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Chronic Kidney Disease, Part 1: Overview

Dana Hutchinson, DVM, DACVN, Angell Animal Medical Center

S. Dru Forrester, DVM, MS, DACVIM (SAIM), Hill's Pet Nutrition

Angela Witzel Rollins, DVM, PhD, DACVN, University of Tennessee

Larry G. Adams, DVM, PhD, Purdue University

Todd L. Towell, DVM, MS, DACVIM, Global Veterinary Consulting

This content was published originally in the Small Animal Clinical Nutrition textbook. It has been updated and provided to readers of Clinician's Brief courtesy of the Mark Morris Institute.

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Chronic Kidney Disease, Part 1: Overview

"When things are investigated, then true knowledge is achieved." Confucius 

INTRODUCTION

Chronic kidney disease (CKD) is the most common disease affecting the kidneys of dogs and cats. It may be recognized by reduced kidney function or the presence of kidney damage. CKD is defined as kidney damage present for at least three months, with or without decreased glomerular filtration rate (GFR) or greater than 50% reduction in GFR persisting for at least three months (Polzin et al, 2005).  Kidney damage is further defined as either 1) microscopic or macroscopic pathologic changes detected by histologic or direct visualization of the kidneys or 2) markers of damage detected by blood or urine tests or imaging studies. In the past, multiple terms were used to define the severity of renal functional abnormalities including renal insufficiency, renal failure and uremia. However, there has not been uniform agreement on the specific definition of renal insufficiency vs. renal failure. Therefore, it has been proposed by the International Renal Interest Society (IRIS) to replace these terms with a scheme to classify severity of CKD into four stages. Staging is based initially on fasting blood creatinine concentration, assessed on at least two occasions in the stable patient (Table 37-1). The patient is then substaged based on proteinuria and blood pressure (Tables 37-1A and 37-1B). Two of the foundational assumptions inherent in this classification scheme are that the presence of CKD has been confirmed and that azotemia, if present, has been localized as renal in origin.

This classification scheme emphasizes the continuum of severity of renal injury of dogs and cats starting from those at risk for developing CKD, to those with documented presence of kidney damage but without azotemia in stage 1 CKD, to progressively more severe CKD with resultant increasing serum creatinine concentration for stages 2 to 4. Furthermore, by using the term “kidney disease” and staging the severity of disease, it is possible to facilitate understanding, communication and application of management guidelines for patients in each stage.

The goals of this chapter are to provide pathophysiologic concepts and practical nutritional management recommendations for dogs and cats with CKD. Nutritional management of patients with CKD includes measures to reduce signs of uremia and slow progression to later stages of disease. There is general agreement regarding nutritional management of CKD when overt signs exist; however, the role of nutritional intervention during earlier stages of CKD is less well defined. Thus, in a sense, the question is not whether to use nutritional management but when should it be initiated. Historically detection of CKD in its early stages was difficult however, recent advances in renal biomarkers (e.g. symmetric dimethylarginine (SDMA)) that correlate with decreasing glomerular filtration rate allow for detection of kidney disease well before azotemia develops (Relford et al, 2016). Armed with this new diagnostic tool, investigators are beginning to understand the role of nutritional intervention in patients with stage 1 CKD (Hall et al, 2016; Hall et al, 2016a). Given this new information and since there appears to be no harm in avoiding nutrient excess (e.g., phosphorus) during earlier stages, nutritional management should be considered in stage 1 CKD and is clearly indicated when serum creatinine exceeds 2 mg/dl (179 μmol/l) (Jacob et al, 2002; Ross et al, 2006). Similarly, significant and persistent renal proteinuria, even in the absence of azotemia, reflects marked renal damage and signals the need for nutritional management regardless of the CKD stage.

Table 37-1. IRIS Staging System† for Chronic Kidney Disease in Dogs and Cats.

Table 37.1A. IRIS Substaging by Proteinuria*

Table 37.1B. IRIS Substaging by Arterial Blood Pressure*

CLINICAL IMPORTANCE

Prevalence of Chronic Kidney Disease

CKD, when present, commonly results in morbidity and mortality in dogs and cats. Reported CKD prevalence varies between populations. In a cross-sectional study of 31,484 dogs and 15,226 cats evaluated in private practices across the United States in 1995, the prevalence of kidney disease was 2.2% in cats and 0.8% in dogs (Kirk et al, 2001).

Prevalence in Dogs

The prevalence of CKD in a database of 107,214 dogs seen at 89 veterinary practices in the United Kingdom between 2010-2011 was 0.37% (O’Neill et al, 2013). In a recently published insurance claims study from Sweden, investigators found an estimated prevalence of 1.6% for kidney related claims (Pelander et al, 2015). A retrospective study of hospital visits of dogs presenting to an academic medical center from 2010-2014 found moderately to severely elevated serum creatinine in 11.5% of all evaluated dogs. Interestingly, out-patients were slightly more likely to have elevated levels than inpatients, 12.9% and 10.2% respectively (Babyak et al, 2016).  The discrepancy between this and other studies might represent a difference in the investigated populations and so-called referral bias or distortion of the true prevalence of a disease for dogs presenting to a referral hospital. However, this represents one of the largest veterinary epidemiologic studies of companion animals with patient level data. Even when selection bias was addressed by using sensitivity analyses assuming a 1% prevalence in unevaluated dogs the authors calculated a minimum risk of 2.2% in outpatients and 6.5% in in-patients. These adjusted rates are higher than previously reported. Even these elevated rates may under estimate the true prevalence given the poor sensitivity of serum creatinine as a biomarker for kidney function.

Prevalence in Cats

During 1990, the diagnosis of CKD in cats of all ages reported to the Veterinary Medical Data Base was 16 cases/1,000 cats examined. By 2000, diagnosis of CKD in cats of all ages was 96 cases/1,000 cats examined (Ross et al, 2006). In a large UK study (2009 – 2014, n=3,583) the prevalence of feline kidney disease in first opinion practices was ~4% (O’Neill et al, 2014). In 2010 CKD was diagnosed in 1.5% of all Banfield Pet Hospital feline patients (n=444,419) (Lefebvre, 2011). In this population the prevalence of CKD appears to be increasing. The age adjusted prevalence increased from 0.8% (79 cases per 10,000 cats seen) in 2006 to 1.6% (160 cases per 10,000) in 2011 (Lefebvre 2011). Increased diagnosis of CKD in cats may be due to a longer average lifespan, more cats being screened for CKD and/or increased awareness of CKD by veterinarians. CKD appears to be a common cause of death in dogs and cats. In a retrospective study of dogs, 2% died from chronic nephritis, 2% from pyelonephritis and 1% from glomerulonephritis (Bronson, 1982). Thus, the overall mortality from kidney diseases was 5%. With the exception of cancer, kidney disease was the most common cause of death in this study. From 1995 to 2006 the reported kidney related mortality of 548,346 Swedish dogs with mortality insurance was 9.7 deaths /10,000 dog years at risk (DYAR) (Pelander et al, 2015). The mean age of dogs that died or were euthanized for kidney disease was 6.5 ± 2.7 years. In a 1991 survey by the Morris Animal Foundation of readers of Companion Animal News, respondents indicated that of 325 cats that had died, 94 succumbed to kidney disease (MAF, 1991). By comparison, 39 of the 325 died of feline leukemia and 45 died due to other causes. In a Swedish study of insured cats, disorders of the kidneys or ureters were the most commonly identified cause of mortality, with an age-standardized mortality rate of 713 per 10,000 cat-years at risk (Egenvall et al, 2009). From 2009 to 2014 kidney disease was the most common cause of mortality in cats ⩾5 years of age in a UK study, being the cause of death of >13% of cats at a median age of 15 years (O’Neill et al, 2015).

Relationship Between Age and Kidney Disease

CKD occurs in dogs and cats of all ages, but it is most frequently a disease of older pets. In a 1995 survey of private practices, the mean ages of dogs and cats with kidney disease were 10.2 and 13.2 years, respectively (Kirk et al, 2001). In human medicine, it is known that GFR declines with age because of structural change, tubular dysfunction and a decrease in functioning nephrons (Glassock et al, 2009). Several different mechanisms can contribute to age-related organ dysfunction, including mitochondrial injury, telomere shortening, oxidative stress, profibrogenic and pro-inflammatory mediators, and an imbalance between cell repair and cell death. However, many of these mechanisms occur not only during aging but also as part of an organ’s response to injury and as part of the healing process. In cats, preliminary data evaluating telomere shortening support the concept of an aging process affecting the kidney. Telomere shortening has been documented in proximal tubules of geriatric cats with CKD compared with age-matched and young controls despite no difference in telomere length in skin or liver from the same groups (Quimby et al, 2013). It therefore seems feasible that aging may be a component of the decline in renal function seen in older cats, but it is also likely that other individual and environmental factors contribute to an individual’s overall risk of developing CKD. 

Studies in Cats

In first opinion practices in the UK CKD was most common in cats ≥ 10 years of age (7.5% [5.498/73,396]) (O’Neill et al, 2014). Eighty-one percent of cats diagnosed with CKD at Banfield Pet hospitals were ≥ 10 years of age while 17% were mature adults (≥ 3- < 10 years) (Lefebvre, 2011). In a study of 175 cats diagnosed with CKD in Australia from 2000 to 2003, ages ranged from two to 21 years (mean, 13.2 ± 3.7 years). However, the majority (69%) were 12 to 18 years old (White et al, 2006). The mean age for cats diagnosed with CKD at the Animal Medical Center in New York from 2000 to 2002 was 12.8 ± 4.4 years (Boyd et al, 2008). Analysis of data from university teaching hospitals contributed to the Veterinary Medical Data Base from 1980 to 1990 indicated that 37% of cats with CKD were less than 10 years old, 31% of cats were between 10 and 15 years old and 32% of cats were older than 15 years (Lulich et al, 1992). One limitation of these studies is the dependence on insensitive markers for the detection of early decline in renal function. Recent studies that include patients recognized as having nonazotemic stage 1 or 2 CKD suggest the prevalence of CKD is relatively stable in cats < 15 years of age (~40%)  but may be as high as 80% in cats over 15 years old (Marino et al, 2014).

Studies in Dogs

Studies in dogs show a similar relationship between aging and occurrence of CKD. Prevalence of CKD was reported to be nine cases/1,000 dogs of all ages examined, 12.5 cases/1,000 in dogs between seven and 10 years old, 24 cases/1,000 in dogs between 10 and 15 years old and 57 cases/1,000 in dogs over 15 years old (Polzin et al, 1995). In a population of inpatient and outpatient dogs evaluated at an academic medical center nearly 1 in 5 dogs older than 11 years had elevated serum creatinine (Babyak et al, 2017). Consistent with previous studies and regardless of patient status (inpatient or outpatient) geriatric dogs had a higher risk and young dogs had a lower risk of elevated serum creatinine compared to all dogs. In the Swedish insurance claims study, the mean age of all dogs when they had their first registered episode of kidney disease was 6.9±3.3 years (Pelander et al, 2015).

To date all of these studies have depended on serum creatinine as the marker for kidney function. A major limitation of serum creatinine level is its dependence on muscle mass. Serum creatinine levels may be significantly increased in heavily muscled dogs or significantly decreased in dogs and cats with muscle loss (Braun et al, 2003). Despite losses in muscle mass associated with aging and therefore less creatinine generation, studies confirm geriatric pets are more likely to have elevated creatinine. Because of these opposite effects, an elevated creatinine in an older pet with loss of lean body mass can represent more severe disease than a younger pet with the same measured creatinine. Monitoring symmetric dimethylarginine (SDMA) with the IDEXX SDMA Test TM offers a more accurate assessment of kidney function since it accurately reflects glomerular filtration rate (GFR) and is not affected by lean body mass (Relford et al, 2016). A prospective study in older cats with age-related loss of muscle mass, as measured by dual energy x-ray absorptiometry, confirmed that creatinine level underestimates the loss of kidney function as GFR declines. In contrast, SDMA level showed no correlation with lean body mass. GFR declined with age, and serum SDMA level increased in concordance, better identifying the function loss (Hall et al, 2014). A complimentary study in healthy dogs showed comparable findings between lean body mass and creatinine level (r = 0.54; P = .0003), whereas SDMA level was not influenced by total lean body mass (r = -0.12; P = .45) (Hall et. al, 2015). SDMA data collected to date by IDEXX Reference Laboratory  support that kidney disease is more prevalent than was previously reported, and increases with increasing pet age. In the first ~ 750,000 IDEXX SDMA tests performed in the United States, dog samples outnumbered cat samples approximately 2 to 1. These samples showed that 11% of feline samples and 6% of canine samples had an increase in creatinine level above the reference interval. However, there was an additional 15% of cats and 6% of dogs identified to have increased SDMA levels while creatinine remained within the reference interval. These findings suggest that using SDMA, a more sensitive biomarker, allows veterinarians to diagnose kidney disease 2.4 times more often in cats and 2.0 times more often in dogs. (Data courtesy of IDEXX) Future studies using SDMA to assess kidney function may provide more accurate assessments of the prevalence of CKD in the general population and the relationship between age and kidney disease. 

Causes of Kidney Disease

Familial Kidney Diseases

Juvenile kidney disease increases suspicion of a familial nephropathy; however, juvenile kidney disease may be due to non-genetic causes. The specific term juvenile nephropathy has been used to describe disorganized nephrogenesis including kidney failure in young dogs. The term renal dysplasia describes abnormal differentiation of the kidneys. Specific histologic findings in renal dysplasia include fetal glomeruli, atypical tubular epithelia and persistent mesenchyme. Although renal dysplasia occurs most often as an inherited disorder, it can also be an isolated congenital abnormality that is not inherited. Juvenile nephropathy has been reported to occur in Alaskan malamutes, boxers and golden retrievers. Both males and females were affected. The lesions included moderate to severe interstitial fibrosis and mild to moderate lymphoplasmacytic interstitial inflammation. Mild to moderate tubular dilatation and atrophy were also present. Cystic glomerular atrophy and periglomerular fibrosis were prominent findings in most dogs (de Morais and DiBartola, 1995; de Morias et al, 1996; Chandler et al, 2007).

Familial disorders resulting in CKD have been documented or suspected to occur in a number of breeds (Table 37-2) (Lees, 1996). Familial nephropathies should be suspected when CKD is diagnosed in related pets with a higher frequency than would be expected by chance and there is no apparent underlying cause. Age of cats and dogs with familial nephropathies at presentation often is less than that of most pets presenting with  CKD. In some familial nephropathies, the kidneys are seemingly normal at birth but because of an inborn metabolic defect, progressive structural and functional deterioration develops in the first few years of life. The term hereditary nephropathy is reserved for conditions in which an inherited basis has been documented by pedigree analysis or breed testing.

Hereditary nephropathy has been reported to occur in several breeds of dogs including Samoyeds, English cocker spaniels and bull terriers. Affected male Samoyed dogs with X-linked hereditary nephritis have splitting of glomerular basement membranes and develop overt CKD within the first year of life (Valli et al, 1991; Grodecki et al, 1997).  The underlying inborn error is a defect in the formation of Type IV collagen. Carrier females with X-linked nephritis have isolated splitting of glomerular basement membranes although advanced CKD is not observed until later in life (Valli et al, 1991). In English cocker spaniels, a Type IV collagen defect is transmitted as an autosomal recessive trait (Davidson et al, 2007).

Proteinuria is the initial finding and affected dogs typically die of terminal CKD between six and 24 months of age (Nash, 1989). Light microscopic renal lesions are mild and nonspecific but distinctive electron microscopic changes are observed in the glomerular basement membrane (Lees et al, 1998). The defect in bull terriers appears to be an autosomal dominant disorder (Hood and Savige, 1995). The rate of progression in bull terriers is quite variable with dogs dying of terminal CKD from a few months to 10 years of age. Hematuria is observed in many affected bull terriers. Two distinct familial nephropathies have been reported to occur in soft-coated wheaten terriers (Littman et al, 2000; Ericksen and Grondalen, 1984). One nephropathy is a form of renal dysplasia. Kidneys from affected dogs are small, irregular and fibrous. Glomeruli are small and hypercellular and there are increased numbers of fetal glomeruli. The second form of nephropathy in soft-coated wheaten terriers is characterized by protein-losing enteropathy and concomitant nephropathy. Although a genetic basis for this syndrome has not been proven, dogs become symptomatic between two and five years of age. Membranoproliferative glomerulonephritis, glomerulosclerosis, or both, are present microscopically.  Renal amyloidosis has been recognized in related dogs of two breeds (beagles, Chinese Shar-Peis) and related Abyssinian cats (Chew et al, 1982; Boyce et al, 1984; Bowles and Mosier, 1992; DiBartola et al, 1986, 1990). Histologic findings in renal tissue from beagles include moderate to severe glomerular amyloidosis with inconsistent mild medullary interstitial amyloidosis (Bowles and Mosier, 1992). Medullary amyloid was identified in all Chinese Shar-Pei dogs and nine dogs (64%) had glomerular involvement (DiBartola et al, 1990). In 15 Abyssinian cats involved in one study, amyloid was deposited in the medullary interstitium of all cats and 11 cats had glomerular involvement (DiBartola et al, 1986).

Table 37-2. Kidney diseases suspected or confirmed to be inherited in dogs and cats.

Acquired Kidney Diseases

CKD is a complex disease that is likely influenced by genetic, individual and environmental factors. There is accumulating evidence that CKD is a progressive disease resulting from recurrent or sustained injury to the kidneys which promotes active interstitial inflammation and fibrosis. Triggers for injury include unresolved primary disease (eg, glomerulonephritis), comorbid conditions (eg, systemic hypertension, heart disease and regional ischemia), chronic medications (eg, angiotensin-converting enzyme inhibitors, diuretics, antibiotics, and nonsteroidal anti-inflammatory drugs), chronic inflammation, chronic immune stimulation, recurrent infection, and proteinuria, among others (Cowgill et al, 2016). Studies in models of CKD illustrate that diverse and seemingly uncoordinated insults can promote a common, generally inflammatory cellular response in the kidney. The kidney responds to these stresses with similar reactions intended to combat the insult and heal damaged cells. However, those responses can become maladaptive when the stress or injury is sustained or insurmountable. A recent study documented a clear increase in mRNA expression of inflammatory cytokines interleukin-1α  (IL-1 α), interleukin-1β (IL-1β) and transforming growth-factor β (TGF-β) in blood samples from client owned dogs with both AKI and CKD (Nentwig et al, 2016). Predictably, the underlying cause of feline CKD, where the primary histopathologic finding is tubulointerstitial nephritis, is still poorly understood. Infectious, inflammatory and immune-mediated diseases (e.g., leptospirosis, rickettsial diseases, pyelonephritis, amyloidosis, periodontal disease) may cause inflammation of the renal interstitium or glomeruli. Glomerulonephritis secondary to systemic infectious, inflammatory or neoplastic diseases may be a common cause of CKD, especially in dogs. Renal neoplasia, particularly lymphoma in cats, may be a cause of CKD. Drugs that may cause nephrotoxicosis include antimicrobials (aminoglycosides), antifungals (amphotericin B), analgesics (aspirin, ibuprofen and phenylbutazone), immunosuppressive agents (penicillamine) and chemotherapeutic drugs (cisplatin, methotrexate and daunorubicin) (Grauer, 1996). Geriatric patients may be at greater risk for drug-induced nephrotoxicity because of a decline in kidney function associated with aging, use of multiple drugs with nephrotoxic potential and altered metabolism and excretion that occurs in older patients.

There are relatively few clinical studies that have evaluated phenotypic, environmental, or lifestyle risk factors for the development of CKD in dogs and cats. In recent studies periodontal disease has been identified as a common risk factor or comorbid condition in both dogs and cats (Greene et al, 2014, Finch, et al, 2016, Glickman et al, 2011, O’Neill et al, 2013, Pavlica et al, 2008). One study in cats indicated that poor body condition, periodontal disease, cystitis, being male neutered rather than female spayed, and anesthesia or documented dehydration in the preceding year were risk factors for CKD (Greene et al, 2014). Another identified annual or frequent vaccination and severe dental disease as risk factors for development of CKD in cats (Finch, et al, 2016). Periodontal disease has also been associated with increased risk of CKD in dogs. A retrospective, longitudinal study compared 164,706 dogs with periodontal disease and a cohort of age-matched dogs with no periodontal disease from a national primary care practice from 2002 – 2008 (Glickman et al, 2011). The hazard ratio for azotemic CKD increased with increasing severity of periodontal disease (1.8, 2.0, and 2.7 for stage 1,2, and 3/4 respectively). Increasing severity of periodontal disease was also associated with serum creatinine >1.4 mg/dl and blood urea nitrogen >36 mg/dl, independent of a veterinarian's clinical diagnosis of CKD. The association between periodontal and systemic disease is further supported by a retrospective observational study that identified a significant correlation between chronic infected periodontal lesions and morphologic alterations in internal organs of dogs (Pavlica et alt, 2008). In this population of dogs with naturally occurring periodontal disease the overall likelihood of greater histopathologic changes in the kidney was 1.4 times higher for each cm2 increase in periodontal disease burden. Together these findings are significant considering the prevalence of periodontal disease in dogs and cats. In two large surveys of 142,576 cats and 3,884 dogs seen at first opinion practices in the UK periodontal disease was the most prevalent disorder recorded in cats (13.9%) and the second most prevalent in dogs (9.3%) (O’Neill et al, 2014; O’Neill et al, 2014). In 2015 dental disease was diagnosed in 76% of dogs and 68% of cats presented to Banfield Pet hospitals (Lund, 2016). While it is not possible to establish a clear cause and effect relationship between periodontal disease and CKD, presence of chronic infectious/inflammatory conditions are thought to be a source of chronic inflammation in renal interstitium and glomeruli.

Patient Assessment

History

Historical findings in patients with CKD may include polyuria/polydipsia (PU/PD), lethargy, inappetence, vomiting, weight loss, nocturia, constipation, diarrhea, acute blindness (associated with hypertension) and seizures or coma (terminal uremia). Recent studies in dogs and cats highlight the frequency pets with a  history of halitosis / periodontal disease are diagnosed with CKD (Bartlett et al, 2010, Greene et al, 2014, O’Neill et al, 2013, Finch et al, 2016). Cats also may have ptyalism and muscle weakness with cervical ventriflexion due to hypokalemic myopathy.

In a retrospective study of cats with CKD, polyuria and polydipsia were observed in 40%, vomiting in 52%, inappropriate urination in less than 10% and diarrhea in 3% (Lulich et al, 1992). In a case-controlled study designed to determine what clinical signs cat and dog owners observed before a veterinarian diagnosed their pet with CKD cat owners reported PU/PD a year before diagnosis (Barrlett et al, 2010). Dog owners reported PU/PD over half a year before diagnosis and weight loss almost 4 months prior. Bad breath was noticed over a year before recognition of CKD by a veterinarian. However, in a retrospective case-controlled study of cats (n= 1,230 with CKD and 1,230 age matched controls) evaluated at primary care veterinary hospitals the probability of CKD diagnosis increased when vomiting, PU/PD, appetite or energy loss or halitosis was present at the time of diagnosis but not when those signs were reported by owners 5 to 12 months earlier (Greene et al, 2014). Median weight loss during the 6 to12 months prior to diagnosis was 5 times greater on a percentage basis in cats diagnosed with CKD than those without (10.8% and 2.1% respectively). Historical factors that also increased the odds of diagnosis of CKD in cats included a documented finding of dehydration, undergoing general anesthesia and diagnosis of periodontal disease or cystitis in the preceding year. Rarely, signs of thromboembolic disease (e.g., severe respiratory distress, posterior paresis) may be present in patients with nephrotic syndrome (i.e., proteinuria, hypoalbuminemia, hypercholesterolemia and ascites/peripheral edema).

Occurrence of clinical signs may depend on the stage of CKD at diagnosis. Dogs and cats with stage 1 CKD generally have no or minimal clinical signs. However, polyuria/polydipsia may occur in some patients during this stage. Systemic clinical signs become more obvious in stages 3 and 4.

Physical Examination

A thorough physical examination is indicated for patients with suspected CKD, with emphasis on those items listed in Table 37-3. Particular attention should be paid  to changes that may facilitate early diagnosis of CKD (eg periodontal disease and body weight/composition). 

Table 37-3. Elements of the physical examination that should be emphasized in patients with suspected chronic kidney disease.

  • Temperature, pulse, heart and respiratory rates
  • Body weight, body and muscle condition score
  • Cardiovascular system: Abnormal heart sounds? Increased tortuosity of superficial veins? Systemic blood pressure (direct or indirect measurement) abnormalities? Pulse rate and character?
  • Cervical region: Thyroid masses (cats)?
  • Ocular: Retinal detachment? Hemorrhage? Increased tortuosity of arteries? Retinal edema? Lipemia retinalis?
  • Genitourinary tract (urethra, prostate gland, penis, prepuce, vulva): Shape? Position? Pain? Discharge?
  • Hydration status
  • Kidneys: Both palpable? Size? Shape? Position? Surface contours? Pain? Bilaterally symmetrical?
  • Musculoskeletal: Muscle masses? Evidence of osteodystrophy?
  • Oral examination: Mucosal ulcers? Pallor? Necrosis or discoloration of tongue? Periodontal disease?
  • Urinary bladder: Size? Position? Shape? Pain? Thickness of wall? Intraluminal masses? Grating sensation?

While useful, body condition scoring has some limitations in patients undergoing catabolism associated with injury or disease. BCS methods focus on the assessment of body fat through evaluation of the body silhouette and palpation of adipose tissue but do not evaluate muscle mass (Laflamme et al, 1997). Both underweight and overweight patients can undergo catabolism of lean body mass (LBM) which will not be recognized using a standard BCS system (Hutchinson et al, 2012). Instead muscle condition must be assessed separately from body condition. Catabolism of LBM can occur rapidly and may account for a disproportionate amount of body mass lost in ill patients (Michel et al, 2011). It is important to recognize loss of lean body mass because while the loss of adipose tissue represents loss of energy reserves, there is no analogous reserve of endogenous protein. Virtually all endogenous proteins are serving some function, and, consequently, continued catabolism will eventually have deleterious consequences for the patient (Freeman, 2012). Therefore, the process of body composition assessment should include not only BCS to assess energy reserves but also a separate evaluation of muscle mass (muscle condition score [MCS]) as an estimate of lean tissue status. Evaluation of muscle mass includes visual examination and palpation over the temporal bones, scapulae, lumbar vertebrae and pelvic bones. A simple MCS scale has been validated in healthy cats (Michel et al, 2011). The WSAVA guidelines consider BCS and MCS integral parts of a nutritional assessment screening evaluation in every patient (Freeman et al, 2011). Much like BCS, MCS is graded on a scale based on careful palpation where a score of 3 indicates normal muscle mass and 0 represents severe wasting (Table 37.4).

Table 37-4. Description of the muscle condition scoring system.

Score Muscle Mass
0 On palpation over the spine, scapulae, skull or wings of the ilium, muscle mass is severely wasted
1 On palpation over the spine, scapulae, skull or wings of the ilium, muscle mass is moderately wasted
2 On palpation over the spine, scapulae, skull or wings of the ilium, muscle mass is mildly wasted
3 On palpation over the spine, scapulae, skull or wings of the ilium, muscle mass is normal
Adapted from: Michel KE, Anderson W, Cupp C, et al. Correlation of a feline muscle mass score with body composition determined by dual-energy X-ray absorptiometry. Br J Nutr. 2011;106 Suppl 1:S57-59.

Dehydration (70%) and decreased body condition (58%) were the most common abnormal physical examination findings in a clinical series of cats with CKD (Lulich et al, 1992). An abnormally large kidney was detected by palpation in 25% of cases and an abnormally small kidney in 16% of cases in this series. The reported prevalence of weight loss in cats with CKD ranges from 42%-82% and depends on stage of disease, comorbid conditions and treatment (Freeman et al, 2016). Several studies have documented a negative association between body weight and survival time in dogs and cats with CKD (Freeman et al, 2016, King et al, 2007, Parker et al, 2011). A large (n=569 cats) multicenter retrospective study of cats found weight loss is present at least 3 years before the diagnosis of CKD (Freeman et al, 2016). In this study weight loss increased progressively over time. While not specifically designed to evaluate the effects of obesity the results showed a U-shaped survival curve. Similar to a study of cats with congestive heart failure, survival was shortest in obese and thin cats (Finn et al, 2010). Obesity is considered a significant risk factor in people for development of CKD (Chang et al, 2016, Zhang et al, 2015). Experimentally induced obesity in dogs increases mean arterial pressure and plasma renin activity which alters renal function and causes histologic changes (Weeth, 2016). A recent study of renal biomarkers in dogs undergoing weight loss has demonstrated changes that support subclinical alterations in renal function in canine obesity (Tvarijonaviciute et al, 2013). Not all studies have found similar correlations. In a study of 100 dogs with CKD, a significant association was found between thin body condition and shorter survival compared to dogs that were normal weight or overweight. However, that study was not sufficiently powered to evaluate the effects of the highest body condition (e.g. 8-9 on a 9 point scale) compared to overweight (6-7 on a 9 point scale) (Parker et al, 2011). Periodontal disease is another common comorbid condition and may be a source of chronic infection /inflammation. A large retrospective longitudinal study of dogs in primary care practices found a positive correlation between increasing severity of periodontal disease and incidence of a clinical diagnosis of azotemia CKD over time (Glickman et al, 2011). Firm swellings in the nasomaxillary region, including the maxillary and mandibular gingival surfaces and extending to frontal sites, may be present in young dogs with stage 4 CKD. These changes result from renal osteodystrophy. Ascites or peripheral edema may be identified in patients with nephrotic syndrome; this finding is more common in dogs than cats.

The primary abnormal findings in some patients with CKD are due to ocular changes (e.g., retinal hemorrhage and detachment) associated with hypertension. In one study, 15 of 23 cats (65%) with CKD had indirect blood pressure measurements consistent with systemic hypertension (Stiles et al, 1994). Twelve of the 15 cats (80%) with hypertension had active hypertensive retinopathy including increased tortuosity of arteries, retinal edema and focal detachments. In a larger study of cats with CKD in a primary care practice setting, prevalence of hypertension in cats with CKD was about 20% (Syme et al, 2002). Screening a population of geriatric cats (≥ 8 years) with ocular fundic examinations identified hypertensive ocular lesions in 16% of cats (Carter et al, 2014). CKD was the most commonly diagnosed concurrent disease in cats with ocular lesions. Hypertensive retinopathy has been reported to occur in dogs with CKD, but it appears to be less common than in cats (Jacob et al, 2003).

Routine Laboratory Evaluation

Most major renal functions can be evaluated diagnostically by routine laboratory tests including complete blood counts (CBC), serum biochemistry profiles and urinalyses (DiBartola, 2005). Table 37-5 lists diagnostic tests that are recommended for patients with suspected CKD. CBC results are useful in dogs and cats with CKD to evaluate the presence of anemia and concurrent disorders such as inflammation from systemic infection. CKD is often associated with a non-regenerative anemia. While the primary pathologic mechanism for this is decreased erythropoietin secretion, in dogs, occult gastrointestinal bleeding (OGIB) may also be a contributing factor. Results of one study document dogs with CKD have a significantly higher incidence of OGIB than healthy controls (Crivellenti et al, 2017). Although the majority (80%) of dogs with stage 2 CKD were not anemic, 90% tested positive for OGIB. Serum hemoglobin, transferrin, and iron concentrations in the CKD group were statistically lower than in the control group and correlated with fecal occult bleeding. This study suggested that fecal occult blood testing may be useful in dogs with CKD.

Table 37-5. Diagnostic tests for evaluating patients with suspected chronic kidney disease.

  • Complete blood cell count
  • Serum biochemistry profile
  • SDMA (symmetric dimethylarginine; IDEXX Reference Laboratory)
  • Systemic blood pressure measurement
  • Urinalysis, including microscopic examination of urine sediment
  • Urine protein to creatinine ratio
  • Bacterial urine culture
  • Diagnostic imaging (abdominal radiography and/or ultrasonography)
  • Excretory urography, if indicated for obstructive uropathy
  • Fecal occult blood test (dogs)
  • Renal biopsy, if indicated for evaluation of persistent proteinuria or suspected renal neoplasia

Azotemia is defined as increased serum urea nitrogen or creatinine (serum creatinine) concentrations. Increased serum concentrations of urea nitrogen or creatinine may result from pre-renal, renal or post-renal disorders (See Glomerular Filtration and Localization of Azotemia below). Results of serum biochemistry profiles reveal renal azotemia from reduced GFR in patients in stages 2 to 4 CKD. Since serum creatinine does not exceed laboratory reference intervals until up to 75% of functional renal mass has been lost dogs and cats with stage 1 CKD do not have azotemia. Dogs and cats with CKD have impaired urine concentrating ability and usually have urine specific gravity values <1.030 (dogs) or <1.040 (cats), with concurrent clinical dehydration or azotemia. Some cats with stage 2 CKD may retain urine concentrating ability (urine specific gravity values >1.040). However, these patients have gradually decreasing urine specific gravity values as CKD progresses (e.g., over a period of 18 months) (Polzin et al, 2005). Additional notable urinalysis findings may include proteinuria (See Altered Membrane Permselectivity below), glucosuria from tubular dysfunction or pyuria associated with urinary tract infection.

Renal Biomarkers

Glomerular filtration rate (GFR) is considered the gold standard for evaluating kidney function. However, GFR assessment is time-consuming, labor-intensive and not routinely available in clinical practice (See Glomerular Filtration below). The commonly used indirect GFR markers, serum creatinine and urea, are not sufficiently sensitive or specific to detect early renal dysfunction. Therefore, there is a need for better methods to diagnose and monitor patients with kidney disease. The development of clinically useful biomarkers is an active field of research in human and veterinary medicine (Smets et al, 2010, Cobrin et al, 2013, Ghys et al, 2014, Ghys et al, 2016, Williams et al, 2016, Williams et al, 2016 b, Hokamp et al, 2016, Yerramili et al, 2016, Whitehouse et al, 2017). An ideal biomarker would identify site and severity of injury, correlate with renal function, be non-invasive and rapidly available from a reference laboratory or point of care assay. To date only one, symmetric dimethylarginine (SDMA), has proven reliable in dogs and cats and is readily available from a reference laboratory (IDEXX Reference Laboratory, Inc.) (Hall et al, 2014, Hall et al, 2014b, Hall et al, 2015, Nabity et al, 2015, Hall et al, 2016, Hall et al, 2017, Dahlem et al, 2017). SDMA is eliminated primarily by glomerular filtration and is not affected by tubular reabsorption or secretion. Therefore, it can be used as an intrinsic GFR marker. In contrast to serum creatinine, SDMA is not influenced by changes in muscle mass making it more reliable for assessing kidney function in animals with chronic kidney disease or other conditions that result in weight and muscle loss, such as hyperthyroidism (Hall et al, 2014, Hall et al, 2015). A recent retrospective study found 92% of cats with kidney stones had increased serum SDMA concentrations at the time of diagnosis while only 17% were azotemic (Hall et al, 2017). In these cats SDMA was increased a mean of 26.9 months (range, 0-60 months) before serum creatinine was elevated. The authors concluded that using SDMA as a biomarker for reduced kidney function allows for earlier detection of kidney stones and recommend imaging studies in mid to older aged cats with increased SDMA especially if urine specific gravity is > 1.035. Since SDMA increases when GFR is decreased by as little as 25% in cats and as little as 20% in dogs it permits earlier diagnosis of kidney disease than serum creatinine which requires loss of 75% of kidney function (Hall et al, 2014, Nabity et al, 2015). SDMA has been included as part of the IRIS CKD guidelines, as modified in 2015, for staging of both early and advanced CKD. A persistent elevation in SDMA (> 14 mcg/dL on two separate occasions 2-4 weeks apart), accompanied by an isosthenuric USG, even if serum creatinine levels are within normal limits (< 1.4 mg/dL dogs or 1.6 mg/dL cats) indicates reduced renal function and IRIS stage 1 CKD. Like serum creatinine, hydration status and physical examination findings must be taken into consideration when interpreting SDMA values (Grauer, 2016). For example, pre-renal azotemia is the likely cause of an elevated SDMA concentration (e.g. 16 mcg/dL) in a dehydrated dog or cat with USG of > 1.040. Dogs and cats with borderline serum creatinine and/or SDMA concentrations should be retested. Initially two weeks after first testing to confirm the value, then approximately every 3 months thereafter to assess renal function stability.

Diagnostic Imaging

Once CKD is diagnosed, medical imaging studies may reveal an underlying cause. Causes that may be detected include polycystic kidney disease (PKD), nephrocalcinosis, urinary obstructive disease and renal neoplasia; additionally signs of feline infectious peritonitis (FIP) or pyelonephritis may be identified (Paepe et al, 2013). Radiography and ultrasonography are complementary imaging modalities that help assess renal structure and localize disease within the urinary tract (Rivers and Johnston, 1996). Survey radiographs can assess renal size by comparing the length of the kidneys with the length of the second lumbar vertebral body on the ventrodorsal view. In a retrospective series of cats with CKD, 33% had small kidneys, 40% had kidneys of normal size and 27% had larger than normal kidneys as determined by imaging procedures (DiBartola et al, 1987). Abdominal radiography may also reveal uroliths. Contrast radiography may improve urolith detection and localization. More detailed information regarding internal renal architecture can be obtained with ultrasonography (DiBartola, 2010). Typical renal ultrasonographic findings in cats with CKD are small and irregularly outlined kidneys, increased cortical and/or medullar echogenicity, loss of corticomedullary demarcation, areas of mineralization and poor visualization of internal architecture (Widmere et al, 2004). However, there is poor correlation between ultrasonographic findings and the degree of renal dysfunction. Moreover, because renal ultrasonographic abnormalities are frequently seen in healthy cats, further research regarding the clinical relevance of renal ultrasonographic abnormalities is required (Paepe et al, 2013). One study in cats identified a positive association between urolithiasis and CKD but it remains unknown whether urolithiasis is a predictive factor for, or a consequence of, CKD (Cleroux et al, 2017). More detailed information on ultrasonography of the feline kidney is provided in a recent review article (Debruyn et al, 2012). Contrast-enhanced ultrasound (CEUS) is an emerging technique to evaluate tissue perfusion. Promising results have been obtained in the evaluation of renal perfusion in health and disease, both in human and veterinary medicine. One study shows that CEUS is able to detect changes in feline renal perfusion (Stock et al, 2016). A recent study in dogs and cats found assessment of renal cortical echogenicity to be a poor test to discriminate between normal and chronically affected kidneys in dogs. Pathological changes were evident only in chronic stages of disease in cats thus limiting the usefulness of ultrasonography in detecting mild renal disease (Banzato et al, 2017). Excretory urography can be used to qualitatively assess renal function and detect evidence of upper urinary tract obstruction.

Radiography also is useful in the diagnosis of renal osteodystrophy. In young dogs with advanced CKD, radiographs of the skull reveal generalized osteopenia, irregular mineralization and dense soft-tissue swelling of the mandibles, maxillae and zygomatic arches. The most striking radiographic finding is demineralization of lamina dura dentes (i.e., bone surrounding the teeth). Radiographs of long bones reveal normal-appearing cortices with a coarse trabecular pattern of the metaphyseal and epiphyseal regions, suggesting demineralization. Spontaneous fractures may be evident. The radiographic diagnosis of fibrous osteodystrophy is applied to this constellation of findings.

Blood Pressure Measurement

Systemic blood pressure varies markedly in healthy pets and may be compounded further by effects of anxiety associated with blood pressure measurement in a hospital environment, and other factors (Bodey and Michell, 1996; Remillard et al, 1991; Brown et al, 2007). Several studies have evaluated different techniques for measuring blood pressure in dogs and cats. In the clinical setting, however, blood pressure is most often measured indirectly (e.g., Doppler ultrasonography, oscillometric techniques). To obtain the most reliable blood pressure values it is important to follow a standard protocol (Table 37-6) (Brown et al, 2007). The IRIS has proposed that dogs and cats with CKD should be sub-staged on the basis of risk of hypertensive injury as determined by serial blood pressure measurements (Table 37-1b). Dogs and cats with CKD with indirect systolic blood pressures less than 150 mm Hg are considered to have minimal risk of hypertensive injury. Patients with CKD and moderate or high risk of hypertensive injury or with overt evidence of hypertensive injury (e.g., hypertensive retinopathy) should be treated with appropriate antihypertensive medications. Despite difficulties measuring blood pressure and confusion regarding diagnostic criteria, hypertension is a clinically important problem because of its apparent prevalence and potential for associated end-organ damage (e.g., retinal hemorrhage and left ventricular hypertrophy) (Morgan, 1986; Littman, 1994; Elliott et al, 2006a; Brown et al, 2007).

Table 37-6. Standard protocol for measuring blood pressure in dogs and cats.*

Canine Studies

About 10% of apparently healthy dogs (Remillard et al, 1991) and 9% to 93% of dogs with CKD are hypertensive (Brown et al, 2007). Measurement of blood pressure in dogs is now commonly performed with noninvasive techniques and a variety of devices are available. However, because no specific requirements for the validation of veterinary devices exist, some currently marketed devices have not been validated. Confounding this issue is the lack of a standard validation methodology which makes direct comparison between devices difficult or impossible. One study compared 3 indirect arterial blood pressure measurement devices; Doppler ultrasonic flow detector, standard oscillometric device and high definition oscillometric device, in hospitalized dogs (Wernick et al, 2012). The coefficient of variation (CV) differed greatly for all 3 devices with the Doppler device having the least variation and lowest estimated overall CV. Results of this study suggested that for an individual dog meaningful clinical comparison can only be made between blood pressure readings obtained by the same indirect blood pressure measurement device. A study designed to assess the effects of age, body condition score (BCS) and muscle condition score (MCS) on indirect radial and coccygeal Doppler systolic arterial blood pressure (SAP) in client owned dogs found no association with patient variables but concluded that the same site should be used for serial SAP measurements (Mooney, et al 2017). In this study radial SAP measurements were higher than coccygeal SAP measurements (mean difference 9 mm Hg, P<0.01) but discordance occurred in both directions. Body position also significantly affects SAP. Using Doppler ultrasonography mean ± SD SAP was significantly higher (172.1 +/- 33.3 mm Hg) when dogs were sitting (on hind limbs with non-measured forelimb bearing weight) compared to measurements obtained when laterally recumbent (147.0 +/- 24.6 mm Hg) despite maintaining the cuff position at the level of the right atrium for both positions (Rondeau et al, 2013). Additionally, SAP measurements were less variable when dogs were laterally recumbent. Management of systemic hypertension requires serial measurements to assess response to therapy or progression of disease. To obtain the most reliable representation of changes in SAP over time each dog should be evaluated with the same device, preferably Doppler ultrasonography, using the same cuff placement site and body positioning (preferably lateral recumbency).

Feline Studies

Increased serum creatinine concentrations occur in up to 74% of hypertensive cats and 19%–65% of cats with CKD are hypertensive (Syme et al, 2002; Brown et al, 2007; Taylor et al, 2017). Two recent studies provide evidence that blood pressure increases with age in all cats (Bijsmans et al, 2015, Payne et al 2017). In the only study designed to follow changes in systolic blood pressure (SBP) over time found it increased with age in both healthy and CKD cats. Cats with CKD that developed hypertension had higher baseline blood pressure than their normotensive counterparts (Bijsmans et al, 2015). The authors recommend monitoring SBP in all elderly cats and that cats with CKD with baseline blood pressure ≥ 140 mm Hg should be more closely monitored.

A study of client owned nonazotemic geriatric (≥ 9 years) cats found 12.7% were hypertensive upon initial evaluation (Jepson et al, 2009). While some of these cats may have had white-coat hypertension, hypertensive choroidopathy was identified in 60% as primary evidence of target organ damage. The remaining cats had persistently elevated SBP before antihypertensive treatment was initiated. These nonazotemic cats were not evaluated with SDMA but did have significantly lower USG and higher urine albumin to creatinine ratios than did normotensive cats. In a large study of apparently healthy cats (n=780) factors independently associated with a higher systolic blood pressure were increasing age, being nervous, being male, being neutered and being a stray (Payne et al, 2017). The median systolic blood pressure in this population, measured using an auscultatory Doppler technique, was 120.6 (110.4-132.4) mm Hg. It is important to note that the magnitude of ‘white coat hypertension’ in healthy cats has been shown to be as much as 80 mm Hg in response to a simulated clinic visit (Belew et al, 1999). The most commonly used methods for blood pressure measurement in cats are Doppler sphygmomanometry with the cuff placed at the mid-forelimb, and oscillometric techniques with the cuff placed at the tailhead. The technical aspects of these techniques have been well described (Syme et al, 2002, Jepson et al, 2005, Haberman et al, 2004). Either method may be used to accurately estimate systolic blood pressure (SBP) in a clinical patient. However, some studies suggest that traditional oscillometry is less accurate than Doppler in conscious cats, often underestimating BP at higher values. Additionally, there are many cats for which it is difficult or impossible to achieve BP measurements with traditional oscillometry equipment (Haberman et al, 2004, Jepson et al, 2005, Pedersen et al, 2002). Recently, high-definition oscillometry (HDO) equipment has been developed to overcome the problems of traditional oscillometry. It has shown to provide accurate results and appears that there are fewer cats for which it is difficult to obtain a reading (Martel et al, 2013, Cannon et al, 2012). As in other species, BP in cats is labile and varies considerably within and between individuals, depending in part on their level of arousal, activity or stress. Clinical assessment of SBP is also affected by many external variables including the operator, conditions, environment, equipment, position of the cat, size of the cuff, and site of measurement (Haberman et al, 2004, Jepson et al, 2005, Gouni et al 2015). Careful measurement of systolic blood pressure in conjunction with evaluation for evidence of hypertensive choroidopathy (funduscopic examination) and hypertensive cardiac changes (thoracic auscultation) are essential to the diagnosis of systemic hypertension in cats (Stepien, 2011). Target organ damage is common in hypertensive cats; ocular abnormalities are detected in about 40%–60% of hypertensive cats, auscultable cardiac abnormalities are detected in about 50%–70% and neurologic abnormalities in approximately 15% (Taylor et al, 2017).

Evaluation of Renal Function

The primary functions of the kidneys are to excrete metabolic wastes (e.g., urea, creatinine), regulate fluid, electrolyte and acid-base balance and produce or activate several hormones including erythropoietin, calcitriol and renin. Anatomically, these functions occur in glomeruli (i.e., glomerular filtration and membrane permselectivity), renal tubules (i.e., urine con- centration and tubular resorption) and other areas of the kidney (i.e., erythropoietin, calcitriol, renin). CKD may be associated with generalized renal dysfunction or it may involve only one function (e.g., tubular resorptive defect in Fanconi syndrome).

Glomerular Filtration

The most commonly evaluated renal function is glomerular filtration, which is determined by estimating or measuring GFR. Under steady state conditions, serum concentrations of urea nitrogen and creatinine are the time-honored methods for indirectly estimating GFR. These tests are useful for detecting large decreases in GFR (75% or greater), but lack sensitivity for detecting smaller decreases in glomerular filtration (Figure 37-1). In addition, serum urea nitrogen and creatinine values are affected by non-renal factors, which contribute to the broad ranges for normal values.

Clinician's Brief

Figure 37-1. The relationship between serum creatinine concentration and % of normal glomerular filtration rate (GFR) or % of remaining functional nephrons is not linear. As a result, small changes in GFR during early chronic kidney disease do not result in increased serum creatinine concentrations. Note that values for serum creatinine do not exceed the upper reference range (broken line) until kidney dysfunction is marked (i.e., when 75% of nephrons are nonfunctional).

Urea is produced in the liver from ammonia derived from the ornithine cycle, which catabolizes amino acids. The catabolized amino acids come from exogenous (dietary) and endogenous proteins. Urea is distributed throughout intracellular and extra- cellular water and is freely diffusible; therefore, it is common to use the terms blood urea nitrogen, serum urea nitrogen and plasma urea nitrogen interchangeably. The kidneys excrete urea by glomerular filtration, and serum urea nitrogen concentrations are inversely proportional to GFR. However, because urea is passively reabsorbed in the tubules, especially at reduced tubular flow rates, urea clearance is not an accurate measure of GFR. Clinical conditions that can increase serum urea nitrogen concentration include gastrointestinal hemorrhage, consumption of high-protein foods and catabolic drugs (e.g., glucocorticoids). Severe hepatic disease (e.g., portosystemic vascular shunts), feeding a low-protein food and conditions causing increased urine volume (e.g., intravenous fluid therapy) can decrease serum urea nitrogen concentrations independent of renal function.

Creatinine results from the nonenzymatic breakdown of muscle phosphocreatine. During steady states, creatinine production is constant and related to muscle mass. Serum creatinine concentration is less influenced by feeding than serum urea nitrogen concentration. However, it may be affected by breed and body size (Gleadhill, 1995). In a study of retired racing greyhounds, mean values for serum creatinine concentration (1.8 ± 0.1 mg/dl) and GFR (3.0 ± 0.1 ml/min./kg) were significantly greater than values from control dogs. However, blood urea nitrogen values were not different (Drost et al, 2006). Increased serum creatinine levels in greyhounds may be due to increased muscle mass in this breed. In contrast, it is possible for serum creatinine concentration to remain lower than expected or to not be increased in proportion to the decrease in GFR in older patients with decreased muscle mass and kidney disease.

When considering the magnitude of azotemia, it’s important to recognize that the relationship between serum urea nitrogen and creatinine concentrations and GFR is not linear (Figure 37-1). Thus, very large changes in GFR early in the natural course of CKD cause only small changes in serum urea nitrogen and creatinine concentrations. These small changes may not exceed the upper limit of the laboratory reference range and thus may go unrecognized throughout most of stage 1 CKD. Small decreases in GFR cause disproportionately large increases in serum urea nitrogen and creatinine concentrations in more advanced CKD (stages 3 and 4).

Evaluation of serum urea nitrogen and creatinine is used to indirectly assess GFR in most patients; however, directly measuring GFR is helpful for identifying kidney dysfunction that occurs before the onset of azotemia (e.g., breeds known to have familial kidney disease, patients with polyuria/polydipsia due to kidney disease, when potentially nephrotoxic treatment will be used). Urinary clearance of infused inulin is the gold standard for measuring GFR. However, this technique is limited to research settings because it requires collection of multiple, timed blood and urine samples and a constant rate infusion of inulin. Other methods have been used to estimate GFR but each has disadvantages. Endogenous creatinine clearance underestimates GFR because non-creatinine chromogens are present in plasma. Exogenous administration of creatinine reduces this potential problem by decreasing the proportion of non-creatinine chromogens in plasma. A newer creatinine-specific enzymatic analytical method eliminates the problem (Finco et al, 1993). However, in cats, exogenous creatinine clearance does not accurately estimate GFR (Finco et al, 1996). In addition, factors other than GFR (e.g., hydration status) can affect creatinine clearance and serum creatinine concentration. Clearance of iohexol, a readily available radiographic contrast medium, has been used to reliably estimate GFR in dogs and cats and is a method that can be used in clinical practice (Finco et al, 2001; Miyamoto 2001, 2001a; Goy-Thollot et al, 2006; Sanderson, 2009).

Recently, symmetric dimethylarginine (SDMA) has been shown to be a specific endogenous renal biomarker in dogs and cats that is not influenced by extra-renal factors (see Renal Biomarkers above) (Relford, et al 2016). SDMA is derived from intranuclear methylation of L-arginine by protein-arginine methyltransferases; it is released into the blood after proteolysis. SDMA is eliminated primarily by glomerular filtration and is not affected by tubular reabsorption or secretion. Therefore, it can be used as an intrinsic GFR marker. Several studies in humans have documented the utility of serum SDMA concentrations as a biomarker of renal function; a meta-analysis of 18 studies involving more than 2,100 people documented a high correlation of SDMA to both GFR and serum creatinine (Braff et al, 2014).

In addition to correlating well with GFR, serum SDMA may be a more sensitive biomarker for detection of early CKD than serum creatinine. In longitudinal studies in cats that developed CKD, SDMA increased above normal (> 14 mcg/dL) in 17 of 21 cats a mean of 17 months (range, 1.5–48 months) before serum creatinine exceeded its reference range (>2.1 mg/dL) (Hall et al, 2014). SDMA detected CKD earlier because it was elevated when measured GFR (mGFR) was on average 40% below baseline and in some cases when mGFR decreased by as little as 25%. In this feline study, serum SDMA had a sensitivity of 100%, specificity of 91%, positive predictive value (PPV) of 86%, and negative  predictive value (NPV) of 100% when using a 30% decrease from median mGFR (by iohexol) as the reference limit to confirm decreased renal function. The specificity and PPV of SDMA were affected by what were considered as 2 false- positives. In both cases, SDMA level was increased above the reference interval but mGFR was 25% below the median reference; this might mean that SDMA testing was able to detect CKD even earlier in these cats. In this same study, serum creatinine had a sensitivity of only 17%, specificity of 100%, PPV of 100%, and NPV of only 70%. Similarly, in dogs that developed CKD, SDMA increased above normal (> 14 mcg/dL) a mean of 17 months (range, 11–26 months) before serum creatinine exceeded its reference interval (> 1.8 mg/dL). (Hall et al, 2016) 50 In male dogs with X-linked hereditary nephropathy, SDMA identified, on average, a less than 20% decrease in GFR significantly earlier than serum creatinine (Nabity et al, 2015). In addition, with use of a single cutoff value for SDMA, reductions in GFR were detected earlier compared with a single serum creatinine cutoff value or serum creatinine trends over time. Preliminary results suggest that serum SDMA:creatinine ratios may have prognostic value in dogs and cats with CKD (as long as the SDMA value is > 14 mcg/dL); ratios greater than 10 were associated with mortality within 1 year (Yerramilli et al, 2014). Results of these studies confirm serum SDMA is an earlier biomarker than serum creatinine for diagnosing and monitoring CKD in cats and dogs allowing more time for practitioners to positively intervene. Unlike creatinine, SDMA is not influenced by muscle mass, age, and breed. An SDMA assay specifically developed for veterinary applications and validated for both cats and dogs is commercially available (IDEXX Laboratories, Inc) making its incorporation into serum screening and monitoring protocols practical in clinical cases, unlike more invasive methods of assessing GFR.

Altered Membrane Permselectivity

Persistent proteinuria with an inactive urine sediment is an established marker of CKD (Lees et al, 2004). Proteinuria results when the normal renal handling of protein malfunctions or is overwhelmed. Normally the small amount of protein that is present in the filtrate is passed through the glomerular capillary wall and reabsorbed by the proximal tubule. The glomerular capillary wall serves an anatomical barrier and the primary mechanism by which proteinuria is prevented. In patients with glomerular disease, permselective properties of the glomerular capillary wall are altered and increased amounts of protein are present in urine. Proteinuria may be caused by physiologic or pathologic conditions. Physiologic or benign proteinuria is usually transient, of low magnitude, and abates when the underlying cause is corrected. Examples of conditions that may cause physiologic proteinuria include strenuous exercise, seizures, fever, exposure to extreme heat or cold, and stress.

Pathologic proteinuria may be classified as urinary or non-urinary in origin. Non-urinary disorders include “prerenal” proteinuria (e.g. production of immunoglobulin light chains (Bence Jones proteins) by neoplastic plasma cells) and genital tract inflammation (e.g., prostatitis or metritis). Pathologic urinary proteinuria may be renal or non-renal in origin. Non-renal proteinuria most frequently occurs in association “post renal” lower urinary tract inflammation or hemorrhage. Clinical signs and urine sediment findings are usually compatible with lower urinary tract disease; pollakiuria, dysuria, stranguria, and/or hematuria and pyuria, hematuria, bacteriuria, and increased numbers of transitional epithelial cells respectively. Renal proteinuria is typically caused by increased glomerular filtration of plasma proteins associated with intraglomerular hypertension, the presence of immune complexes, vascular inflammation in glomerular capillaries, or structural defects in the glomerular basement membrane. A small degree of renal proteinuria may also be caused by decreased reabsorption of filtered plasma proteins due to tubulointerstitial disease. In some cases, tubulointerstitial proteinuria may be accompanied by normoglycemic glucosuria and increased excretion of electrolytes (e.g., Fanconi syndrome and acute tubular damage). Glomerular lesions usually result in more severe proteinuria than tubulointerstitial lesions. Renal proteinuria may also be caused by inflammatory or infiltrative disorders of the kidney (e.g., pyelonephritis, leptospirosis, neoplasia) which are often accompanied by an active urine sediment and ultrasonographic changes in the kidney.

Clinical significance of proteinuria depends on its severity and persistence. In the absence of hyperproteinemia, hematuria and urinary tract inflammation, persistent proteinuria usually indicates kidney disease and severe proteinuria (urine protein-creatinine ratio [UPC] ≥ 2) is generally associated with glomerular disease. The magnitude of proteinuria does not predict reversibility of the underlying disease. However, there is growing evidence linking renal proteinuria and progression of CKD in dogs and cats; the greater the magnitude of proteinuria, the greater the risk for progression of renal disease and possible death (Jacob et al, 2005, Syme et al, 2006, Kuwahara et al, 2006, Jepson et al, 2007, King et al 2007, Jepson et al, 2009, Jepson et al, 2010, Chakrabarti et al, 2012, McLeland et al, 2015). Importantly, treatments that attenuated proteinuria in dogs and cats with CKD also have been associated with slowed progression of CKD, improved survival, or both (Jepson et al, 2007, King et al, 2007, Grauer et al, 2000, Mizutani et al, 2006). For these reasons, screening for renal proteinuria and longitudinal assessment of renal proteinuria is important for prognosis and assessment of response to treatment. 

The urine dipstick colorimetric test is the most common first-line screening test for the detection of proteinuria/albuminuria; however, false-positive reactions are common and limit the test’s utility (Grauer et al, 2004, Zateli et al, 2010, Hanzlicek et al, 2012, Mamone et al, 2014). While false-positive results (decreased specificity) are common in both species cats are more frequently affected. However, one recent study suggests one brand of dipsticks (Aution Sticks 10PA Aution Sticks 10EA, ARKRAY, Kyoto, Japan) can be used to screen dogs and cats for persistent proteinuria. In this study of urine from 101 dogs and 50 cats the dipstick UPC correlation with the quantitative method was good in cats (rs=0.89 p < 0.0001) and fair in dogs (rs =0.75 p<0.001) (Defontis et al, 2013). The authors note automated reading of the dipsticks (Aution Eleven reflectometer AE-4020, ARKRAY, Kyoto, Japan) was better than visual reading and is the preferred method for urine dipstick examination when available and positive results should be submitted to a reference laboratory for quantitative measurement. Disparate results were documented in a study of 599 canine and 347 feline urine samples analyzed by conventional urine protein test strip method (Multistix Reagent Strips; Bayer Corporation, or Roche Chemstrip 9; Roche Diagnostic Corporation) and a canine or feline albumin-specific quantitative enzyme-linked immunosorbence assay (ELISA) (Heska Corporation) (Lyon et al, 2010). Based on this study in canine urine, if the urine dipstick or SSA result is ≥2+ there is a high likelihood that the sample is positive for albumin. However, if the dipstick analysis is trace or 1+ positive, a turbidimetric SSA analysis should be performed to confirm the diagnosis of proteinuria. To increase specificity, when the dipstick and SSA tests are performed simultaneously, they should be interpreted in series (both tests should be positive to consider the sample positive for albuminuria), rather than in parallel. If dipstick and SSA results both fall into the trace to 1+ range, positive results should be confirmed with a more specific assay such the ELISA-based test. In these studies of feline urine samples, both routine-screening tests (dipstick and SSA) performed poorly and appear to be of minimal diagnostic value because of an unacceptable high number of false positives (Lyon et al, 2010). For both dipstick and SSA tests, the positive and negative likelihood ratios were close to 1 and the positive and negative predictive values were close to 50%, indicating that neither test provided useful information. Based on these data, some investigators suggest, urine albumin detection in the feline patient should always be performed with a higher quality assay such as the species-specific ELISA (Grauer, 2011). Historically, proteinuria detected by these screening methods has been interpreted in light of urine specific gravity and urine sediment such that a trace or 1+ positive dipstick reading in hypersthenuric urine was attributed to urine concentration rather and abnormal proteinuria. Additionally, positive dipstick reading in the presence of an active urine sediment (hematuria or pyuria) was attributed to urinary tract hemorrhage or inflammation. However, these interpretations may be inaccurate. Except in the case of false-positive results, given the limits of conventional dipstick test sensitivity, any positive result for protein regardless of urine concentration may be abnormal. Additionally, not all dogs with microscopic hematuria and pyuria have albuminuria (Vaden et al, 2004). In patients with gross hematuria and/or microscopic pyuria, the source of the hemorrhage and/or inflammation should be diagnosed and treated before further assessment of the proteinuria.

If the results of the screening tests show persistent proteinuria, urine protein excretion should be quantified to facilitate IRIS staging (Table 37-1b), evaluate the severity of renal lesions and to assess the response to treatment or the progression of disease. Urinary protein is most accurately measured by a quantitative analytical technique rather than by dipstick. Methods used to quantitate proteinuria include UPC and immunoassays for albuminuria. Persistent microalbuminuria is the mildest, and often earliest, detectable form of proteinuria. Microalbuminuria (MA) is defined as concentrations of albumin in the urine that are greater than normal (> 1.0 mg/dL) but below the limit of detection using conventional dipstick urine protein screening methodology (i.e., ≤ 30 mg/ dL). 

Indications for Use of MA Tests

  1. When equivocal or conflicting results or false-positive results are obtained/suspected with conventional screening tests for proteinuria;
  2. When conventional screening tests for proteinuria are negative in apparently healthy, older dogs and cats and a more sensitive screening test is desired;
  3. When conventional screening tests for proteinuria are negative in apparently healthy, young dogs and cats that have a familial risk for developing proteinuric renal disease and a more sensitive screening test is desired;
  4. When conventional screening tests for proteinuria are negative in dogs and cats with chronic illnesses that are often associated with proteinuria renal disease and a more sensitive screening test is desired;
  5. Confirmation/longitudinal monitoring of previously positive MA tests.  

Like other tests for proteinuria, MA tests can be affected by lower urinary tract inflammation. A negative MA result is a useful finding because it preempts any concern about albuminuria until the next monitoring point. A positive test result is more complex and must be confirmed with repeat testing in 7 to 10 days. If the follow up test is negative, the most common explanation is transient, benign, or physiologic albuminuria that is unlikely to have any long-term consequence for the patient. If follow-up tests are positive, more frequent monitoring and further investigation are indicated. Increases in magnitude of MA are indicative of active, ongoing renal injury and should prompt further investigation to detect any neoplastic, infectious, or noninfectious inflammatory disease that might be the underlying cause of kidney disease (Grauer, 2011).

The UPC from spot urine samples accurately reflects the quantity of protein/albumin excreted in the urine over a 24-hour period, but it is ideal to base clinical decisions on the average of more than one UPC. Most studies have shown that normal urine protein excretion in dogs and cats is ≤10 mg/kg/24 hours and that normal UPCs are ≤0.2. (Previously suggested reference values for canine UPC of ≤ 1.0 have been lowered.) Currently a UPC of 0.2 to 0.5 in dogs and 0.2 to 0.4 in cats is considered borderline proteinuria (Lees et al 2005).99 Persistent proteinuria that results in UPC > 0.4 in cats and 0.5 in dogs, where prerenal and postrenal proteinuria have been ruled out, are consistent with glomerular or tubulointerstitial CKD, whereas UPC >2.0 is strongly suggestive of glomerular disease (Lees et al, 2005, Hokamp et al, 2016). It is likely that the definition of a normal UPC will continue to change with additional research. Studies in dogs and cats with CKD indicate that proteinuria is an important predictor of survival (Syme et al, 2006; Jepson et al, 2007; Jacob et al, 2005). Cats with UPC values consistently less than 0.2 have significantly longer survival than cats with UPC values greater than 0.4 (Syme et al, 2006; Jepson et al, 2007). When nonazotemic cats were evaluated prospectively and longitudinally, proteinuria was found to be associated significantly with the development of azotemia by 12 months (Jepson et al, 2009). Similarly, dogs with CKD and UPC values above 1.0 had significantly shorter survival than dogs with UPC values less than 1.0 (Jacob et al, 2005). Despite correlation of survival with proteinuria in cats with CKD, there is considerable overlap of survival times across the severity range of proteinuria. Accurate prediction of survival time for individual patients is not possible based on severity of proteinuria (Syme et al, 2006).

Urine Concentration

Disorders of urine concentrating ability generally involve abnormalities in the secretion of, or response to, antidiuretic hormone. Loss of concentrating ability can be one of the earliest indicators of kidney dysfunction, which is generally recognized when two-thirds of nephrons are nonfunctional. In CKD, the renal interstitial osmolality gradient is decreased because of increased urine flow per nephron or because of inability to establish and maintain the medullary concentration gradient. The resultant decrease in responsiveness to antidiuretic hormone leads to excretion of urine with osmolality or specific gravity values similar to those of plasma (i.e., isosthenuria).

Estimation of urine concentrating ability from urine specific gravity or refractive index is most often used for clinical purposes. The physiologic range for urine specific gravity is 1.001 to 1.070 in dogs and 1.001 to 1.080 in cats. Any urine specific gravity value may be normal; therefore, it’s important to interpret specific gravity in the context of clinical findings including hydration status, concurrent disease and medications. (See Diagnosis of Chronic Kidney Disease.) In a retrospective series of cats with CKD, 37% had urine specific gravity values between 1.008 to 1.012 and 60% were between 1.013 and 1.034 (Lulich et al, 1992). However, some cats with CKD may have urine specific gravity values greater than 1.040 and remain persistently azotemic (up to 18 months) before losing concentrating ability (Polzin et al, 2005 White et al, 2006, Jepson et al, 2009). In a prospective longitudinal cohort study monitoring a population of healthy non-azotemic geriatric (median age 13 [11-15] years) cats 30.5% developed azotemia within the 12-month study period. Among other variables USG was significantly associated with development of azotemia in the univariable analysis (P≤.05) (Jepson et al, 2009). At entry into the study the mean USG for all cats was 1.047 (1.030 – 1.058). Of these 31.4% (37/118) had USG ≤ 1.035. Those cats that developed azotemia at 12 months had significantly lower USG at entry (n=29, mean USG = 1.042, range 1.023 – 1.051) than did those that remained non-azotemic (n=66 mean USG = 1.050, range 1.032-1.060). They also showed a significant decrease in USG between entry to the study and the point of development of azotemia. At 12 months mean (range) USG for non-azotemic cats (n= 52) was 1.037 (1.029 – 1.060) and 1.020 (1.016-1.030) for azotemic cats (n=22). Interestingly. 4 cats in this study developed azotemia and clinical signs consistent with CKD but maintained urine concentrating ability (USG 1.064,1.050, 1.041, 1.036).

A retrospective case-controlled study designed to identify risk factors associated with the diagnosis of CKD reported the median USG was 1.018 (range 1.001-1.034) in 1,230 cats with CKD (Greene et al, 2014). The distribution of IRIS CKD stages among the 1,230 case cats was: 424 (34.5%) stage 2, 544 (44.2%) stage 3 and 262 (21.3%) stage 4. Result of clinical parameters for a small group of client owned cats with IRIS stage 1-4 CKD and healthy older control cats documented no differences in USG between control (n=11) and stage 1 (n=8), USG 1.044 (1.035-1.061) and 1.021 (1.008 -1.029) respectively. Iris stage 2 (n=38) and 3 (n=21), USG 1.015 (1.010 -1.034) and 1.014 (1.008 – 1.026) respectively, were significantly different from stage 1 but not each other. Predictably stage 4 cats had the lowest median USG 1.009 (1.007 – 1.014) which was significantly lower than all other groups  (Whitehouse et al, 2017).47 The authors note that future studies should also incorporate SDMA measurements, which allow identification of more cats with stage 1 CKD, because SDMA concentration can become abnormal before the serum creatinine concentration threshold of 1.6 mg/dL. In a prospective cross section study designed to examine USG of apparently healthy cats presented to first opinion practices USG was > 1.030 in 91% and > 1.035 in 88% of 976 apparently healthy cats. The USG was < 1.030 in 121 adult cats (> 6 months old) and < 1.035 in 5 kittens (< 6 months old) (Rishniw et al, 2015). Of these cats a pathological cause was identified in 27 adult cats (26 > 9 years old, and one 9 months old) and none of the kittens. CKD and hyperthyroidism were the most common diagnosis in the older cats. Cats over 9 years old had a higher probability of having a subclinical disease process identified as a cause of a USG of <1.035 than younger cats. Logistic regression identified three factors that independently affected the odds of an apparently healthy cat having a USG of < 1.035: age, visit reason and diet. Odds increased with increasing moisture content of the diet, age and reason for presentation to the first opinion practitioner (annual examination vs. elective anesthetic procedure). Interestingly, the USG differed with analysis method, specifically; urine analyzed by reference laboratories had higher USG than that analyzed by in-clinic refractometers. No difference was found between types of in-clinic refractometers (those with feline specific scales vs. those without). Two recent studies have suggested that some in-clinic refractometers do not accurately reflect USG. In some studies measured specific gravity is lower than expected SG and the discrepancy increased with increasing USG in both dogs and cats (Tvedten et al, 2014, Tvedten et al, 2015). However, reported accuracy of refractometers vary, other studies report devices are highly correlated to the urine osmolality and valid for assessment of USG in clinical practice in cats and dogs (Miyagawa et al, 2010, Bennett et al, 2011, Paris et al, 2012). While the majority of cats with spontaneously occurring CKD have urine specific gravity values less than 1.035 (Polzin et al, 2005) as the definition of early kidney disease evolves, use of ‘cut off’ values as an indication of kidney disease may become irrelevant.

Although it has not been reported, it is generally accepted that urine specific gravity in dogs with naturally occurring CKD is less than 1.030. In a cross-sectional study median USG was significantly different in healthy controls (n=20) compared to dogs with CKD (n=10); 1.035 (1.008 – 1.050) vs. USG 1.010 (1.008 – 1.017) p<0.0001 respectively (Smets, et al, 2010). In a retrospective study of 180 samples submitted to the International Veterinary Renal Pathology Service from 2008-2013 median (range) USG in dogs with naturally occurring CKD was 1.017 (1.003-1.048) (Hokamp et al, 2016). Dogs diagnosed with immune complex-mediate glomerulonephritis (n=62) were more likely to have USG > 1.014 (sensitivity 80.6, specificity 47.5 p<0.01) while dogs diagnosed with tubular disease (n=15) were more likely to have USG < 1.014 (sensitivity 60.0, specificity 69.1 p<0.05) and those with amyloidosis (n=18) were more likely to have USG < 1.013 (sensitivity 50.0, specificity 73.5 p<0.05). In a study of 210 senior dogs (mean age 9.7 years, range 7-15 years) with serum creatinine within reference range mean USG was 1.030 ± 0.001. In a subset of these dogs (n=18) SDMA was ≥ 14 µg/dl indicating renal insufficiency (IRIS Stage 1). Mean USG in these dogs ranged from 1.030 ± 0.004 to 1.024 ± 0.003 during the 6-month study (Hall et al, 2016). As with cats, early diagnosis of kidney disease and development of increasingly specific biomarkers of kidney damage may change the clinical relevance of a ‘cut off’ value for USG.

Tubular Resorption

Water and many solutes are reabsorbed from the tubular lumen into the peritubular interstitial fluid and ultimately the blood. In general, tubular resorption conserves substances that are essential for normal function (e.g., electrolytes, water, glucose and amino acids). Alterations in the renal handling of solutes may indicate kidney dysfunction. Abnormalities in tubular resorption may be generalized or limited to one or more tubular transport processes. Clinical syndromes are defined by the particular transport process involved. These syndromes include diverse disorders such as nephrogenic diabetes insipidus, renal tubular acidosis, renal glucosuria and aminoaciduria (e.g., cystinuria). Diagnosis is based on urinalysis findings (e.g., cystine crystalluria) or other tests such as quantitation of urinary amino acid concentrations.

Endocrine Function

Renal endocrine function can be evaluated by directly measuring the plasma concentration of the hormone or by indirectly assessing the action of that hormone. Erythropoietin concentration can be measured, but it is more practically assessed by serial monitoring of CBCs to detect progressive non-regenerative anemia that may occur in patients with stages 2 to 4 CKD. In CKD, the development of renal secondary hyperparathyroidism is influenced by complex interactions of ionized calcium, phosphorus, vitamin D metabolites, parathyroid hormone (PTH), and fibroblast growth factor-23 (FGF-23). Reduced renal excretion of phosphorus causes phosphorus retention, which in turn stimulates increased parathyroid hormone (PTH) production and secretion. The recently identified fibroblast growth factor-23, a hormone produced mainly by osteoblasts and osteocytes, promotes renal phosphorous excretion. FGF-23 is secreted in response to hyperphosphatemia, early in the course of CKD. It down regulates 1α-hydroxylase activity, thus further decreasing calcitriol levels and worsening renal secondary hyperparathyroidism (Nabsehima, 2008, Parker et al, 2015, Parker et al, 2017). Increased serum FGF-23 concentration has been demonstrated to be one of the earliest  metabolic derangements in patients with CKD, often elevated while patients are still normophosphatemic and have normal PTH concentrations (Ketteler et al, 2013). Phosphorus retention and hyperphosphatemia also inhibit renal tubular activity of 1α-hydroxylase, the enzyme responsible for renal conversion of inactive vitamin D to its active form, calcitriol. Decreased calcitriol concentrations, along with hypocalcemia (decreased ionized calcium) and hyperphosphatemia, contribute to development of hyperparathyroidism. Diagnosis of hyperparathyroidism is based on increased plasma concentrations of intact PTH. Commercial assays are currently available for canine and feline PTH measurement; it is hoped that FGF-23 assays will become readily available in the future (Foster, 2016). PTH should be measured (with serum calcium, phosphorus and ionized calcium) when calcitriol is administered for management of CKD. In the future, it may be recommended to monitor serum PTH and FGF-23 concentrations in all patients with CKD, before the onset of hyperphosphatemia, so that treatment (e.g., dietary phosphorus restriction) can be adjusted to control metabolic derangements.

References

END OF PART 1. NEXT: Part 2

Chronic Kidney Disease, Part 2: Diagnosis & Etiopathogenesis

Chronic Kidney Disease, Part 2: Diagnosis & Etiopathogenesis

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