpredictable. Fair, good, or excellent prognoses indicate varying degrees of probable recovery, while poor or grave prognoses indicate that recovery is improbable or hopeless. Loss of renal function is irreversible in patients with CKD. In this context, recovery refers to improvement of biochemical deficits and excesses and amelioration of clinical signs rather than recovery of renal function. Factors to be considered in establishing meaningful prognoses for patients with CKD include; 1) the nature of the primary renal disease, 2) severity and duration of clinical signs and complications of uremia, 3) probability of improving renal function (reversibility, primarily of prerenal, postrenal, and newly acquired primary renal conditions), 4) severity of intrinsic renal functional impairment, 5) rate of progression of renal dysfunction with or without therapy, 6) age of the patient. In addition, blood pressure and the magnitude of proteinuria are risk factors influencing prognosis in dogs with CKD.17 Severity of uremic signs is often a relatively good predictor of short-term prognosis. Patients with stable CKD without clinical signs of uremia usually have a good short-term prognosis. Untreated patients with severe clinical signs of uremia typically have a guarded to poor short-term prognosis. However, it is best to determine whether renal function and clinical signs can be therapeutically improved in such cases before establishing the short-term prognosis. A uremic crisis often occurs in patients with CKD as a consequence of superimposed acute kidney injure (AKI) or prerenal or postrenal conditions (so-called acute-on-chronic uremic crisis). Although CKD is an irreversible condition, improvement of renal function is potentially possible when uremia results from the sum effects of CKD and a potentially reversible cause of azotemia. If treatment results in improved renal function and ameliorates clinical signs of uremia, the short-term prognosis often becomes guarded to good. Severity of renal dysfunction as determined by serum creatinine concentration or measurement of GFR provides a less accurate means of assessing short-term prognosis than does the clinical condition of the patient. The relationship between magnitude of renal dysfunction and clinical signs of uremia is often unpredictable. Therefore, short-term prognosis should not be established on the basis of a single measurement of the severity of renal function. In addition, a single determination of renal function is unreliable as an index of the potential for improvement in renal function, Assessment of the severity of renal dysfunction is typically more useful in establishing long-term prognoses. In general, severe renal dysfunction is associated with shorter long-term survival and, often, a lower quality of life. This generalization is supported by findings of a recent study of cats with spontaneous CKD.2 For cats with CKD without apparent clinical signs and having a mean plasma creatinine concentration of 2.6 mg/dl, mean survival was 397 days. For cats with CKD with one or more clinical signs attributable to CKD and a mean plasma creatinine concentration of 3.6 mg/dl, mean survival was 313 days. Uremic cats with a mean plasma creatinine concentration of 10.3 mg/dl survived less than 3 days. However, in a recent clinical trial in dogs with spontaneous CKD, mean serum creatinine concentration did not appear to influence survival when dogs were fed a renal diet.18 Median survival for 21 dogs with a mean serum creatinine concentration of 3.3 mg/dl was 615 days. Median survival for a subpopulation of dogs in this group with serum creatinine values between 2.0 and 3.1 mg/dl was also 615 days. However, among 17 dogs fed a maintenance diet in this study, median survival for dogs with a mean serum creatinine of 3.7 mg/dl was 252 days, while survival for the subpopulation with serum creatinine values between 2.0 and 3.1 mg/dl was 461 days. In summary, the prognosis should be established in the context of the clinical condition of the patient, rate of progression of renal dysfunction, response to therapy, cause of the underlying renal disease (if known), and other complicating factors (e.g. urinary tract infection, nephrotic syndrome, etc.). Systemic hypertension has been linked to progression of CKD in humans for decades.19 Increasing systolic blood pressure has been recently increased risk of uremic crises and death been shown to be associated with in dogs with spontaneous CKD.17 In this study, systolic blood pressure values determined at the time of initial patient evaluation was compared to long-term outcome. Increased risk of developing a uremic crisis and of death was observed in the patients with the highest blood pressure values. In addition, a greater decline in renal function over time was observed in these dogs. While this study was not designed to prove a cause-and-effect relationship between hypertension and progressive renal disease, it does indicate that initial blood pressure values should be considered in formulating a prognosis for dogs with CKD. The prognostic significance of blood pressure values in cats with CKD has yet to be established. Results of a clinical trial from the University of Minnesota Veterinary Medical Center revealed that proteinuria may be a risk factor for uremia and death in dogs with spontaneous CKD.(Jacob et al 2004) In this study, the risk of death associated with CKD increased by 60% for each unit of urine protein-to-creatinine ratio above 1.0. Whether proteinuria conferred this adverse risk as an independent mediator of renal injury or as a consequence of the biological behavior of glomerular diseases is unclear. In dogs, glomerulopathies have been associated with poor long-term prognoses.12 This may be related to the observation that proteinuria has been implicated in promoting progressive renal injury.20 Therapeutic amelioration of proteinuria using angiotensin converting enzyme inhibitors may stabilize renal function in humans and dogs with glomerular disease, further suggesting a likely role for proteinuria in the progression of CKD.21 A similar relationship between proteinuria and progression of CKD has been observed in cats. (Syme, 2003) Compared to the rate of progression of CKD in middle aged to older dogs with acquired renal disease, CKD often progresses at a much slower rate in dogs with congenital and familial nephropathies such as renal dysplasia. A comparably slower rate of progression has also been observed in young dogs with acquired CKD (e.g. following nephrotoxin exposure). Many of these patients appear remarkably resistant to developing clinical signs of uremia despite substantial elevations in serum creatinine and urea nitrogen concentrations. CLINICAL CONSEQUENCES OF CHRONIC KIDNEY DISEASE Uremia Uremia is the clinical state toward which all progressive, generalized renal diseases ultimately converge. Diverse clinical and laboratory findings characterize uremia and emphasize the polysystemic nature of CKD. The term uremia was adopted originally because of the presumption that all of the abnormalities result from retention in the blood of end-products of metabolism normally excreted in the urine. However, uremia involves more than renal excretory failure alone. A variety of metabolic and endocrine functions normally performed by the kidney are also impaired, resulting in anemia; malnutrition; impaired metabolism of carbohydrates, fats, and proteins; defective utilization of energy; alterations in immunity and metabolic bone disease. Urea, once thought to be "the" uremic toxin, is not a major cause of uremic toxicity, although it may contribute to some of the clinical abnormalities, including anorexia, malaise, and vomiting. Numerous nitrogenous compounds with a molecular mass of 500 to 12,000 Daltons (so-called middle molecules) are retained in CKD and appear to contribute to morbidity and mortality in uremic subjects.22 In addition to impaired excretion, many middle-sized molecules along with various cytokines and growth factors accumulate in CKD because the kidney's capacity for catabolizing many substances is also impaired. Further, plasma levels of many polypeptide hormones, including parathyroid hormone (PTH), insulin, glucagon, luteinizing hormone, and prolactin, increase in patients with CKD because of impaired renal catabolism as well as enhanced glandular secretion. Gastrointestinal Consequences Gastrointestinal complications are common and prominent clinical signs of uremia. Anorexia and weight loss are non-specific findings that may precede other signs of uremia in dogs and cats. The patient's appetite may be selective for certain foods, and it may wax and wane throughout the day. Factors promoting weight loss and malnutrition include anorexia, nausea, vomiting and the subsequent reduction in nutrient intake, hormonal and metabolic derangements, and catabolic factors related to uremia, particularly acidosis. Anorexia appears to be multifactorial in origin. Recent research, using a rodent model, has suggested that an "anorectic factor" in the plasma of uremic patients that can suppress appetite.23 It appears to be a middle molecule in size and may be a peptide. Elevated serum leptin concentrations have also been implicated as a factor contributing to anorexia.24 Vomiting is a frequent, but inconsistent finding in uremia. It results from the effects of as yet unidentified uremic toxins on the medullary emetic chemoreceptor trigger zone and from uremic gastroenteritis. The severity of vomiting correlates crudely with the magnitude of azotemia. Because uremic gastritis may be ulcerative, hematemesis may occur. Vomiting may be a more frequent complaint in uremic dogs than cats. Nonetheless, vomiting is reportedly found in one quarter to one third of cats with clinical signs of uremia.2 Vomiting may impair compensatory polydipsia enhancing the risk of dehydration and exacerbating prerenal azotemia and clinical signs of uremia. Uremic gastropathy is characterized microscopically by glandular atrophy, edema of the lamina propria, mast cell infiltration, fibroplasia, mineralization, and submucosal arteritis. Elevated gastrin levels have been implicated in development of uremic gastropathy.25 Gastrin induces gastric acid secretion directly by stimulating receptors located on gastric parietal cells as well as by increasing histamine release from mast cells in the gastric mucosa. Enhanced histamine release may also promote gastrointestinal ulceration and ischemic necrosis of the mucosa through a vascular mechanism characterized by small venule and capillary dilatation, increased endothelial permeability, and intravascular thrombosis.26 Because up to 40% of the circulating gastrin is metabolized by the kidneys, reduced renal function may promote hypergastrinemia. Elevated gastrin levels have been documented in cats with spontaneous CKD.25 Although the prevalence of hypergastrinemia appeared to increase as renal dysfunction become more severe, there was great variability of gastrin levels among cats with similar degrees of renal dysfunction, suggesting that additional factors in addition to the degree of renal impairment likely affect serum gastrin levels in CKD. Gastrin-induced gastric hyperacidity may lead to uremic gastritis, gastrointestinal hemorrhage, and nausea and vomiting. Back diffusion of hydrochloric acid and pepsin into the stomach wall may lead to hemorrhage, inflammation, and release of histamine from mast cells. Thus, the cycle may be perpetuated as mast-cell derived histamine causes further stimulation of parietal cells to produce hydrogen ions. However, gastric hyperacidity is not universally found with uremic gastritis. Some human uremic patients have hypochlorhydria. Thus, hypergastrinemia is not the only reason for uremic gastritis. Other factors implicated in the genesis of uremic gastropathy include: psychological stress related to illness, an increase in proton back-diffusion caused by high urea levels, erosions caused by ammonia liberated by bacterial urease acting on urea, ischemia caused by vascular lesions, decreased concentration and turnover of gastric mucous, and biliary reflux due to pyloric incompetence (which may be an indirect consequence of elevated gastrin levels). In a recent study of 80 cats with spontaneous CKD, dysphagia and oral discomfort occurred in 7.7% of uremic cats and 38.5% of cats with end-stage CKD.2 Periodontal disease was observed in 30.8% of uremic and 34.6% of end-stage CKD cats in the same study. Halitosis was reported in 7.7% of cats in both groups. Moderate to severe CKD may result in uremic stomatitis characterized by oral ulcerations (particularly located on the buccal mucosa and tongue), brownish discoloration of the dorsal surface of the tongue, necrosis and sloughing of the anterior portion of the tongue (associated with fibrinoid necrosis and arteritis), and uriniferous breath. The mucous membranes may also become dry (xerostomia). Degradation of urea to ammonia by bacterial urease may contribute to many of these signs. Poor oral hygiene and dental disease may exacerbate the onset and severity of uremic stomatitis. Uremic enterocolitis, manifested as diarrhea, may occur in dogs and cats with severe uremia, but it is typically less dramatic and less common than uremic gastritis. Owners of 80 cats with spontaneous CKD did not report diarrhea.2 However, when present, uremic enterocolitis is often hemorrhagic. Considerable gastrointestinal hemorrhage may initially escape clinical detection. Intussusception may occasionally complicate uremic enterocolitis. Constipation is a relatively common complication of CKD, particularly in cats. It appears to be primarily a manifestation of dehydration, but can occur as a complication of intestinal phosphate binding agents. Impaired Urine Concentrating Ability, Polyuria, Polydipsia, and Nocturia Among the earliest and most common clinical manifestations of CKD is onset of polyuria, polydipsia, and sometimes nocturia due to reduced urine concentrating ability. Polydipsia was the single most commonly reported clinical sign reported in a study of 80 cats with CKD. Cat owners recognized polydipsia over twice as often as polyuria. Although urine specific gravity values of cats in stages 2, 3 and 4 CKD are usually below 1.035, the authors have seen cats that have remained persistently (up to 18 months) azotemic prior to losing adequate concentrating ability (i.e. specific gravity> 1.040). A decrease in adequate urine concentrating ability results from several factors including: increased solute load per surviving nephron (solute diuresis), disruption of the renal medullary architecture and counter-current multiplier system by disease, and primary impairment in renal responsiveness to antidiuretic hormone. Loss of renal responsiveness to antidiuretic hormone may result from an increase in distal renal tubular flow rate, which limits equilibration of tubular fluid with the hypertonic medullary interstitium. Additionally, ADH-stimulated adenyl cyclase activity and water permeability in the distal nephron may be impaired in uremia.27 Polydipsia is of course a compensatory response to polyuria. If fluid intake fails to keep pace with urinary fluid losses, dehydration will ensue because of the inability to conserve water by concentrating urine. Dehydration subsequent to inadequate fluid intake is a common problem in cats with CKD. Arterial Hypertension and Cardiovascular Consequences Hypertension may be either a cause or consequence of CKD. When present, it may adversely affect long-term prognosis.17 It is a common complications of CKD, reportedly occurring in up to 66% of cats with CKD.28 Although one recent study suggested that hypertension may be unusual in dogs with CKD,29 other studies have reported incidences of from 30 to 93% of dogs with CKD.17,29 Dogs with glomerular diseases are at increased risk for hypertension. Neuromuscular Consequences ENCEPHALOPATHIES AND NEUROPATHIES Metabolic encephalopathies and peripheral neuropathies may occur in dogs and cats with uremia.30,31 It is reported that as many as 65% of dogs and cats with primary renal insufficiency/failure have neurological manifestations. Of dogs with neurological signs, altered consciousness (31% of patients) and seizures (29% of patients) were the most common signs.31 In our experience, acute onset of altered mentation is an important neurological finding in dogs and cats with CKD that typically heralds a poor short-term prognosis. Other common signs include limb weakness, ataxia and tremors. Patients may develop what has been described as the "twitch-convulsive" state wherein there is the simultaneous combination of tremor, myoclonus, and seizures. In advanced CKD, patients may have neurologic signs that are cyclical and episodic, varying from day to day. The severity and rate of progression of neurological signs appears to vary directly with the rapidity with which CKD develops. The pathogenesis of uremic neurological signs remains unclear, but important roles for parathyroid hormone and the uremic environment are suspected.30 Both the sodium potassium adenosine triphosphate pump and several of the calcium pumps are altered in uremia. Alterations in the calcium pumps have been thought to be due at least in part to PTH acting through monophosphate-independent pathways. Calcium pumps are particularly suspected of playing a role in uremic encephalopathy because they mediate neurotransmitter release and information transfer at nerve terminals. Clinical signs of tremors, myoclonus, and tetany may develop due to hypocalcemia. Arterial hypertension may also lead to neurologic signs in patients with otherwise well-controlled CKD. Clinical signs are acute in onset and may include seizures, behavioral changes, dementia, isolated cranial nerve deficits, and death. In our experience, many of the patients with acute onset of neurological signs also had hypertension. Imbalances of neurotransmitter amino acids within the brain have also been implicated in uremic encephalopathy. Analysis of cerebrospinal fluid in humans with uremic encephalopathy has shown decreased levels of glutamine and GABA, and increased levels of glycine, dopamine, and serotonin. MYOPATHIES Hypokalemic polymyopathy is occasionally observed in association with CKD, primarily in cats. Because of the impact of potassium on resting cell membrane potentials, potassium imbalances typically manifest clinically as neuromuscular dysfunction. Hypokalemia increases the magnitude (i.e. increases electronegativity) of the resting potential, thereby hyperpolarizing the cell membrane making it less sensitive to exciting stimuli. The cardinal and most dramatic sign of hypokalemia, regardless of cause, is generalized muscle weakness. In hypokalemic polymyopathy, muscle weakness and pain present clinically as cervical ventroflexion and a stiff, stilted gait.32 Mild cardiac rhythm disturbances may also occur. Serum creatinine kinase and other muscle enzyme activities may be elevated, and in severe instances, rhabdomyolysis may occur. Muscle dysfunction unrelated to serum potassium concentrations may also occur in uremia. In humans with CKD, accumulation of a dialyzable uremic toxin derived from dietary protein has been shown to promote abnormalities in sarcolemma ion flux leading to reduced muscle membrane potential. Hematological Consequences ANEMIA The anemia of CKD is usually characterized by normochromic and normocytic red blood cells. There is usually hypoplasia of the erythroid precursors in the bone marrow with little or no interference with normal leukopoiesis and megakaryocytopoiesis. On blood smears, spiculed and deformed red cells (burr cells or echinocytes) may be noted. Although affected by the patient's age, species, specific renal diagnosis, and concurrent diseases, the severity and progression of the anemia correlates with the degree of CKD and worsens with progressive CKD in both dogs and cats.33 The hematocrit may become profoundly low. At these low hematocrits, compensatory mechanisms such as increased levels of 2,3 DPG, lowered peripheral vascular resistance and an elevated cardiac output (in the absence of previous cardiac disease) help maintain tissue oxygenation. Clinical signs of anemia include pallor of the mucous membranes, fatigue, listlessness, lethargy, weakness, and anorexia. Anemia in patients with CKD is multifactorial and may be exacerbated by concurrent illness. Although experimental and clinical evidence exists for the supporting roles of shortened red cell life span, nutritional abnormalities, erythropoietic inhibitor substances in uremic plasma, blood loss, and myelofibrosis, erythropoietin deficiency has clearly emerged as the principal cause of anemia in humans and animals with CKD. The renal peritubular capillary endothelial cells are the major source of erythropoietin synthesis. It may also be produced by renal interstitial fibroblasts. The kidneys synthesize erythropoietin on demand in response to intrarenal tissue hypoxia due either to decreased oxygen carrying capacity (anemia) or decreased oxygen content (hypoxia). Many CKD patients have a relative, rather than absolute, erythropoietin deficiency in that plasma levels exceed the normal range.34 However, when compared with equivalently anemic but non-uremic patients, plasma erythropoietin concentrations are lower. Anemic CKD cats have been reported to have plasma erythropoietin concentrations similar to normal cats.35 Erythropoietin deficiency of CKD has been hypothesized to result from decreased renal mass resulting in an insufficient cellular capacity for new hormone synthesis. Other clinically important causes for anemia in dogs and cats with CKD are iron deficiency and chronic gastrointestinal blood loss. In most patients, iron deficiency can only be detected by measuring serum iron, staining bone marrow biopsy samples for iron content, or through response to iron supplementation. Chronic gastrointestinal hemorrhage may occur even in the absence of characteristic color changes in the feces. It can be suspected on the basis of a hematocrit level that is unexpectedly low relative to the magnitude of renal dysfunction, and an elevation in the serum urea nitrogen to serum creatinine ratio. HEMORRHAGIC CONSEQUENCES OF UREMIA Uremia may be associated with a hemorrhagic diathesis that is characterized by as bruising, gastrointestinal hemorrhage with hematemesis or melena, bleeding from the gums, or hemorrhage subsequent to venipuncture. Gastrointestinal hemorrhage can be an important route of blood loss leading to anemia and exacerbating azotemia and uremia. In CKD, bleeding results from an acquired qualitative platelet defect, abnormalities in the interaction of platelets and the vessel wall, and biochemical and rheologic abnormalities in the blood itself.36 Uremic platelet dysfunction appears to be multifactorial in origin. The platelet count is usually within the normal range or mildly decreased. Abnormal platelet aggregability, diminished thromboxane-A2 production, abnormal intracellular calcium mobilization, and increased intracellular cAMP have been described in uremic platelets.36 Abnormal glycoprotein function may impair platelet adhesiveness to the subendothelium. In addition, uremia may be associated with increased release of prostacyclin and nitric oxide, which may also impair adhesion of platelets to the endothelium. The largest polymers of von Willebrand's factor, which predominate in the platelet adhesion process, are decreased in uremia. Uremic toxins have also been implicated in impairing platelet function. For example, elevated levels of plasma guanidinosuccinic acid, interfere with activation of platelet factor III by ADP, thus leading to abnormal platelet function. Administration of desmopressin (DDAVP) has been shown to shorten bleeding times and improve clinical bleeding in uremic humans.36 DDAVP is thought to stimulate release of large multimeric von Willebrand's factor complexes from endothelial cells and platelets. Unfortunately, development of tachyphylaxis often limits usefulness of DDAVP after 2 or 3 doses. Alternative therapies have included administration of cryoprecipitates or conjugated estrogens, which may have similar effects. Increasing hematocrit values to above 30 by transfusion or administration of erythropoietin has also been shown to improve bleeding times in humans. Increasing hematocrit may improve bleeding times by a rheological effect or by increasing hemoglobin concentrations which may in turn inactivate the platelet-inhibiting effects of nitric oxide. Renal Secondary Hyperparathyroidism INCIDENCE AND PATHOPHYSIOLOGY In a recent study of cats with spontaneous CKD, the overall prevalence of renal secondary hyperparathyroidism was 84%.37 Hyperparathyroidism occurred in 100% of cats with end-stage CKD and 47% of asymptomatic cats with only biochemical evidence of CKD. Hyperparathyroidism was even detected in some cats with normal serum calcium and phosphrous concentrations. Plasma PTH concentrations have been reported to increase as serum creatinine concentrations increase.38 The pathogenesis of hyperparathyroidism in CKD is multifactorial. Renal secondary hyperparathyroidism occurs in association with phosphorous retention, hyperphosphatemia, low circulating 1,25-dihydroxyvitamin D (calcitriol) levels, reduced blood ionized calcium concentration, and skeletal resistance to the calcemic action of PTH. However, in early to moderate CKD, it is difficult to dissect out the specific factors responsible for hyperparathyroidism because the increase in PTH serves to prevent hypocalcemia, hyperphosphatemia, and the decrease in calcitriol formation.39 Phosphorous retention and hyperparathyroidism develop early in CKD while serum calcium and phosphorus concentrations remain within normal limits.40 Phosphorous retention is intimately related to development of secondary hyperparathyroidism.41,42 Relative or absolute deficiency of calcitriol has been hypothesized to play a pivotal role in development of renal secondary hyperparathyroidism.43 Calcitriol, the most active form of vitamin D, is formed by 1 -hydroxylation of 25-hydroxycholecalciferol in renal tubular cells. Parathyroid hormone promotes renal 1 -hydroxylase activity and formation of calcitriol. In turn, calcitriol limits PTH synthesis by feedback inhibition. Phosphrous retention inhibits renal 1 -hydroxylase activity. Early in the course of CKD, the inhibitory effects of phosphrous retention on renal tubular 1 -hydroxylase activity limits calcitriol production. Because calcitriol normally inhibits PTH synthesis, reduced calcitriol synthesis promotes renal secondary hyperparathyroidism. Initially, the resultant hyperparathyroidism increases 1 -hydroxylase activity despite continued phosphorous retention, thereby restoring calcitriol production toward normal. However, normalization of calcitriol production occurs at the expense of persistently elevated plasma PTH activities - a classic example of the "trade-off hypothesis." As CKD progresses, loss of viable renal tubular cells ultimately limits renal calcitriol synthetic capacity and calcitriol levels subsequently remain low. Deficiency of calcitriol leads to skeletal resistance to the action of PTH and elevates the set-point for calcium-induced suppression of PTH secretion. Skeletal resistance to PTH limits skeletal release of calcium, while elevating the set-point for PTH secretion allows hyperparathyroidism to persist even when plasma ionized calcium concentrations are normal or elevated.38,43 Recent evidence suggests that phosphorous retention may also play a primary role in promoting hyperparathyroidism. Phosphorous has been shown to stimulate PTH secretion in parathyroid cultures.44 Further, phosphorous restriction in dogs and humans with CKD has been shown to decrease PTH secretion without changing serum calcitriol levels.45,46 In untreated human patients with mild to moderate CKD (serum creatinine concentration ? 3.0 mg/dl), serum phosphrous concentrations correlated directly with PTH, independent of serum calcium and 1,25-dihydroxyvitamin D levels.47 Interestingly, this correlation was present despite the fact that most patients had serum phosphorous concentrations within the normal range. Notably, in both humans and cats, overt hyperphosphatemia may not be a prerequisite for phosphorous to have an effect on PTH secretion.37,47 It has been suggested that high phosphorous intake may accentuate uremia-induced abnormal phosphorous metabolism causing increased parathyroid cell phosphorous concentration.47 In vitro studies have suggested that parathyroid glands exposed to elevated phosphorous levels respond by increasing PTH secretion.44 Reduced 1,25-dihydroxycholecalciferol may have a permissive effect and/or an additional direct effect on PTH secretion in this setting.47 In more advanced CKD, only serum calcium concentration correlated with serum PTH activity.47 Impaired intestinal absorption of calcium due to low serum calcitriol levels likely plays an important role in hyperparathyroidism in these advanced CKD patients. Blood ionized calcium concentrations are often reduced in cats with spontaneous CKD; in one study, over 50% of cats with advanced end-stage CKD were hypocalcemic.37 CLINICAL CONSEQUENCES Although renal secondary hyperparathyroidism and renal osteodystrophy, are well documented effects of CKD, clinical signs associated with renal osteodystrophy are uncommon in dogs and cats. In dogs, it most often occurs in immature patients, presumably because metabolically active growing bone is more susceptible to the adverse effects of hyperparathyroidism. For unexplained reasons, bones of the skull and mandible may be the most severely affected and may become so demineralized that the teeth become moveable and fibrous changes are obvious, particularily in the maxilla. Marked proliferation of connective tissue associated with the maxilla may cause distortion of the face. Jaw fractures can occur but are uncommon. Other possible but uncommon clinical manifestations of severe renal osteodystrophy include, cystic bone lesions, bone pain, and growth retardation. Although excessive levels of PTH affect bones and kidneys, it affects the function of other organs and tissues, including brain, heart, smooth muscles, lungs, erythrocytes, lymphocytes, pancreas, adrenal glands, and testes as well.48 Toxicity of PTH appears to be mediated through enhanced entry of calcium into cells with PTH or PTH2 membrane receptors. Sustained PTH-mediated calcium entry leads to inhibition of mitochondrial oxidation and production of ATP. Extrusion of calcium from cells is reduced because of the impairment in ATP production and disruption of the sodium-calcium exchanger. Persistently increased basal cytosolic calcium levels promote cellular dysfunction and death.38 Potential non-skeletal clinical consequences of hyperparathyroidism include mental dullness and lethargy, weakness, anorexia, and an increased incidence of infections due to immunodeficiency.38 Hyperparathyroid-induced cellular dysfunction may lead to carbohydrate intolerance, platelet dysfunction, impaired cardiac and skeletal muscle function (due to impaired mitochondrial energy metabolism and myofiber mineralization), inhibition of erythropoiesis, altered red cell osmotic resistance, altered B cell proliferation, synaptosome and T-cell dysfunction, and defects in fatty acid metabolism.38,49 Excess PTH levels may also promote nephrocalcinosis and consequent progressive loss of renal function.38 Renal secondary hyperparathyroidism may be associated with substantial enlargement of the parathyroid glands. This finding may be of clinical importance in cats because of frequent coincident hyperthyroidism that may be suggested by the presence of a thyroid nodule palpable in the cervical region. In a recent report, hyperplastic parathyroid glands were palpable as paratracheal masses in 11 of 80 cats with spontaneous CKD.2 Care should be taken to confirm hyperthyroidism prior to treatment as both hyperparathyroidism and hyperthyroidism can lead to paratracheal masses. Plasma PTH concentrations should be determined by methods that measure intact PTH using a two-site immunoradiometric or immunochemiluminometric assay. The two-site method utilizes antibodies directed against two different regions of the intact PTH molecule. A commercially available two-site immunoradiometric assay (Allegro Intact PTH; Nichols Institute Diagnostics, USA) has been validated for use in dogs and cats. Only intact PTH will be recognized because it will be the only form of the peptide to have both determinants. Older midregion PTH assays typically detect those species of hormone containing amino acids 43-68 of the PTH molecule. However, because renal insufficiency/failure results in reduced renal clearance of the non-biologically active midregion PTH fragments, these methods do not accurately reflect parathyroid glandular secretion. Thus, renal secondary hyperparathyroidism is best monitored by use of a two-site assay for intact hormone. Laboratory Findings METABOLIC ACIDOSIS Metabolic acidosis is a common manifestation of CKD. It results primarily from the limited ability of failing kidneys to excrete hydrogen ions, because of reduced ammoniagenesis, decreased filtration of phosphate and sulfate compounds, and decreased maximal renal tubular proton secretion.50 Impaired renal tubular reabsorption of filtered bicarbonate may also contribute to acidosis. Bicarbonate wasting and chloride retention results in hyperchloremic (normal anion gap) acidosis. When phosphorous and organic acid (uric acid, hippuric acid, lactic acid) retention is sufficient, high anion gap acidosis results. A combination of tubular reabsorption of filtered bicarbonate and excretion of hydrogen ions with ammonia and urinary buffers, primarily phosphorous, maintain normal acid-base balance. As renal function declines, hydrogen ion excretion is maintained largely by increasing the quantity of ammonium excreted by surviving nephrons. However, at some level of renal dysfunction, the capacity to further increase renal ammoniagenesis is lost and metabolic acidosis ensues. Decreased medullary recycling of ammonia due to structural renal damage may also contribute to impaired ammonium excretion. Chronic metabolic acidosis may promote a variety of adverse clinical effects including anorexia, nausea, vomiting, lethargy, weakness, muscle wasting, weight loss, and malnutrition. Alkalization therapy is often of value in reversing these signs. In addition, chronic mineral acid feeding to dogs has been shown to increase urinary calcium excretion and progressive bone demineralization, the magnitude of which depends on age and dietary calcium levels. Studies on the effects of dietary acidification in cats have revealed that chronic metabolic acidosis can cause negative calcium balance and bone demineralization or negative potassium balance which may in turn promote hypokalemia, renal dysfunction, and taurine depletion.51 Severe acidemia may result in decreased cardiac output, arterial pressure, and hepatic and renal blood flows and centralization of blood volume.52 Centralization of blood volume results from peripheral arterial vasodilatation and central venoconstriction. Decreases in central and pulmonary vascular compliance may predispose patients to pulmonary edema during fluid administration, an effect that may be particularly important in patients with acute uremic crises requiring intensive fluid therapy. Acidemia also promotes re-entry arrhythmias and a reduction in the threshold for ventricular fibrillation. Severe acidosis may also influence carbohydrate and protein metabolism, serum potassium concentrations, and brain metabolism. Chronic acidosis may promote protein malnutrition in patients with CKD. Protein catabolism is increased in patients with acidosis to provide a source of nitrogen for hepatic glutamine synthesis, glutamine being the substrate for renal ammoniagenesis.53 The combined effects of reduced protein synthesis due to uremia and accelerated proteolysis due to acidosis promote elevations in blood urea nitrogen, increased nitrogen excretion, and negative nitrogen balance typical of uremic acidosis. Altered branched chain amino acid metabolism appears to be involved. Chronic metabolic acidosis increases the activity of muscle branched chain keto acid dehydrogenase, the rate-limiting enzyme in branched chain amino acid catabolism. This is important in that branched chain amino acids are rate limiting in protein synthesis and play a role in regulation of protein turnover. Alkalization therapy effectively reverses acidosis-associated protein breakdown. There is speculation that changes in intracellular pH accompanying acidosis lead to alterations in gene transcription which increase the activity of the cytosolic, ATP- and ubiquitin-dependent protein degradation pathway. Severe chronic metabolic acidosis has the potential to induce a cycle of progressive protein malnutrition and metabolic acidosis. Excessive protein catabolism may lead to protein malnutrition despite adequate dietary intake. This process may then accelerate breakdown of endogenous cationic and sulfur-containing amino acids, thus promoting further acidosis. Acidosis poses a particularly vexing problem for CKD patients consuming protein-restricted diets. Dietary protein requirements appear to be similar for normal humans and humans with CKD unless uremic acidosis is present. When acid-base status is normal, adaptive reductions in skeletal muscle protein degradation protect patients consuming low-protein diets from losses in lean body mass. Metabolic acidosis blocks the metabolic responses to dietary protein restriction in two ways: 1) it stimulates irreversible degradation of the essential, branched chain amino acids and 2) it stimulates degradation of protein in muscle.53 Thus, acidosis may limit the ability of patients to adapt to dietary protein restriction. Metabolic acidosis also suppresses albumin synthesis in humans and may reduce the concentration of serum albumin. These findings have not yet been confirmed in dogs and cats. AZOTEMIA Azotemia is defined as an excess of urea or other non-protein nitrogenous compounds in the blood. Loss of renal function leads to accumulation of a wide variety of non-protein nitrogen-containing compounds, including urea and creatinine. Many waste products of protein catabolism are excreted primarily by glomerular filtration. Thus, patients with primary CKD have impaired ability to excrete proteinaceous catabolites because of marked reduction in glomerular filtration rate. Retention of metabolic waste may be further aggravated by impaired tubular secretion, and by extrarenal factors that promote renal hypoperfusion and increased catabolism of body tissues. While accumulation of wastes is largely the result of decreased renal excretion or increased protein catabolism, production of some compounds may also be increased (e.g. guanidine). Since these compounds are derived almost entirely from protein degradation, their production increases when dietary protein increases. Urea is synthesized using nitrogen derived from amino acid catabolism. Urea may be excreted by the kidneys, retained in body water, or metabolized to ammonia plus carbon dioxide by bacteria in the gastrointestinal tract. Ammonia produced in the gastrointestinal tract is recycled to urea in the liver yielding no net loss of nitrogen or urea. Regardless of whether urea per se is toxic, BUN concentrations are typically directly related to the protein content of the diet. Further, in patients with CKD, BUN concentrations tend to correlate reasonably well with clinical signs of uremia. For practical purposes, BUN may thus be viewed as a marker of retained "uremic toxins." In addition to increasing protein intake and declining renal function, BUN concentrations may also be increased by gastrointestinal hemorrhage, enhanced protein catabolism, decreasing urine volumes (due to prerenal factors such as dehydration), and certain drugs (eg. glucocorticoids). Urea nitrogen concentrations may decline with portosystemic shunts, hepatic failure, and low protein diets. Reduced BUN concentration may also indicate protein calorie malnutrition. Because many extrarenal factors may influence BUN concentration, creatinine is often used as a more reliable measure of GFR in patients with CKD. Blood urea nitrogen concentrations should be interpreted with knowledge of simultaneously obtained serum creatinine values, particularly in patients consuming reduced protein diets. The ratio of BUN to serum creatinine concentration should decline when dietary protein intake is reduced. In patients consuming reduced protein diets, an increase in the ratio of BUN to serum creatinine concentrations may suggest poor dietary compliance, enhanced protein catabolism, gastrointestinal hemorrhage, dehydration, anorexia or declining muscle mass. HYPERPHOSPHATEMIA The kidneys play a pivotal role in regulating phosphorus balance because they are the primary route of phosphorus excretion. Renal phosphorus excretion is the net of glomerular filtration less tubular reabsorption of phosphorus. If dietary phosphorus intake remains constant, a decline in glomerular filtration rate will lead to phosphorus retention and ultimately hyperphosphatemia. However, during the early stages of CKD, serum phosphorus concentrations typically remain within the normal range because of a compensatory decrease in phosphorous reabsorption in the surviving nephrons. This renal tubular adaptation is largely an effect of renal secondary hyperparathyroidism. Increased parathyroid hormone (PTH) levels promote renal excretion of phosphorous by reducing the tubular transport maximum for phosphorous reabsorption in the proximal tubule via the adenyl cyclase system. When glomerular filtration rates decline below about 20% of normal, this adaptive effect is maximized and hyperphosphatemia ensues. In dogs with CKD, serum phosphorus concentrations typically parallel serum urea nitrogen concentrations. Thus hyperphosphatemia is common in azotemic patients, but unexpected in patients with non-azotemic renal disease. The primary consequence of hyperphosphatemia is development and progression of secondary hyperparathyroidism. Increases in serum PTH activities in dogs and humans with CKD are closely associated with the degree of hyperphosphatemia (figure 2).38,47 Hyperphosphatemia was found to be 72% efficient in predicting hyperparathyroidism in cats with CKD.37 The combination of hyperphosphatemia and a normal plasma calcium concentration produces an elevated calcium-phosphate product (Ca X PO4 in units of mg/dL). If the calcium-phosphate product exceeds approximately 70, there is a tendency for calcium phosphate to precipitate in arteries, joints, and soft tissues. This process is commonly called metastatic calcification. Calcification is especially prominent in proton-secreting organs, such as the stomach and kidneys, in which basolateral bicarbonate secretion results in an increase in pH that promotes calcium hydrogen phosphate (brushite) precipitation.54 However, myocardium, lung, and liver are also commonly mineralized in patients with CKD. Hyperphosphatemia has been directly linked to increased mortality in humans and dogs with CKD.55,56 In humans with CKD receiving hemodialysis therapy, the adjusted relative risk of mortality was stable in patients with serum phosphorous concentrations below 6.5 mg/dl, but increased significantly above this level.55 Patients with serum phosphorous in the 6.6-to 7.8-mg/dl range had 13% higher mortality than patients in the reference range (4.6 to 5.5 mg/dl). Patients in the 7.9-to 16.9-mg/dl range had a relative mortality risk 34% higher than patients in the reference range. Mild hyperphosphatemia (5.0 to 6.5 mg/dl) was not associated with an elevated mortality risk. The calcium X phosphorous product showed a mortality risk trend similar to that seen for phosphate with patients with Ca X PO4 products greater than 72 having a relative mortality risk of 1.34 relative to products between 42 and 52 mg2/dL2.55 Mortality risk associated with hyperphosphatemia appeared to be independent of elevated PTH levels, which alone appeared to have only a weak association with mortality. However, the statistical association between PTH and mortality may have been impaired by use of multiple methods for PTH assay in the patients studied. Analysis of calcium revealed no correlation with relative risk of death. HYPERCALCEMIA, HYPOCALCEMIA, AND HYPERMAGNESEMIA Hypocalcemia is a common disorder of calcium found in patients with CKD. In a recent report, ionized hypercalcemia was detected in 6% and ionized hypocalcemia in 26% of 80 cats with spontaneous CKD.37 Further, mean blood ionized calcium concentration was significantly lower in CKD cats in this study than in normal control cats, and over half of the cats with advanced end-stage CKD were hypocalcemic. However, when these same 80 cats were evaluated using total serum calcium concentrations, hypercalcemia was found in 21% of the cats, while hypocalcemia was detected in only 8%. Clearly, serum total calcium concentrations do not reliably reflect ionized calcium concentrations in cats with CKD. Similar discrepancies have been observed in dogs with CKD.57 The mechanism of serum total hypercalcemia in the face of normal to reduced blood ionized calcium concentrations is unclear, but may be related to increased concentrations of calcium complexed to retained organic and inorganic anions such as citrate, phosphate, or sulfate. In patients with hypercalcemia, it is important to ascertain whether hypercalcemia is the cause, rather than result of CKD. Hypercalcemia due to malignancy or hypervitaminosis D is most likely to induce CKD. One way of discriminating the cause-effect relationship between hypercalcemia and CKD is to determine the patient's blood ionized calcium concentration. Only ionized hypercalcemia promotes CKD. However, true ionized hypercalcemia may occur in patients with CKD as a consequence of excessive dosages of calcitriol or calcium-containing intestinal phosphate-binding agents, or in patients with severe renal secondary hyperparathyroidism with marked hyperplasia of the parathyroid glands. We have also observed small increases in ionized calcium concentrations in dogs with early to moderate CKD that are not receiving calcitriol or calcium therapy and do not have advanced hyperparathyroidism. The mechanism of ionized hypercalcemia in these dogs is unclear. Hypermagnesemia is common in CKD because the kidneys are primarily responsible for magnesium excretion.37 Typically in CKD, the protein binding of magnesium is normal, complexed magnesium is usually increased and ionized magnesium may be increased, normal or decreased. Although the homeostatic mechanisms involved in the control of magnesium are not well documented, they appear to rely on the bone, gut and kidney, as found with calcium and phosphorous control. HYPOKALEMIA An association between CKD and hypokalemia has been recognized in cats by several investigators.58,59 In contrast, hypokalemia appears to be an uncommon finding in untreated dogs with CKD, occurring primarily as an iatrogenic complication of fluid therapy in this species. A particularly intriguing concept is that hypokalemia may be a cause of CKD in cats, rather than simply a consequence of it. In a recent uncontrolled study of the long-term effects of feeding a potassium restricted, acidifying diet, evidence of renal dysfunction developed in 3 of 9 cats and renal lesions consisting of lymphoplasmacytic interstitial nephritis and interstitial fibrosis were observed in 5 of the 9 cats.59 However, it is not clear whether potassium depletion or hypokalemia precede the onset of CKD. In another study, 4 of 7 cats with induced CKD fed a diet containing 0.3% potassium developed hypokalemia while 4 cats with normal renal function fed the same diet did not develop hypokalemia.60 Interestingly, muscle potassium content decreased in normokalemic cats with spontaneous CKD, indicating that a total-body deficit of potassium may develop well before the onset of hypokalemia.61 These findings support the concept that reduced renal function precedes development of hypokalemia. The mechanism of hypokalemia in cats with CKD has remained elusive, but inadequate intake and increased renal losses appear to be likely candidates. Inadequate intake of potassium could reflect decreased appetite or insufficient dietary potassium content. Dietary risk factors for hypokalemia include acidifying ingredients, reduced magnesium content and high protein content. It has yet to be established that renal potassium wasting occurs in cats with CKD. Potassium is normally regulated closely be the kidneys. Although large quantities of K+ appear in glomerular filtrate, essentially all is reabsorbed before reaching the distal tubules. The majority of potassium appears in urine as a result of potassium secretion from tubular cells into the lumen in the distal nephron. Potassium excretion in these segments of the nephron is sensitive to tubular flow rates; rapid urine formation promotes potassium secretion, while slow urine formation limits potassium secretion. Distal potassium secretion is modulated by potassium reabsorption by the intercalated cells in the cortical and outer medullary collecting tubules. Thus, in potassium depletion, net potassium absorption rather than secretion may occur in the distal nephron. In patients with CKD, the residual nephrons maintain potassium balance by increasing distal tubular secretion of potassium. Gastrointestinal secretion of potassium (primarily in the colon) also appears to increase in CKD, and may play an important role in modulating potassium balance. Because of these adaptations, most dogs and cats with CKD are able to tolerate normal dietary potassium intake (about 0.6% dry matter) until renal dysfunction is very severe. However, the ability to rapidly excrete a potassium load may be impaired in CKD resulting in transient hyperkalemia. While hypokalemia continues to be detected with some regularity in cats with CKD, its neuromuscular manifestations are uncommon. Presumably this change is the result of an increase in the potassium content of feline diets that has occurred over the past decade in response to the problem of hypokalemia in cats with CKD. Although generalized muscle weakness has been described as the cardinal sign of hypokalemia, decreased renal function and anorexia are probably more common manifestations of hypokalemia in cats with CKD. In many cats with CKD and hypokalemia, renal function improves following potassium supplementation and restoration of normokalemia, suggesting that hypokalemia may induce a reversible, functional decline in GFR. Recently, renal function was shown to be adversely affected in normal cats when an acidified, potassium restricted diet was fed.62 Potassium depletion and acidosis appeared to have additive effects in impairing renal function in this study. On the basis of these results, it was hypothesized that in cats with CKD, a self-perpetuating cycle of excessive urinary potassium losses and whole body potassium depletion may develop which is likely to further decrease in renal function. Feeding acidified diets or dietary acidifiers to cats with CKD was suggested to exacerbate their tendency develop potassium depletion. Potassium imbalances may disrupt a variety of cell functions. Hypokalemia-impaired protein synthesis has been hypothesized to promote weight loss and poor hair coat.32 Marked potassium depletion has also been linked to polyuria resulting from decreased renal responsiveness to antidiuretic hormone (ADH). This antagonism to ADH appears to be due to interference with generation and action of cyclic AMP and to impairment of the countercurrent mechanism. Locally generated prostaglandins may mediate at least part of this effect. Progression of CKD A progressive decline in kidney function typically occurs over months to years in dogs and cats with naturally occurring CKDs.18,63 It is logical to assume that CKD progresses as a consequence of continuing renal damage induced by the disease process that initiated CRF. While this assumption may be at least partially correct for some patients, the initiating cause cannot be identified at the time of diagnosis of CKD in most patients. Instead, renal lesions observed in progressive nephropathies of diverse origins typically include focal segmental glomerulosclerosis and tubulointerstitial lesions (including tubular dilation and interstitial inflammation and fibrosis). Glomerular lesions accompanied by varying levels of proteinuria are typical of progressive kidney diseases including primary tubulointerstitial diseases. In humans, both the decline in glomerular filtration rate and long-term prognosis are more closely related to the extent of associated tubulointerstitial lesions than glomerular lesions.64 In rodents, loss of a critical mass of functional renal tissue invariably leads to failure of the remaining nephrons, suggesting that CKD may progress through mechanisms independent of the initiating cause.65 For example, removal of approximately three-quarters or more of the nephrons in rats by surgical resection, infarction, or a combination of these techniques, results in a syndrome of progressive azotemia, proteinuria, arterial hypertension, and, eventually, death due to uremia. Lesions that develop in the remaining kidney remnant include focal segmental glomerulosclerosis and tubulointerstitial lesions, including tubular dilation and interstitial inflammation and fibrosis. Progressive renal injury and loss of renal function occurs in this rodent model of kidney failure despite the fact that remaining kidney remnant was initially normal. Numerous studies have been performed in an attempt to determine if findings obtained in partially nephrectomized rodents are relevant in dogs and cats. Reducing renal mass in dogs and cats resulted in mild proteinuria, glomerulopathy, and tubulointerstitial renal lesions.60,66,67 Although these findings are consistent with observations in rats, reducing renal mass by 7/8 or less did not consistently result in a progressive decline in GFR. In studies performed at the University of Georgia, progressive decline in GFR was detected in dogs in which renal mass had been reduced by 15/16.56 These findings confirm that progressive renal disease develops in dogs; however, a marked reduction in renal mass may be necessary to initiate this process in an otherwise normal remnant kidney. The preponderance of clinical and experimental evidence suggest that in dogs and cats with stages 3 and 4 CKD, progression of renal disease may result, at least in part, from factors unrelated to the activity of the inciting disease.4,68,69 These factors may include intraglomerular hypertension, glomerular hypertrophy, hypertension, proteinuria, tubulointerstitial disease, and intrarenal precipitation of calcium phosphate. INTRAGLOMERULAR HYPERTENSION AND GLOMERULAR HYPERTROPHY Long-term elevations in intraglomerular pressure, resulting from transmission of systemic pressures and/or glomerular hemodynamic processes, appear to be deleterious over time. Intraglomerular hypertension, with consequent glomerular hyperfiltration, occur as a compensatory event designed to maintain the total GFR as nephrons are lost to disease. In glomerular diseases, intraglomerular hypertension may also occur as a compensatory adaptation to reduction in permeability of the glomerular capillary wall to small solutes and water. In this setting, the fall in GFR is minimized by elevating intraglomerular pressure. Primary renal vasodilatation may occur in some diseases such as diabetes mellitus. A compensatory increase in glomerular size may also occur in all of these settings. The mechanisms by which intraglomerular hypertension and hypertrophy injury glomeruli are incompletely understood, as multiple factors are involved. Intraglomerular hypertension may directly injure endothelial cells of the glomerular capillaries. In addition, increased glomerular diameter and increased capillary wall stress may cause detachment of glomerular epithelial cells from the glomerular capillary walls. The consequent focal areas of denudation permit increased flux of water and solutes through the glomerular capillary wall. However, macromolecules cannot cross the glomerular basement membrane and are trapped in the subendothelial space. The result is formation of characteristic "hyaline deposits" in glomeruli that progressively narrow the capillary lumens, thereby decreasing glomerular perfusion and filtration. Increased strain on mesangial cells can stimulate them to produce cytokines and extracellular matrix. The release of cytokines, such as transforming growth factor-? (TGF-?) and platelet-derived growth factor, may mediate the rise in matrix synthesis.70 The consequent expansion of mesangial matrix further encroaches on the capillary surface area. While these effects lead to the characteristic glomerular lesions of progressive nephropathies, intraglomerular hypertension also impairs glomerular permselectivity leading to proteinuria. Proteinuria is an important pathophysiological link between glomerular injury, tubulointerstitial injury, and progression of renal disease. SYSTEMIC HYPERTENSION In humans, the association between systemic hypertension and CKD is well established. The Multiple Risk Factor Intervention Trial (MRFIT) identified systemic hypertension as a significant risk factor for development of end stage CKD.71 A similar association has recently been identified in dogs.17 Further, in the Modification of Diet in Renal Disease (MDRD) study, the level of systemic blood pressure was linked to progression of CKD among black and proteinuric human CKD patients.72 Systemic hypertension leads to progression of CKD, at least in part, through unopposed transmission of systemic hypertension to the glomerular capillary bed resulting in glomerular injury. This event occurs particularly in patients with CKD because autoregulation of blood flow, which normally protects glomerular capillaries from excessive pressure, is impaired. Studies in dogs and cats have confirmed that reduced kidney function is associated with an adaptive preglomerular vasodilatation that permits transmission of systemic hypertension to the glomerular capillaries.69,73 PROTEINURIA Proteinuria itself may contribute to progressive renal injury.20 Proteinuria is a strong, independent risk factor for progression to end-stage CKD in humans.74 Studies performed at the University of Minnesota Veterinary Medical Center have shown proteinuria to be a risk factor for uremia and death in dogs with naturally occurring CKD. Proteinuria has also been reported to be related to progression of renal disease in dogs with induced CKD.68 A relationship between proteinuria and progression of renal disease has not yet been established in cats. Proteinuria may promote progressive renal injury in several ways. Some proposed mechanisms include mesangial toxicity, tubular overload and hyperplasia, toxicity from specific proteins such as transferrin/iron, and induction of pro-inflammatory molecules such as monocyte chemoattractant protein-1. Excessive proteinuria may injure renal tubules via toxic or receptor-mediated pathways or via an overload of lysosomal degradative mechanisms. Abnormally filtered proteins accumulate in the renal proximal tubular lumens where, after endocytosis into proximal tubular cells, they contribute to renal tubulointerstitial injury through a complex cascade of intracellular events. These events include upregulation of vasoactive and inflammatory genes such as the endothelin-1 (ET-1) gene, the monocyte chemoattractant protein 1 (MCP-1) gene which encodes for an inflammatory peptide involved in macrophage and T-lymphocyte recruitment, and the RANTES (regulated on activation, normal T-cell expressed and secreted) that encodes for a chemotactic molecule for monocytes and memory T-cells.75 Formed in excessive amounts, these molecules are secreted toward the basolateral side of tubular cells and incite an inflammatory reaction. In addition, complement components escaping through glomerular capillary walls may initiate interstitial injury. Small lipids bound to filtered proteins may also be liberated during resorption. Inflammatory or chemotactic properties of these lipids may promote tubulointerstitial disease. Finally, inspissation of filtered proteins due to tubular reabsorption of water in the distal nephron may lead to formation of casts that obstruct nephrons. TUBULOINTERSTITIAL DISEASE IN GLOMERULOPATHIES In humans, primary glomerular diseases are typically associated with varying degrees of tubulointerstitial lesions. Remarkably, it is the intensity of the accompanying or evolving injury in the tubulointerstitium, rather than injury in glomeruli, that is the most reliable overall predictor of decline in renal function.76 In contrast, primary tubulointerstitial diseases as a group are the more indolent and slowly progressive of all human nephritides. While the etiopathogenesis of canine and feline nephropathies is often uncertain, current evidence suggests that a substantial portion of canine CKD results from primary glomerulopathies, while the majority of feline CKD appears to be of tubulointerstitial origin.11,77 The indolent course of CKD commonly observed in cats may be related to the tubulointerstitial origin of their disease, while many dogs experience a more aggressive decline in renal function as a consequence of the glomerular origin of their primary renal disease. Glomerular diseases have the capacity to incite tubulointerstitial disease. While the mechanisms underlying the development of tubulointerstitial disease in this setting are incompletely understood, multiple factors have been hypothesized to contribute.76 As described above, proteinuria is an important factor.78 Additional factors include tubular ischemia related to decreased postglomerular blood flow; loss of tolerance with subsequent tubulointerstitial damage secondary to immune mechanisms of glomerular injury; seeping of inflammatory mediators from inflamed glomeruli; renal deposition of calcium phosphate; and enhanced tubular ammoniagenesis leading to complement-mediated injury of the tubulointerstitium.76 There is evidence that an active immunologic process may be involved in the tubulointerstitium of patients with glomerulonephritidies beginning early in the course of disease. In some instances this process appears to represent an extension of the inflammation in glomeruli.76 In some models of renal disease, corticosteroids or other immunosuppressive therapy can ameliorate the tubulointerstitial damage without effect on glomeruli.79 INTRARENAL PRECIPITATION OF CALCIUM PHOSPHATE Phosphate retention begins early in the course of CKD and has been implicated in promoting progressive renal injury in several species, including dogs and cats.56,69,80 A role for phosphorus in promoting progressive CKD is based on the observation that dietary phosphorus restriction limited renal-related mortality in dogs and renal mineralization in cats. Phosphorus may promote progression of CKD, at least in part, by precipitation with calcium in the renal interstitium. This renal mineralization may then initiate an inflammatory reaction, resulting in renal interstitial fibrosis and tubular atrophy. OTHER FACTORS Lipids and Progression Experimental studies in rodents indicate that hyperlipidemia may promote progression of renal disease.81 This association is based on the observation that cholesterol loading enhanced glomerular injury, while reducing lipid levels with drugs such as lovastatin slowed the rate of progressive injury. Factors responsible for these effects are incompletely understood. Exposing glomerular and tubular cells to low-density lipoprotein and its oxidized variant stimulates their proliferation, induces injury and apoptosis, and stimulates them to produce extracellular matrix contributing to fibrosis.19 An additive effect of hyperlipidemia and proteinuria has been described in humans with CKD.82 Although hypercholesterolemia is common in dogs and cats with CKD, the clinical applicability of these findings in other species is unclear. Evidence that lipid reduction is beneficial in humans with CKD is conflicting. However, a meta-analysis of 13 prospective controlled studies indicated that lipid reduction was associated with a lower rate of decline in kidney function and decreased proteinuria.83 Metabolic Acidosis Metabolic acidosis has been theorized to enhance progression of CKD by activation of the alternative complement pathway as a result of enhanced renal ammoniagenesis.76 In human patients with CKD, reducing renal ammoniagenesis and renal tubular peptide catabolism was accompanied either by reduced renal tubular injury or by tubular hyperfunction. However, recent studies in rats have failed to confirm a role for acidemia and enhanced renal ammoniagenesis in renal injury and progression of CKD.84 Longer-term studies have suggested that effects initially attributed to enhanced renal ammoniagenesis may have been a transient and/or related to the timing of therapeutic intervention in the previous study. These researchers concluded that metabolic acidosis neither causes nor exacerbates chronic renal injury. Further, the renal protective effect of alkali therapy is unproven in humans with CKD. Studies performed by us in cats with induced CKD have likewise failed to identify an adverse effect of chronic acidosis on renal structure or function. Chronic Hypoxia It has been hypothesized that chronic oxygen deprivation to the tubulointerstitial compartment contributes to scarring in the tubulointerstitium.85 Chronic hypoxia is thought to result from compromise of blood flow to the interstitial capillary network downstream from inflamed glomeruli. Concurrently, the peritubular capillary network downstream from other vasodilated glomeruli may be damaged subsequent to transmission of systemic blood pressures to this normally low-pressure capillary network. The resultant tubulointerstitial hypoxia is hypothesized to promote fibrosis by regulating gene expression of a broad spectrum of molecules including growth factors, hormones, vasoactive compounds, and enzymes. For example, in vitro studies have indicated that hypoxia is a profibrotic stimulus for tubular epithelial cells, interstitial fibroblasts, and renal microvascular endothelial cells. Hypoxia has been shown to induce a wide variety of growth factors, including many implicated in the pathogenesis of progressive renal disease, such as TGF-?1 and platelet derived growth factor. The apparent beneficial role for ACE inhibitors in minimizing progressive renal diseases is consistent with the proposed role for chronic hypoxia. In theory, ACE inhibition could protect the kidneys by enhancing interstitial oxygen delivery through dilating the efferent arterioles, reducing vascular resistance, and improving microvascular flow through the interstitium. DIAGNOSTIC EVALUATION Patients with CKD should be evaluated to determine their diagnosis (type of CKD), severity, complications, comorbid conditions (concurrent diseases unrelated to CKD), and risk for continued loss of kidney function.3 Morphologic diagnoses usually require evaluation of kidney biopsy samples. However, unless the benefit of results of renal biopsies (e.g. the results are likely to substantially change the prognosis or treatment) outweigh the associated risks, we do not recommend them. Currently, this decision this decision must be made on a case by case basis; however, it is essentially never justified to biopsy to biopsy small kidneys from a patient with CKD unless neoplasia or infection are highly suspected (when fine-needle biopsy will usually suffice). Severity of CRD is classified on the basis of the level of renal function. Serum creatinine concentration is the most commonly used measure of severity of renal dysfunction and is the basis for staging CKD (table 2). In order to optimize accuracy of staging of CRD, serum creatinine concentrations used to stage CRD should be evaluated when patient is well hydrated. Multiple measurements are desirable to establish accuracy and stability of renal dysfunction. However, renal function may be more accurately measured using plasma clearances of iohexol, inulin, or other substances excreted exclusively by glomerular filtration.86-90 Plasma clearance studies are indicated in at least 3 settings. First, they provide an accurate measure of renal dysfunction in stages 1 and 2 patients where serum creatinine determinations may be insensitive. Second, they provide a basis for dosage adjustments for drugs that are potentially toxic and are excreted primarily by the kidneys. Third, they are an excellent means of assessing progression of CKD. Because body muscle mass commonly declines as CKD progresses through stages 3 and 4, endogenous production of creatinine from muscle creatine may decline confounding interpretation of serial serum creatinine values. Table 6 - Complications and Comorbid Conditions in CKD
Table 7 - Problem Specific Database for Patients with CKD
Appropriate management of complications and comorbid conditions may improve patient quality of life as well as short-term and long-term survival (table 6). Diagnostics necessary to identify complications and comorbid conditions associated with CKD are outlined in table 7. The prevalence of complications of CKD is mainly related to the level of renal function as reflected in the stage of CKD. Chronic kidney disease is typically characterized by alterations in a variety of kidney functions in addition to impaired GFR. These may include impairment of the 1) filtration barrier for plasma proteins (resulting in albuminuria and proteinuria), 2) reabsorption or secretion of water or specific solutes, and 3) various endocrine functions (anemia due to erythropoietin deficiency, calcitriol deficiency and renal secondary hyperparathyroidism). These functional derangements are the basis of most complications of CKD. Comorbid conditions are concurrent diseases other than CKD. Because patients with CKD are typically middle-aged to older they often have a substantial number of comorbid conditions. Comorbid conditions of particular frequency and concern for dogs and cats with CKD include urinary tract infections, urolithiasis, urinary obstruction, degenerative joint diseases, dental and other oral diseases, and cardiac disease. In addition, hyperthyroidism and upper urinary tract uroliths are common and important comorbid condition in cats with CKD. In a survey of 91 cats with CKD, we found that 25% had upper urinary tract stones. Comorbid conditions may have an important impact on prognosis and treatment. The level of kidney function tends to decline over time for most patients with CKD. It is important to assess the risk for loss of kidney function so that therapy may be designed to minimize progressive decline in GFR can be initiated. The risk of progression of CKD is affected by diagnosis and by modifiable and nonmodifiable factors. Some of these factors can be assessed even before the decline in GFR. Therapies designed to slow progression of CKD may be specific for the diagnosis (e.g. antibiotics for bacterial pyelonephritis), while others are supportive (e.g. dietary intervention, antihypertensive therapy and angiotensin converting enzyme inhibitors). TREATMENT OF CKD Overview of Treatment Treatment of CKD should generally include specific therapy, prevention and treatment of complications of decreased kidney function, management of comorbid conditions, and therapy designed to slow loss of kidney function.3 To this end, a clinical action plan should be developed for each patient based on their diagnosis, stage of CKD, existing complications and comorbid conditions, and risk factors for progression of their CKD. Specific therapy for CKD is based on a renal diagnosis. Treatment is directed at the etiopathogenic processes responsible for the patient's primary renal disease. Because the renal lesions of CKD are irreversible, they cannot be completely reversed or eliminated by specific therapy. Nonetheless, progression of renal lesions may be slowed or stopped by therapy designed to eliminate active renal diseases. Specific therapies are described in the chapters of this text on glomerular diseases, bacterial infections, familial renal diseases, and renal tubular disease. Unfortunately, a renal diagnosis amenable to specific therapy is not obtained for most patients. Treatment directed at the complications of decreased kidney function is often termed conservative medical management. It consists of supportive and symptomatic therapy designed to correct deficits and excesses in fluid, electrolyte, acid-base, endocrine, and nutritional balance thereby minimizing the clinical and pathophysiologic consequences of reduced renal function. Conservative medical management also includes therapy designed to limit the progressive loss of renal function. The goals of conservative medical management of patients with chronic primary CKD are to: (1) ameliorate clinical signs of uremia, (2) minimize disturbances associated with excesses or losses of electrolytes, vitamins, and minerals, (3) support adequate nutrition by supplying daily protein, calorie, and mineral requirements, and (4) modify progression of CKD.91 These goals are best achieved when recommendations regarding conservative medical management are individualized to patient needs based on clinical and laboratory finding. Because CRF is progressive and dynamic, serial clinical and laboratory assessment of the patient, and modification of the therapy in response to changes in the patient's condition, is an integral part of conservative medical management. Dietary Therapy DIETARY MODIFICATIONS IN CKD Diet therapy has been a mainstay in the management of canine and feline CKD for decades and continues to be the most commonly recommended treatment for these patients. In the past, the emphasis has been on reducing protein content. While protein content continues to play an important role in diet formulation, other diet modifications are also important in managing CKD patients. Diets recommended for dogs and cats with CKD are modified from typical maintenance diets in several ways including reduced protein, phosphorus, and sodium content, increased B-vitamin content and caloric density, and a neutral effect on acid-base balance. Feline CKD diets are typically supplemented with additional potassium. Canine CKD diets may have an increased omega-3 to omega-6 polyunsaturated fatty acid (PUFA) ratio. Diets may also have added fiber designed to enhance gastrointestinal excretion of nitrogenous wastes. Of these diet modifications, only phosphate, omega-3 PUFA, and protein have been extensively examined. Diet Phosphate Renal diets are limited in phosphorus content in order to limit phosphorus retention, hyperphosphatemia, renal secondary hyperparathyroidism, and progression of renal disease. Phosphate balance results largely from the interaction between dietary intake and renal excretion. Ingested phosphate is cleared from blood by glomerular filtration, and then total excretion is adjusted by modifying proximal tubular reabsorption. As renal function declines, renal tubular reabsorption of phosphorus declines (increasing renal excretion) in an attempt to compensate for the reduction in glomerular filtration, thereby maintaining phosphorus balance. However, if phosphorus intake continues unabated, the renal adaptive capacity soon becomes overwhelmed and phosphorus retention and hyperphosphatemia develop. While phosphorus retention and hyperphosphatemia probably do not cause clinical signs, they may promote renal secondary hyperparathyroidism and renal mineralization that enhances progressive decline in renal function. Dietary phosphorus restriction has been shown to enhance survival and a slow decline in renal function in dogs with induced CKD.56 In cats, dietary phosphorus restriction has been shown to limit renal mineralization. Available evidence supports a recommendation for dietary phosphate restriction for dogs and cats in stages 3 and 4 CKD. Because protein is a major source for phosphate, it is usually necessary to limit dietary protein in order to limit diet phosphate content. Omega-3 PUFA Dietary supplementation with omega-3 PUFA have been shown to be beneficial in dogs with induced CKD. Compared to dogs fed diets high in saturated fats or omega-6 PUFA, dogs consuming a diet supplemented with omega-3 PUFA had lower mortality, better renal function, fewer renal lesions, less proteinuria, and lower cholesterol levels.92 In dogs fed the omega-3 PUFA diet, renal function actually increased and remained above baseline over 20 months of study. Lesions of glomerulosclerosis, tubulointerstitial fibrosis, and interstitial inflammatory cell infiltrates were also diminished in dogs fed the omega-3 PUFA diet. A variety of effects attributed to omega-3 PUFA supplementation may have contributed to the favorable renal effects observed, including their tendency to reduce hypercholesterolemia, suppress inflammation and coagulation (by interfering with the production of proinflammatory, procoagulant prostanoids, thromboxanes, and/or leukotrienes), lower blood pressure, favorably influence renal hemodynamics, provide antioxidant effects, or limit intrarenal calcification. A subsequent study supported possible roles for altered lipid metabolism, glomerular hypertension and hypertrophy, and urinary eicosanoid metabolism in the beneficial renal effects of omega-3 PUFA.93 Available evidence supports a recommendation for dietary supplementation with omega-3 PUFA for dogs in stages 3 and 4 CKD. The optimum quantity of omega-3 PUFA supplementation and ratio of omega-3 to omega-6 PUFA appropriate for renal diets have not been conclusively established. Additional omega-3 PUFA supplementation may not be appropriate for dogs already consuming a renal diet enhanced with omega-3 PUFA. Currently, there is no evidence to support a recommendation for or against omega-3 PUFA supplementation for cats with CKD. Diet Protein While the ideal quantity of protein to feed dogs and cats with CKD remains unresolved, there is a general consensus of opinion, that reducing protein intake ameliorates clinical signs of uremia in CKD and is therefore indicated for stage 4 CKD. Blood urea nitrogen can be used as a crude measure of compliance with dietary recommendations because it declines as dietary protein intake is reduced. While not generally regarded as an important uremic toxin, BUN is a surrogate marker for retained non-protein nitrogenous waste products and typically correlates better with clinical signs than serum creatinine concentration. The concept of reducing dietary protein intake in CKD patients that do not have clinical signs of uremia has been questioned. Limiting protein intake has been advocated for these patients in order to slow progression of CKD. This suggestion derives from studies in rats indicating that dietary protein restriction limits glomerular hyperfiltration and hypertension and slows the spontaneous decline in kidney function that follows reduction in kidney mass.65 Studies in humans have supported the concept that protein restriction slow progression of CKD, albeit this effect may be small.94 In contrast, multiple studies have failed to confirm a beneficial role for protein restriction in limiting progression of CKD in dogs or cats.91 When not excessive, limiting protein intake does not appear to have any adverse effects, and it may be easier to initiate treatment with renal diets before the onset of clinical signs of uremia. In addition, protein restriction may delay onset of clinical signs of uremia as renal disease progresses. While a role for protein restriction in slowing progression of canine and feline CKD has not been entirely excluded, available evidence fails to support a recommendation for or against protein restriction in patients with stage 3 CKD. DIET THERAPY - EVIDENCE FROM CLINICAL TRIALS The effectiveness of diet therapy in minimizing uremic episodes and mortality in dogs with naturally occurring stage 3 and stage 4 CKD has been established in a double-masked, randomized, controlled clinical trial.18 The study compared a renal diet to a prototypical canine maintenance diet. The renal diet was characterized by reduced quantities of protein, phosphorus, and sodium compared to the maintenance diet., and was supplemented with omega-3 PUFA. In this study, the risk of developing an uremic crisis was reduced by approximately 75% in dogs fed the renal diet compared to dogs fed an adult maintenance diet, and the median interval before development of uremic crisis in dogs fed the renal diet was twice as long as that observed in dogs fed the maintenance diet. Further, the risk of death irrespective of the cause was reduced by at least two-thirds when dogs were fed the renal diet, and renal death risk was reduced by 70%. Dogs fed the renal diet survived at least 13 months longer than dogs fed the maintenance diet. In addition, owners of dogs fed the renal diet reported significantly higher quality of life scores for their dogs than owners of dogs consuming the maintenance diet. The delay in development of uremic crises and reduced mortality observed in dogs fed renal diet was associated, at least in part, with reduction in the rate progression of CKD. The effectiveness of diet therapy in cats has been tested in a prospective study comparing a renal diet characterized by protein and phosphorus restriction to no diet change.63 Cats that would not accept the renal diet, either due to pet or owner issues, continued to eat their regular diet. Therefore, this study was neither randomized nor blinded, but nonetheless yielded results similar to those observed in the canine study. Cats fed the renal diet (mean survival time = 633 days) survived substantially longer than cats that continued to consume their regular diet (mean survival time = 264 days). In addition, plasma urea nitrogen, phosphorus, and parathyroid hormone concentrations were reduced in cats that consumed the renal diet. Results of more recent randomized controlled clinical trial performed in our clinical trial unit found that feeding a maintenance diet to cats with serum creatinine values between 2.0 and 4.5 mg/dl was associated with a 2-year mortality rate of 22%. In contrast, none of the cats fed the renal diet died over the 2 years of study. This more controlled trial supports the findings of the study described above, confirming the value of renal diets in managing cats with CKD. INDICATIONS FOR DIET THERAPY In the past, criteria for timing of dietary intervention in dogs and cats with spontaneous CKD have been based on empirical observations. An often-cited guideline has been to initiate dietary therapy when serum creatinine exceeds 2.5 mg/dl or the SUN exceeds 60-80 mg/dl. More recently, one investigator recommended a staged approach whereby dietary phosphorus restriction and omega-3 PUFA dietary supplementation be implemented in dogs with serum creatinine values below 4.0 mg/dl with dietary protein restriction recommended only in dogs with serum creatinine values exceeding 4.0 mg/dl.4 However, the clinical trial data available to date have demonstrated a benefit of dietary intervention in both stage 3 and stage 4 CKD. In a randomized, controlled clinical trial in dogs with naturally occurring CKD, diet therapy significantly reduced the risk of uremic crises and death in dogs with serum creatinine concentrations between 2.0 and 3.0 mg/dl.18 These studies did not selectively determine the benefits of modifying individual dietary components, but rather report the results of a "diet effect." While studies on individual dietary components have been reported in dogs and cats with induced CKD, the potential interactions between components have not been examined, nor have the results of these studies been confirmed in clinic patients. Currently available data supports recommending therapy with appropriately modified diets in dogs and cats in stages 3 and 4 CKD. The value of diet therapy in stages 1 and 2 CKD has not been established, therefore there is no evidence to support a recommendation for or against diet therapy in these patients. In cats, clinical trials have confirmed the value of renal diets beginning in the middle of CKD Stage 2 (serum creatinine concentrations 2.0 mg/dl and higher). Drugs - Medication Review and Dose Modification A review of current medications should be performed at each clinic visit, including dosage adjustment based on level of kidney function, detection of potential adverse effects on kidney function or complications of CKD, detection of drug interactions, and, where indicated, therapeutic drug monitoring.3 Ensure that all current medications are still necessary and that new medications have specific indications and do not pose a risk of drug interaction. Because the kidneys are responsible for elimination of many drugs from the body, renal drug clearance is reduced as renal function declines causing the half-life of the drug to be prolonged. In addition, distribution, protein binding, and hepatic biotransformation of drugs may be altered. For example, two protein binding defects are seen in CKD.49 One group of primarily acidic drugs shows decreased binding leading to increases in free, active drug fractions in plasma (e.g. theophylline, methotrexate, diazepam, digoxin, and salicylate). The effect of this change in binding is that lower doses of drugs are required to achieve therapeutic levels, but conventional doses may result in toxic levels. Basic drugs, such as propranolol or cimetidine, have increased binding leading to a decrease in free drug levels, thus diminishing the therapeutic effect. Increased total drug levels may be required to achieve the desired therapeutic effect with these drugs. However, these effects may be complicated by decreased renal clearance of the drugs. Further, accumulation of active drug metabolites may augment drug potency or toxicity. The sum effect of these changes is that for many drugs normally excreted by the kidneys, there is a tendency for drug to accumulate in patients with CKD. Excessive drug accumulation promotes an increased rate of adverse drug reactions and nephrotoxicity. If drugs requiring renal excretion must be administered to patients with CKD, dosage regimens should be adjusted to compensate for decreased organ function. However, dosage adjustments may not be appropriate for drugs that are administered to a physiologic endpoint or effect such as antihypertensive agents.95 Because drug accumulation in patients with reduced kidney function is primarily a result of reduced renal drug clearance, dosage adjustments should be made according to changes in drug clearance. Net renal excretion of a drug is a composite of glomerular filtration, tubular secretion, and tubular reabsorption. Generally it is assumed that these 3 factors all decline in parallel. Therefore, drug clearance may be estimated by measuring GFR, either by plasma disappearance rate (e.g. iohexol disappearance rate) or classical clearance studies. Drug dosage may then be adjusted according to the percentage reduction in GFR (i.e. the ratio of patient GFR to normal GFR), also known as the dose fraction (Kf): Dosage regimens can be adjusted by increasing the normal dosage interval or decreasing the normal dose in direct proportion to Kf.96 The interval extension method is particularly useful for drugs with wide therapeutic ranges and long plasma half-lives in patients with renal impairment. Interval lengthening will result in wide swings of the plasma drug concentrations from peak to trough levels. If the range between the toxic and therapeutic levels is too narrow, either toxic or subtherapeutic plasma concentrations may result. For drugs excreted 100 percent unchanged by the kidneys, a precise increase in dosage interval may be calculated by dividing the normal dosing interval by Kf: For example, if a drug is normally administered every 8 hours and the patient's GFR is 25% of normal (i.e. Kf = 0.25), then the appropriate dosing interval is (8 hrs ÷ 0.25) or 32 hrs. The calculated dose interval should be rounded to a convenient time schedule. Alternatively, the size of the individual doses can be reduced while maintaining the time interval between doses normal. Decreasing the individual doses reduces the difference between peak and trough plasma concentrations. This effect is important for dugs with narrow therapeutic ranges and short plasma half-lives in patients with renal dysfunction and is recommended for drugs for which a relatively constant blood level is desired. Dose reduction may be determined by multiplying the normal dose by Kf: For example, if the normal dosage is 10 mg/kg given every 8 hours and the patient's GFR is 25% of normal (i.e. Kf = 0.25), then the appropriate dosage is (10 mg/kg x 0.25) or 2.5 mg/kg given every 8 hours. Even using the reduced dosage, normal interval method, the first dose of drug should be administered at the usual dosage to initiate therapeutic drug concentrations in tissues and blood. There have been no controlled clinical trials to establish the efficacy of the two methods for drug-dose alteration in patients with CKD. Prolonging the dose interval is usually more convenient and less expensive. A combination of interval prolongation and dose size reduction may also be convenient and effective. Dosage of antimicrobial drugs may be modified according to 3 general patterns, depending on the fraction of the drug eliminated by the kidneys (table 8): (1) doubling the dosing interval or halving the drug dosage in patients with severe reduction in renal function, (2) increasing the dosage interval according to ranges of creatinine clearance values, and (3) precise dosage modification as described above. Drugs in the first category are relatively nontoxic. The second class includes drugs requiring dosage modification according to GFR values because they are more likely to be toxic. For drugs in this class, dosing interval is increased two-fold when GFR is between 1.0 and 0.5 ml/min/kg, three-fold when GFR is between 0.5 and 0.3 ml/min/kg, and four-fold when GFR is less than 0.3 ml/min/kg. Drugs in the third class include relatively toxic antimicrobial drugs that are excreted solely by glomerular filtration (particularly aminoglycoside antibiotics). They require precise dosage modification according to Kf. For these drugs, increased interval, fixed dosage regimens appear to result in less nephrotoxicity than reduced dose, fixed interval methods. A combination of dosage reduction and interval extension has been recommended for animals with markedly reduced kidney function (GFR less than 0.7 ml/min/kg). Although GFR is the preferred measure of renal dysfunction for modifying drug therapy, serum creatinine concentration is a more universally available measure of renal dysfunction. A regression equation relating serum creatinine concentration to glomerular filtration rate in dogs has been established.97 Although the relationship between serum creatinine concentration and GFR is not linear, the reciprocal of serum creatinine concentration may be used to approximate GFR when serum creatinine concentration is less than 4 mg/dl. This rule of thumb will overestimate GFR when serum creatinine concentration exceeds 4 mg/dl. Despite increased expense and effort involved, it is recommend that GFR be used as the basis for modifying drug dosage schedules whenever possible. This recommendation is particularly relevant when a potentially nephrotoxic drug must be administered. Patients with preexisting renal disease and CKD may also be predisposed to nephrotoxicity. For this reason, nephrotoxic drugs and drugs requiring renal excretion should generally be avoided in patients with CKD. Where possible, less nephrotoxic drugs should be chosen. If nephrotoxic drugs are unavoidable, therapeutic drug monitoring or serial evaluation of renal function is essential. So-called "complementary medications" (sometimes called herbal medicines, naturopthic remedies and phytomedicines) are becoming increasingly popular. The potential for interactions with prescribed medications or simple adverse consequences in patients with reduced kidney function should be considered for patients receiving these medications. Herbal products which should be avoided in patients with renal dysfunction include aristolochic acid, barberry, buchu, Chinese herbal drugs, juniper, licorice, and noni juice.95 Table 8 - Drug Dosage Modifications for Patients with Renal Insufficiency and Failure
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