Kidney Diseases in the Cavalier King Charles Spaniel


A dog's kidneys play a major role in the blood circulatory system, filtering the blood and removing waste products, and regulating blood pressure. Kidneys are essential to the urinary system. They produce highly concentrated urine which efficiently excretes a large quantity of toxins in a relatively small quantity of water. Kidney failure -- or renal failure -- occurs when the kidney cannot filter the toxins and other wastes in concentrated urine.

Here we discuss chronic kidney disease (more specifically, cardio-renal disorders), which is more prevalent in the cavalier King Charles spaniel than in most other breeds. In a separate article, we discuss another kidney disorder prevalent in the CKCS, called xanthinuria, which are crystals or sediment in the dogs' urinary tract.

Chronic Kidney Disease

Chronic kidney disease* (CKD) is defined as a progressive loss in kidney function over a period of three or more months. Cavalier King Charles spaniels and Cocker spaniels reportedly are at increased risk to develop CKD, according to a July 2013 UK study.

* CKD is also referred to as chronic renal disease. "Renal" refers to kidney functions.

In addition, CKD may develop as a consequence of either deteriorating cardiac function or the administration of diuretics, such as furosemide and torsemide, which can severely affect the kidney by activating the renin-angiotensin aldosterone system (RAAS), since reduction in the total circulating blood volume results in activation of RAAS. Further, deteriorating renal function can lead to cardiac dysfunction. This connection of cardiac dysfunction and renal dysfunction has been referred to as "cardio-renal syndrome" (CRS). CRS is defined as “disorders of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other.”

Cardio-renal syndrome has been categorized into five types, depending upon the initial cause and its severity, as shown in this chart:

Cardio-Renal Syndrome Chart

Renal dysfunction develops over time in cardiac patients, usually increasing incrementally as the cardiac disease progresses, then increasing more swiftly when cardiac medical therapy, particularly after diuretics and some vasodilators commence. Furosemide and other diuretics can severely affect the kidneys by activating the renin-angiotensin aldosterone system (RAAS)*, since reduction in the total circulating blood volume results in activation of RAAS.

* When the RAAS is activated, it causes the kidneys to over-work by retaining more water and sodium and excreting more potassium. As a result of this process, the overall volume of blood increases, meaning that more blood is pumped through narrowed arteries, which also increases the blood pressure.

In some cases, inadequate therapy of venous congestion may contribute to renal dysfunction, resulting in congestive kidney failure. See this October 2011 presentation for details.

In a September 2015 report, a team of 9 veterinary cardiologists and 7 veterinary nephrologists from Europe and North America have issued a "Consensus Statement" to increase the awareness of and codify the definition, classification, diagnosis, and management strategies for veterinary patients with CRS, with an emphasis on the pathological interplay between the two organ systems. They acknowledge "a growing understanding of the complexity of interplay between renal and cardiovascular systems in both health and disease."

Pathways between heart failure and renal dysfunction.They have observed: "The concept of CRS, which involves a bidirectional pathway of injury wherein disease of either organ directly or indirectly contributes to injury of the other." And they have included a chart showing postulated mechanisms underlying the relationship between heart failure (HF) and renal dysfunction. (Click on the thumbnail chart at right.)

Among their consensus statements, are:

"Statement 8: Thoracic radiography is recommended to assess the presence or absence of congestive heart failure, and echocardiography is recommended to assess cardiac morphology, lesions, and to estimate relevant haemodynamic parameters.

"Statement 9: Renal imaging is recommended to improve diagnosis, prognosis and guide potential therapies in CvRD. Conventional abdominal radiographs and ultrasound are recommended to help detect morphological abnormalities and determine underlying aetiology.

"Statement 10: As the kidney and heart are two organs at risk for damage due to systemic hypertension, and as kidney disease is often associated with systemic arterial hypertension, systemic arterial blood pressure should be systematically monitored in both kidney and cardiovascular diseases. * * *

"Statement 13: ... particular attention should be directed towards the following when managing any form of [CRS]: 1) identification and treatment of elevated blood pressure as per IRIS recommendations; 2) stepwise titration of dosages of diuretics, ACEI, inotropes and/or fluids with frequent monitoring of renal function, body weight, hydration, electrolyte status, and systemic blood pressure (i.e. performed and rechecked within 3–5 days following initiation or dose adjustment of these drugs); 3) proper nutrition, with respect to reduced dietary sodium and phosphate and appropriate protein and caloric intake."
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-- Symptoms

In CKD's earliest stages, the dog may urinate more often than usual, or in larger quantities, due to the failure of the kidneys to concentrate the urine.  This resulCanine Kidneysts in dehydration and thirst, so the dog tends to drink more water than usual. In the July 2013 UK study of over 100,000 dogs, the most significantly associated clinical signs included halitosis, anemia, weight loss/cachexia, excessive urination and thirst, urinary incontinence, and vomiting.

As the kidneys' function decreases, any of several symptoms may appear.  Blood pressure may increase, due to an overload of fluids and the production of vasoactive hormones created by the kidneys' renin-angiotensin aldosterone system (RAAS). Urea may accumulate, leading to azotemia, followed by uremia (retention of ammonia, nitrogen, acids, and other chemical wastes in the blood and tissues), with symptoms ranging from apathy, depression, loss of appetite and weight, a dry haircoat, a brownish discoloration of the tongue, and an ammonia odor to the breath. At that stage, the dog may drink less than normal.

As the kidneys' efficiency declines, fluid volume will overload, with symptoms of various levels of pulmonary edema and pericarditis (an inflammation of the pericardium, the fibrous sac surrounding the heart). Urea could be excreted through the skin. Potassium levels may increase in the blood (hyperkalemia) with symptoms varying from fatigue to cardiac arrhythmias. Ulcers may appear in the mouth. Vomiting, diarrhea, and gastrointestinal bleeding may occur. At the end stage of kidney failure, the dog has seizures and will fall into a coma.

Kidney dysfunction is tied closely to heart failure, and for the cavalier King Charles spaniel in particular, mitral valve disease (MVD) and CKD go hand-in-hand.  In the July 2013 UK study, cardiac disorders were among the most common co-diseases with CKD.

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-- Diagnosis

CavalierHealth.org Copyright © 2013 Blenheim CompanyChronic kidney disease is detected by urinalysis, including urine specific gravity (USG) to determine how well the dog is concentrating urine and for protein levels, and by a blood test showing an increase in serum creatinine. Higher levels of creatinine indicate a lower flow rate of fluids through the kidneys (glomerular filtration rate) and as a result a decreased capability of the kidneys to excrete waste products. Creatinine levels may be normal in the early stages of CKD, and the condition is discovered if urinalysis shows that the kidneys are allowing the flow of proteins or red blood cells into the urine. A downside of this testing is that creatinine does not increase until 75% of kidney function is lost.

Tomography (a form of medical imaging) and renal biopsies may be performed to determine the cause for the kidneys' malfunction.

CKD may be classified in five stages, with Stage 1 being the mildest, with few symptoms, and Stage 5 being the most severe and often called chronic kidney failure (CKF) or chronic renal failure (CRF) or end stage renal disease (ESRD).

The September 2015 Consensus Statement issued by the international team of veterinary cardiologists and nephrologists, includes these diagnosis recommendations:

"Statement 8: Thoracic radiography is recommended to assess the presence or absence of congestive heart failure, and echocardiography is recommended to assess cardiac morphology, lesions, and to estimate relevant haemodynamic parameters.

"Statement 9: Renal imaging is recommended to improve diagnosis, prognosis and guide potential therapies in CvRD. Conventional abdominal radiographs and ultrasound are recommended to help detect morphological abnormalities and determine underlying aetiology.

"Statement 10: As the kidney and heart are two organs at risk for damage due to systemic hypertension, and as kidney disease is often associated with systemic arterial hypertension, systemic arterial blood pressure should be systematically monitored in both kidney and cardiovascular diseases."

In January 2015, Idexx Laboratories announced a new biomarker test for CKD, called symmetric dimethylarginine (SDMA), which reportedly will enable diagnosis of CKD several months or even years earlier than creatinine tests. SDMA is a methylated form of the amino acid arginine, which is released into the circulation during protein degradation and is excreted almost exclusively by the kidneys. SDMA reportedly increases earlier than creatinine in CKD; it increases on average with 40% loss of kidney function versus creatinine, which does not increase until 75% of kidney function is lost. See also this March 2016 article and this November 2016 article discussing symmetric dimethylarginine.

In a September 2016 study by a team of Korean cardiology researchers, they examined serum concentration levels of two kidney function biomarkers -- Cystatin-C or cystatin 3 (Cys-C) and symmetric dimethylarginine (SDMA). They confirmed the findings of previous studies involving SDMA, noting that SDMA does not appear to be influenced by age, body weight or gender. Regarding Cys-C, they disagreed with prior studies findings that the Cys-C concentration was influenced by age and body weight. They stated, "However, our study strongly suggested that the Cys-C was not influenced by age or body weight." Nevertheless, they concluded that, "Although the Cys-C is a promising renal marker for canine kidney disease, test standardization and reference range have yet been clearly established in dogs."

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-- Treatment

There is no cure for chronic kidney disease.  The veterinarian's goal is to control the disease as well as possible for the rest of the dog’s life. Restricting the CKD dog's salt intake, to help prevent edema, ascites, and hypertension, likely will be prescribed. Periodic blood tests will be recommended, to detect changes in kidney function and the progression of the disease.

The vets may prescribe special diets, including low-protein ones, depending upon the vets' nutrition Standard Process' Canine Renal Supportphilosophy. Some studies have indicated that protein may be poorly metabolized by dogs with kidney failure, and some veterinarians believe a diet rich in meat, or one that contains poor-quality protein, creates an increased nitrogen load that can lead a CKD dog into uremia by feeding them more protein than they can handle. However, there are contrary studies, such as this 1999 report and this 2008 report.

A general kidney support supplement often recommended by holistic veterinarians is Canine Renal Support by Standard Process.

Medications to lower phosphorus levels usually are prescribed. Sufficient quantities of water must always be available. The dog must be able to take in enough water to compensate for her large urine output. Subcutaneous (known as sub-Q or SQ) fluids may be necessary.

Some types of kidney failure are acute, and are mild enough that if the dog is well supported medically, there will be a complete recovery. More commonly, dogs will have at least some renal function deficit and need a change in care for the rest of their lives.

Peritoneal dialysis, which supplements the filtering tasks of the kidneys, may be advised. In peritoneal dialysis, fluids are fed into the abdomen using a catheter, to allow them to perform the filtering process, after which, the fluids are removed through the catheter, taking filtered toxins out with them. Hemodialysis is a technique in which the dog’s blood is circulated through a filtering machine.

Kidney transplants are a rare option.

The September 2015 Consensus Statement issued by the international team of veterinary cardiologists and nephrologists, includes these treatment recommendations:

"Statement 13: ... particular attention should be directed towards the following when managing any form of [CRS]: 1) identification and treatment of elevated blood pressure as per IRIS recommendations; 2) stepwise titration of dosages of diuretics, ACEI, inotropes and/or fluids with frequent monitoring of renal function, body weight, hydration, electrolyte status, and systemic blood pressure (i.e. performed and rechecked within 3–5 days following initiation or dose adjustment of these drugs); 3) proper nutrition, with respect to reduced dietary sodium and phosphate and appropriate protein and caloric intake."
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Research News

October 2016: Korean researchers find cystatin-C or cystatin 3 (Cys-C) and symmetric dimethylarginine (SDMA) as useful biomarkers for canine kidney disease. Dr. Changbaig HyunIn a September 2016 study by a team of Korean cardiology researchers (Bum-Sul Choi, Hyeong-Sun Moon, Sang-Hyuk Seo, Changbaig Hyun [right]), they examined serum concentration levels of two kidney function biomarkers -- Cystatin-C or cystatin 3 (Cys-C) and symmetric dimethylarginine (SDMA). They confirmed the findings of previous studies involving SDMA, noting that SDMA does not appear to be influenced by age, body weight or gender. Regarding Cys-C, they disagreed with prior studies findings that the Cys-C concentration was influenced by age and body weight. They stated, "However, our study strongly suggested that the Cys-C was not influenced by age or body weight." Nevertheless, they concluded that, "Although the Cys-C is a promising renal marker for canine kidney disease, test standardization and reference range have yet been clearly established in dogs."

January 2016: Renal lesions were found in 52.2% of post-mortem samples of cavaliers in UK study. In an April 2016 article, UK researchers (Kent, Andrew C. C.; Constantino-Casas, Fernando; Rusbridge, Clare; Corcoran, Brendan; Carter, Margaret; Ledger, Tania; Watson, Penny J.) searched for pancreatic, hepatic (liver) and renal (kidney) lesions in post-mortem samples from 54 cavalier King Charles spaniels (CKCSs). The rate of diagnosis of renal disease prior to death was in 16.7% of the CKCSs, but the post-mortem examination found evidence of renal lesions in 52.2% of the dogs. The researchers concluded that renal lesions are common in the breed, and that clinicians should be aware of this when presented with clinical cases.

September 2015: International team of cardiologists and nephrologists issue a Consensus Statement on cardio-renal disorders. In a September 2015 report, a team of 9 veterinary cardiologists and 7 veterinary nephrologists from Europe and North America (J. L. Pouchelon, C. E. Atkins, C. Bussadori, M. A. Oyama, S. L. Vaden, J. D. Bonagura, V. Chetboul, L. D. Cowgill, J. Elliot, T. Francey, G. F. Grauer, V. Luis Fuentes, N. Sydney Moise, D. J. Polzin, A. M. Van Dongen, N. Van Israël) have issued a "Consensus Statement" to increase the awareness of and codify the definition, classification, diagnosis, and management strategies for veterinary patients with cardio-renal syndrome (CRS), with an emphasis on the pathological interplay between the two organ systems. They acknowledge "a growing understanding of the complexity of interplay between renal and cardiovascular systems in both health and disease."

Pathways between heart failure and renal dysfunction.They have observed: "The concept of CRS, which involves a bidirectional pathway of injury wherein disease of either organ directly or indirectly contributes to injury of the other." And they have included a chart showing postulated mechanisms underlying the relationship between heart failure (HF) and renal dysfunction. (Click on the thumbnail chart at right.)

Among their consensus statements, are:

"Statement 8: Thoracic radiography is recommended to assess the presence or absence of congestive heart failure, and echocardiography is recommended to assess cardiac morphology, lesions, and to estimate relevant haemodynamic parameters.

"Statement 9: Renal imaging is recommended to improve diagnosis, prognosis and guide potential therapies in CvRD. Conventional abdominal radiographs and ultrasound are recommended to help detect morphological abnormalities and determine underlying aetiology.

"Statement 10: As the kidney and heart are two organs at risk for damage due to systemic hypertension, and as kidney disease is often associated with systemic arterial hypertension, systemic arterial blood pressure should be systematically monitored in both kidney and cardiovascular diseases. * * *

"Statement 13: ... particular attention should be directed towards the following when managing any form of [CRS]: 1) identification and treatment of elevated blood pressure as per IRIS recommendations; 2) stepwise titration of dosages of diuretics, ACEI, inotropes and/or fluids with frequent monitoring of renal function, body weight, hydration, electrolyte status, and systemic blood pressure (i.e. performed and rechecked within 3–5 days following initiation or dose adjustment of these drugs); 3) proper nutrition, with respect to reduced dietary sodium and phosphate and appropriate protein and caloric intake."

Lynn HellströmJuly 2015: Swedish vet student reports the cavalier has a high incidence of kidney disease in Sweden. In a July 2015 graduate thesis, a Swedish veterinary student, Lynn Hellström (right), reviewed veterinary records of insured dogs in Sweden diagnosed with kidney diseases. She reports that the cavalier King Charles spaniel and the Shetland sheepdog had the highest incidence of kidney disease, while noting that "Neither one of these breeds are commonly mentioned as particularly affected by kidney diseases in the literature of veterinary medicine." She could find "no specific etiology of kidney disease ... diagnosed more often than others in ... CKCS dogs. Renal dysplasia was diagnosed in dogs of both breeds."

January 2015: Idexx Labs announces new early test -- SDMA -- for chronic kidney disease. Idexx LaboratoriesIn a January 2015 report by Dr. Jane Robertson, Idexx Laboratories has announced a new biomarker test for CKD, called symmetric dimethyl-arginine (SDMA), which reportedly will enable diagnosis of CKD several months or even years earlier than creatinine tests. SDMA is a methylated form of the amino acid arginine, which is released into the circulation during protein degradation and is excreted almost exclusively by the kidneys. SDMA reportedly increases earlier than creatinine in CKD; it increases on average with 40% loss of kidney function versus creatinine, which does not increase until 75% of kidney function is lost.

Idexx states that it expects to begin trials with several hundred North American veterinary clinic customers by the end of March 2015. Following the conclusion of those trials, Idexx states that it will include the SDMA test as part of the standard chemistry panel in North America in the summer of 2015.

May 2013: UK study finds cavaliers at "significant risk" for chronic kidney disease. In a July Royal Veterinary College2013 study of 107,214 dogs treated in 2010 and 2011 at 89 UK veterinary clinics, the Royal Veterinary College researchers found that cavalier King Charles spaniels and Cocker spaniels were a "significant risk factor" for developing chronic kidney disease (CKD). They also reported that cardiac disease was a significant co-disease with CKD.

Key findings from the study included:
    • Overall canine CKD prevalence 0.21%.
    • Dogs aged over 12 years had 5 times the odds of kidney disease, compared with dogs aged between 7 and 12 years.
    • Predisposed breeds included the cavalier and Cocker spaniel.
    • The median survival time after CKD diagnosis was 266 days.
    • IRIS staging and blood urea analysis values at diagnosis were useful predictors of survival.
    • The study shows the power of primary practice data to better understand disorders seen in primary practice.

The study concluded that chronic kidney disease compromises dog welfare. Increased awareness of CKD risk factors and association of blood biochemistry results with survival time should facilitate diagnosis and optimize case management to improve animal survival and welfare.

Professor Jonathan Elliott, one of the co-authors, commented that:

"This is an exciting paper that provides valuable information for clinicians in relation to the types of dogs that are at increased risk of kidney disease and their likely prognosis following diagnosis. This type of study is only possible because of the extensive database of case records that VetCompass provides. Vets in practice can use this information to improve the evidence on which they can base their advice to owners."
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Related Links

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Veterinary Resources

Xanthine calculi in a dog. Kidder, D. E. & Chivers, P. R. Vet.Rec. 1968;83(9):228-229. [The dog was a cavalier King Charles spaniel.]

The renin-angiotensin-aldosterone system in congestive failure in conscious dogs. L Watkins, Jr, J A Burton, E Haber, J R Cant, F W Smith, A C Barger. J Clin Invest. June 1976;57(6):1606–1617. Quote: "The role of the renin-angiotensin-aldosterone system in the development of congestive failure has been assessed in the conscious dog by use of the nonapeptide converting enzyme inhibitor. Constriction of the pulmonary artery or thoracic inferior vena cava was maintained for 2 wk while daily measurements were made of plasma renin activity, plasma aldosterone, plasma volume, hematocrit, serum sodium and potassium concentrations, sodium and water balance, body weight, and arterial, caval, and atrial pressures. The initial response to constriction was a reduction in blood pressure, a rise in plasma renin activity, plasma aldosterone, and water intake, and nearly complete sodium retention. In the days after moderate constriction plasma volume and body weight increased (with development of ascites and edema); blood pressure, sodium excretion, plasma renin acvitity, and plasma aldosterone returned to normal. In animals in which blood pressure was not restored, plasma renin activity and plasma aldosterone remained elevated throughout the period of constriction. Single injections of converting enzyme inhibitor reduced blood pressure when plasma renin activity was elevated. Chronic infusion of the inhibitor in dogs with thoracic inferior vena caval constriction prevented the restoration of blood pressure and suppressed the rise in plasma aldosterone; sodium retention and volume expansion were less than in control experiments. Thus the renin-angiotensin-aldosterone system plays an essential role in the maintenance of blood pressure during the genesis of congestive failure. Initially, the restoration of blood pressure is dependent upon circulating angiotensin II; in the later stages, blood pressure is dependent upon the increase in plasma volume."

Renal Dysplasia in a Cavalier King Charles Spaniel. Murphy, M.G. Irish Veterinary Journal 42:96-97, 1989. Quote: "A 5-month-old female Cavalier King Charles Spaniel developed polydipsia, polyuria (specific gravity:1.010), vomiting and diarrhoea. Biochemical tests showed elevated blood urea nitrogen (15.05 mmol/litre)."

Effects of Dietary Protein Intake on Renal Functions. Delmar R. Finco. Veterinary Forum. 1999;16(10):34–44. Quote: "Older dogs have a higher incidence of chronic renal disease than young dogs, and restricting protein intake in these dogs has been advocated as a renoprotective maneuver. In a study designed to test this hypothesis, experimental dogs 7 to 8 years of age were divided into two groups. Dogs in both groups had uninephrectomy performed to increase vulnerability of the remaining kidney to any protein effects. One group was fed a low protein diet, and the other group received a high protein diet for the subsequent 4 years. Results of this study indicated that there were no adverse effects of the high protein diet (Table 1), and mortality was actually higher in the low protein group. A similar study was conducted in another laboratory, and, likewise, no adverse effect of high protein diets was detected. In the latter study, however, increased mortality in dogs receiving the low protein diet did not occur."

Mythology of Protein Restriction for Dogs with Reduced Renal Function. Kenneth C. Bovée. Compendium on Continuing Education for the Practicing Veterinarian. Nov. 1999;21(11):15-20. Quote: "Advantages and Disadvantages of Dietary Protein Restriction in Dogs: Based on the previous data, the only advantages appear to be a lowering of BUN and the possibility of reduced nausea. Quantifying the value of these effects has not been reported in dogs. On the contrary, there appear to be disadvantages to reduced protein intake. These include reduced kidney function as measured by GFR and renal plasma flow, possibility of a negative nitrogen balance, and the promotion of a catabolic state in the presence of proteinuria. In practical application the use of a vague dietary recommendation appears to lead to complacency about long-term surveillance of the animal or the need for individualized specific treatment. Because some sort of management appears available, the search for a more specific etiologic diagnosis is usually not mounted. Finally, the use of arbitrary diets leads to a delusion of ourselves and clients about treatment and increases the cost to owners. Why Is Dietary Alteration Still Used if There Is No Proven Benefit?: The continued use of protein restriction in the absence of scientific evidence deserves thoughtful consideration. I would suggest that the dogma and mythology of a possible benefit are so embedded in the thought process of veterinarians and owners that these cannot be easily dislodged despite the scientific evidence. I would refer to this as the myth of dietary protein and characterize it as a negative myth."

Body size, but neither age nor asymptomatic mitral regurgitation, influences plasma concentrations of dimethylarginines in dogs. L.G. Pedersen, I. Tarnow, L.H. Olsen, T. Teerlink, H.D. Pedersen. Research in Vet. Sci. 2006;80:336-342. Quote: Asymmetric dimethylarginine (ADMA) is a marker of various cardiovascular diseases in man. The aim of the present study was to test if Cavalier King Charles Spaniels (CKCS) with varying degrees of mitral regurgitation (MR) had increased plasma concentration of ADMA and furthermore, characterize the plasma level of ADMA and symmetric dimethylarginine (SDMA) in normal dogs. Seventy-six dogs were included (44 CKCS and 32 dogs of other breeds). The CKCS had various degrees of MR, whereas the remaining dogs had either no or minimal MR. Apart from cardiac murmurs, no dogs showed signs of cardiac or systematic disease. The degree of MR had no significant influence on ADMA (P = 0.33). Body weight was directly associated with ADMA (P = 0.0004) and creatinine was directly associated with SDMA (P < 0.0001). Furthermore, the plasma concentration of ADMA was three to four times higher than found in healthy humans.

Pet Food Safety: Dietary Protein. D.P. Laflamme. Topics in Companion Animal Medicine. Aug. 2008;23(3):154-157. Quote: "Based on a comprehensive review, there remains no evidence that dietary protein causes kidney damage, or any other adverse effects, in healthy dogs. Even in dogs with chronic kidney disease, dietary protein does not appear to contribute to kidney damage. However, in chronic kidney disease, there can be an accumulation of byproducts of protein metabolism, which may contribute to uremic signs. Hence, in these patients, dietary protein restriction may be of benefit. On the other hand, dietary protein is important to support normal protein turnover and maintain lean body mass. Healthy, aging dogs have an increased requirement for dietary protein. Vhen insufficient protein is provided, it can aggravate the age-associated loss of lean body mass and may contribute to earlier mortality. Unless medically indicated, intake of dietary protein should not be restricted."

99mTc-DTPA diuretic renal scintigraphy in dogs with nephroureterolithiasis. Silke Hecht, S. Meg Lawson, India F. Lane, Dorothy E. Sharp, Gregory B. Daniel. Can Vet J 2010;51:1360–1366. Quote: "This study evaluated the results of diuretic renal scintigraphy in dogs with urolithiasis. Eighty-three kidneys with nephroureterolithiasis 1/2 renal pelvis/ureteral dilation were included in the study [including two cavalier King Charles spaniels]. Sixty-three kidneys showed a non-obstructive pattern, with a steep drop or gradual downward slope of renal time-activity curve (TAC). Excretion half-time of radiopharmaceutical (T1/2) was 3.99 (2.99 to 7.95) min. Three kidneys showed an obstructive pattern, with continuous rise of the TAC and median T1/2 of 210.71 (25.20 to 217.56) min. Fifteen kidneys had non-diagnostic studies characterized by flat TAC. Individual kidney glomerular filtration rate was , 0.5 mL/min/kg body weight in most non-diagnostic studies. Diuretic renal scintigraphy appears to be a useful adjunct modality to rule out or confirm ureteral obstruction in dogs. Additional diagnostic procedures may be necessary to achieve a definitive diagnosis in cases of severely impaired renal function."

Cardio-Renal Syndrome, what is behind it? A rock and a hard place: cardiorenal syndrome in clinical canine veterinary patients. Rebecca L. Stepien. CEVA CardioSymposium, October 2011. Quote: "Cardio-renal syndrome has been variously defined. In clinical medicine, it may be viewed as 'a state In which therapy to relieve heart failure symptoms is limited by worsening renal function', but this arguably is a clinical view reflecting a cardiologist's concern; a nephrologist may be more likely to define CRS as ' ... a normal kldney that is dysfunctional because of a diseased heart ...'. An expansive, multisystem view is required In order to understand the complex bidirectional interactions of these two critical body systems, in which '... each dysfunctional organ has the ability to initiate and perpetuate disease in the other organ through common hemodynamic, neurohormonal, and immunological/ biochemical feedback pathways'. ... Cardio-renal syndrome may be divided into 5 types. Type 2 CRS appears to be of significant clinical concern in cardiac patients. ... The prevalence of azotemia and decreased renal function in canine CHF patients is similarly high. In a report in 2010, 24.1% of 223 dogs with heart disease were azotemic, although the prevalence of CHF in this cohort of heart patients was not specified. In an eartler study, Nicolle and colleagues reported that 50% of small dogs (<13 kg) with degenerative valve disease were azotemic either by Blood Urea Nitrogen (BUN) or Creat or both. This study included dogs in all stages of heart failure (NYHA grades I-IV) and some were treated at the time of the study. As their NYHA class increased, a greater percentage of patients were azotemic and were also more likely to have already been treated with some combination of angiotensin-converting enzyme inhibitors, furosemide, spironolactone and digoxin. Older dogs were also more likely to be azotemic. The severity of CHF was also linked to renal function; Class III-IV dogs had 45% decrease in GFR compared with class I-II dogs, and 7/9 grade III-IV dogs had abnormally decreased GFR. In human and canine patients, the presence and severity of RAAS activation and azotemia is affected by therapy, especially furosemide and vasodilators. ... In some cases, inadequate therapy of venous congestion may contribute to renal dysfunction, resulting in 'congestive kidney failure'. Human and veterinary literature supports the use of ACEI and aldosterone receptor antagonists such as spironolactone to limit the RAAS activation that has beer documented with CHF therapy, and use of these modalities has prolonged survival times in affected patients. The topic of cardiorenal syndrome is becoming an increasingly important concern in clinical veterinary medicine. Avoidance of WRF in dogs before and during CHF therapy is crucial to maintain quality of life as survival in dogs with this common disease increases."

Chronic Kidney Disease in Dogs in UK Veterinary Practices: Prevalence, Risk Factors, and Survival. D.G. O’Neill, J. Elliott, D.B. Church, P.D. McGreevy, P.C. Thomson, and D.C. Brodbelt. J.Vet.Intern.Med. July 2013;27(4):814-821. Quote: "Background: The prevalence for chronic kidney disease (CKD) in dogs varies widely (0.05–3.74%). Identified risk factors include advancing age, specific breeds, small body size, and periodontal disease. Hypothesis/Objectives: To estimate the prevalence and identify risk factors associated with CKD diagnosis and survival in dogs. Purebred dogs were hypothesized to have higher CKD risk and poorer survival characteristics than crossbred dogs. Animals: A merged clinical database of 107,214 dogs attending 89 UK veterinary practices over a 2-year period (January 2010–December 2011). Methods: A longitudinal study design estimated the apparent prevalence (AP) whereas the true prevalence (TP) was estimated using Bayesian analysis. A nested case-control study design evaluated risk factors. Survival analysis used the Kaplan-Meier survival curve method and multivariable Cox proportional hazards regression modeling. Results: The CKD AP was 0.21% (95% CI: 0.19–0.24%) and TP was 0.37% (95% posterior credibility interval 0.02–1.44%). Significant risk factors included increasing age, being insured, and certain breeds (Cocker Spaniel, Cavalier King Charles Spaniel). Cardiac disease was a significant comorbid disorder. Significant clinical signs included halitosis, weight loss, polyuria/polydipsia, urinary incontinence, vomiting, decreased appetite, lethargy, and diarrhea. The median survival time from diagnosis was 226 days (95% CI 112–326 days). International Renal Interest Society stage and blood urea nitrogen concentration at diagnosis were significantly associated with hazard of death due to CKD. Conclusions and Clinical Importance: Chronic kidney disease compromises dog welfare. Increased awareness of CKD risk factors and association of blood biochemistry results with survival time should facilitate diagnosis and optimize case management to improve animal survival and welfare."

Cardiorenal Syndrome: Cardiologist vs. Nephrologist. Joao S. Orvalho, Larry D. Cowgill. ACVIM Forum. June 2014. Quote: "Introduction: It has become increasingly recognized by cardiologists and nephrologists that there are important bidirectional functional and pathological interactions between the heart and the kidney, wherein dysfunction of either organ promotes clinical worsening of the other.1 Cardiovascular disease constitutes a significant threat for patients with renal disease, and renal dysfunction is also often present in patients with cardiac disease. The clinical consequences of these interactions have gained increasing focus and have prompted further definition, classification, and understanding. These interactions are the pathophysiological basis for the clinical entity termed cardiorenal syndrome (CRS) in human medicine. Cardiorenal syndrome per se has not been well characterized in veterinary medicine. ... Conclusions and Future Directions: An accurate appreciation of the kidney and the cardiovascular system and their interactions may have practical clinical implications. A multidisciplinary evaluation including the expertise of cardiologists and nephrologists may be the most appropriate approach for the patient at risk for CRS.43 The outcome of CRS patients is likely to improve with the increasing awareness and ability to identify and understand the pathophysiological characteristics of cardiorenal syndrome."

Earlier Diagnosis of Kidney Disease: SDMA allows earlier intervention for more effective management of kidney disease. Jane Robertson. Idexx Labs. January 2015. Quote: "Over their lifetime, 1 in 3 cats and 1 in 10 dogs could develop chronic kidney disease (CKD)—a leading cause of death, particularly in cats. Symmetric dimethylarginine (SDMA) is a revolutionary new kidney function test that will enable veterinarians to diagnose CKD in cats and dogs months or even years earlier than traditional methods, making it possible to intervene earlier and more effectively manage kidney disease. SDMA is a methylated form of the amino acid arginine, which is produced in every cell and released into the body’s circulation during protein degradation. SDMA is excreted almost exclusively by the kidneys, making it a good marker for estimating kidney function. Research has shown that SDMA can identify CKD an average of 9 months earlier in dogs and 17 months sooner in cats—in one cat 4 years earlier. In addition, SDMA is not impacted by muscle mass, thereby providing practitioners a better tool for diagnosing and monitoring CKD in thin geriatric animals, especially cats and animals with other diseases that cause muscle wasting."See this Idexx article: "Introduction to a New Kidney Test: SDMA".

Polymorphisms in the canine and feline renin–angiotensin–aldosterone system genes. Kathryn M. Meurs, Lhoucine Chdid, Yamir Reina-Doreste and Joshua A. Stern. Animal Genetics. January 2015.

  Cardiovascular–renal axis disorders in the domestic dog and cat: a veterinary consensus statement. J. L. Pouchelon, C. E. Atkins, C. Bussadori, M. A. Oyama, S. L. Vaden, J. D. Bonagura, V. Chetboul, L. D. Cowgill, J. Elliot, T. Francey, G. F. Grauer, V. Luis Fuentes, N. Sydney Moise, D. J. Polzin, A. M. Van Dongen, N. Van Israël. J.Small Animal Prac. September 2015;56(9):537-552. Quote: "Objectives: There is a growing understanding of the complexity of interplay between renal and cardiovascular systems in both health and disease. The medical profession has adopted the term “cardiorenal syndrome” (CRS) to describe the pathophysiological relationship between the kidney and heart in disease. CRS has yet to be formally defined and described by the veterinary profession and its existence and importance in dogs and cats warrant investigation. The CRS Consensus Group, comprising nine veterinary cardiologists and seven nephrologists from Europe and North America, sought to achieve consensus around the definition, pathophysiology, diagnosis and management of dogs and cats with “cardiovascular-renal disorders” (CvRD). To this end, the Delphi formal methodology for defining/building consensus and defining guidelines was utilised. Methods: Following a literature review, 13 candidate statements regarding CvRD in dogs and cats were tested for consensus, using a modified Delphi method. As a new area of interest, well-designed studies, specific to CRS/CvRD, are lacking, particularly in dogs and cats. Hence, while scientific justification of all the recommendations was sought and used when available, recommendations were largely reliant on theory, expert opinion, small clinical studies and extrapolation from data derived from other species. Results: Of the 13 statements, 11 achieved consensus and 2 did not. The modified Delphi approach worked well to achieve consensus in an objective manner and to develop initial guidelines for CvRD. Discussion: The resultant manuscript describes consensus statements for the definition, classification, diagnosis and management strategies for veterinary patients with CvRD, with an emphasis on the pathological interplay between the two organ systems. By formulating consensus statements regarding CvRD in veterinary medicine, the authors hope to stimulate interest in and advancement of the understanding and management of CvRD in dogs and cats. The use of a formalised method for consensus and guideline development should be considered for other topics in veterinary medicine. ... This consensus statement is meant to increase the awareness of and codify the definition, classification and means of identification and provide provisional information on management of CvRD."

Chronobiology and Pharmacologic Modulation of the Renin-Angiotensin-Aldosterone System in Dogs: What Have We Learned? Jonathan Paul Mochel, Meindert Danhof. Reviews of Physiology, Biochemistry & Pharmacology. October 2015. Quote: "Congestive heart failure (CHF) is a primary cause of morbidity and mortality with an increasing prevalence in human and canine populations. Recognition of the role of renin-angiotensin-aldosterone system (RAAS) overactivation in the pathophysiology of CHF has led to significant medical advances. By decreasing systemic vascular resistance and angiotensin II (AII) production, angiotensin-converting enzyme (ACE) inhibitors such as benazepril improve cardiac hemodynamics and reduce mortality in human and dog CHF patients. Although several experiments have pointed out that efficacy of ACE inhibitors depends on the time of administration, little attention is paid to the optimum time of dosing of these medications. A thorough characterization of the chronobiology of the renin cascade has the potential to streamline the therapeutic management of RAAS-related diseases and to help determining the optimal time of drug administration that maximizes efficacy of ACE inhibitors, while minimizing the occurrence of adverse effects. We have developed an integrated pharmacokinetic-pharmacodynamic model that adequately captures the disposition kinetics of the paradigm drug benazeprilat, as well as the time-varying changes of systemic renin-angiotensin-aldosterone biomarkers, without and with ACE inhibition therapy. Based on these chronobiological investigations, the optimal efficacy of ACE inhibitors is expected with bedtime dosing. The data further show that benazepril influences the dynamics of the renin-angiotensin-aldosterone cascade, resulting in a profound decrease in AII and aldosterone (ALD), while increasing renin activity for about 24 h. From the results of recent investigations in human, it is hypothesized that reduction of AII and ALD is one of the drivers of increased survival and improved quality of life in dogs receiving ACE inhibitors. To support and consolidate this hypothesis, additional efforts should be directed toward the collection of circulating RAAS peptides in spontaneous cases of canine CHF. If such a link could be established, profiling of these biomarkers could support determination of the severity of heart failure, complement clinical and echocardiographic findings, and be used for therapeutic drug monitoring purposes. ... The research summarized herein is not a static and completed piece of work but is, instead, a starting point for further data integration and hypothesis testing."

Effects of high doses of enalapril and benazepril on the pharmacologically activated renin-angiotensin-aldosterone system in clinically normal dogs. Marisa K. Ames, Clarke E. Atkins, Seunggon Lee,Andrea C. Lantis, James R. zumBrunnen. Am. J. Vet. Res. December 2015;76(12):1041-1050. Quote: "Objective: To determine whether high doses of enalapril and benazepril would be more effective than standard doses of these drugs in suppressing the furosemide-activated renin-angiotensin-aldosterone system (RAAS). Animals: 6 healthy Beagles. Procedures: 2 experiments were conducted; each lasted 10 days, separated by a 2-week washout period. In experiment 1, all dogs received furosemide (2 mg/kg, PO, q 12 h) and enalapril (1 mg/kg, PO, q 12 h) for 8 days (days 0 through 7). In experiment 2, dogs received furosemide (2 mg/kg, PO, q 12 h) and benazepril (1 mg/kg, PO, q 12 h) for 8 days. Effects on the RAAS were determined by assessing serum angiotensin-converting enzyme (ACE) activity on days −1, 3, and 7; serum aldosterone concentration on days −2, −1, 1, 3, and 7; and the urinary aldosterone-creatinine ratio (UAldo:C) in urine collected in the morning and evening of days −2, −1, 1, 3, and 7. Results: High doses of enalapril and benazepril caused significant reductions in serum ACE activity on all days but were not more effective than standard doses used in other studies. Mean UAldo:C remained significantly higher on days 2 through 7, compared with baseline values. Serum aldosterone concentration also increased after drug administration, which mirrored changes in the UAldo:C. Conclusions & Clinical Relevance: In this study, administration of high doses of enalapril and benazepril significantly inhibited ACE activity, yet did not prevent increases in mean urine and serum aldosterone concentrations resulting from furosemide activation of RAAS. This suggested that aldosterone breakthrough from ACE inhibition was a dose-independent effect of ACE inhibitors."

Early Diagnosis of Chronic Kidney Disease in Dogs & Cats: Use of Serum Creatinine & Symmetric Dimethylarginine. Gregory F. Grauer. Today's Vet. Pract. March 2016;6(2). Quote: Incorporating evaluation of serum SDMA [serum symmetric dimethylarginine] along with closer monitoring of sCr may facilitate early diagnosis of CKD in dogs and cats. In general, diagnostic results that indicate increased monitoring include:
• sCr concentrations of 1.4 mg/dL or greater in dogs or 1.6 mg/dL or greater in cats
• Serum SDMA concentrations greater than 14 mcg/dL.
Longitudinal assessment of these measures almost always provides better data than one-time evaluations. No single laboratory test is perfect; trending laboratory data, with the same test method, tends to improve diagnostic sensitivity.

Prevalence of pancreatic, hepatic and renal microscopic lesions in post-mortem samples from Cavalier King Charles Spaniels. Kent, Andrew C. C.; Constantino-Casas, Fernando; Rusbridge, Clare; Corcoran, Brendan; Carter, Margaret; Ledger, Tania; Watson, Penny J. J. Small Animal Practice. April 2016;57(4):188-193. Quote: "Objectives: To describe the prevalence of pancreatic, hepatic and renal microscopic lesions in post-mortem samples from [54] Cavalier King Charles Spaniels (CKCS) presented to a UK post-mortem collection scheme [The Cavalier Collection Scheme]. Methods: Histopathology was performed on the organs of interest and the prevalence of microscopic lesions described, this was related back to the clinical signs shown ante-mortem. Results: Evidence of chronic pancreatitis was seen in 51.9% of the cases, and age correlated with severity of disease, suggesting that chronic pancreatitis is a progressive condition. Evidence of renal lesions was present in 52.2% of cases, most commonly inflammatory disease. The rate of ante-mortem diagnosis was low for both pancreatic and renal disease, at 25% and 16.7% respectively. Primary hepatic lesions were present in only 11.1% of cases, but secondary hepatic lesions were more common and were present in 64.8%. Clinical Significance: Pancreatic and renal lesions are common in Cavalier King Charles Spaniels and clinicians should be aware of this when presented with clinical cases, they have similar rates of hepatic disease as the general population."

Advances in the evaluation of canine renal disease. Rachel Cianciolo, Jessica Hokamp, Mary Nabity. Vet. J. September 2016;215(Special Issue):21-29. Quote: "Many recent advances in the evaluation of dogs with kidney disease have improved our diagnostic algorithms and impacted our therapeutic strategies. Non-invasive techniques, such as urinary and serologic biomarker evaluation, can help a clinician diagnose and treat a patient that cannot undergo a renal biopsy for clinical or financial reasons. Some biomarkers might help localize the affected structure (glomerulus vs. tubule) and indicate the type or severity of injury present. Although more research is needed, studies indicate that some biomarkers (e.g. urine protein to creatinine ratio and urinary immunoglobulins) can be useful in predicting adverse outcomes. Importantly, the sensitivity and specificity of biomarkers for renal injury should be established and clinicians need to understand the limitations of these assays. If a renal biopsy is performed, then it should be evaluated by a specialty diagnostic service with expertise in nephropathology. A panel of special stains, immunofluorescence for the detection of immunoglobulins and complement factors, and transmission electron microscopy can be routinely employed in cases of glomerular disease. These advanced diagnostics can be used to detect immune deposits in order to definitively diagnose immune complex mediated glomerular disease. Integrating the results of biomarker assays and comprehensive renal biopsy evaluation, the clinician can make informed therapeutic decisions, such as whether or not to immunosuppress a patient. Highlights: • Urinary biomarker analysis is a non-invasive way to help determine the type and severity of renal injury. • Serum biomarkers are used to detect decreased glomerular filtration rate. • Comprehensive evaluation of renal tissue definitively diagnoses immune complex mediated glomerular disease."

Evaluation of serum cystatin-C and symmetric dimethylarginine concentrations in dogs with heart failure from chronic mitral valvular insufficiency. Bum-Sul Choi, Hyeong-Sun Moon, Sang-Hyuk Seo, Changbaig Hyun. Vet. Med. Sci. September 2016. Quote: Reduction in glomerular filtration rate (GFR) is a common complication in advanced stages of heart failure (HF). The convenient and precise assessment for GFR would be useful for early detection of renal impairment in HF dogs. Our hypothesis of this study was the GFR would be reduced in advanced stages of HF from chronic mitral valvular disease (CMVI), as indicated by renal markers including serum cystatin-C (Cys-C) and symmetric dimethylarginine (SDMA) concentrations. Forty-three client-owned dogs consisting of 33 dogs with different stages of HF from CMVI and 10 age-matched healthy dogs were enrolled in this study. Serum Cys-C and SDMA concentrations along with other renal (i.e., urea nitrogen and creatinine) and echocardiographic markers were evaluated in healthy and CMVI dogs. Serum Cys-C concentrations were 1.4 ± 0.4 mg/l in control, 2.1 ± 0.9 mg/l in ISACHC I, 2.9 ± 0.8 mg/l in ISACHC II and 3.6 ± 0.6 mg/l in ISACHC III dogs, whereas serum SDMA concentrations were 8 ± 2 ug/dl in control, 14 ± 3 ug/dl in ISACHC I, 18 ± 6 ug/dl in ISACHC II and 22 ± 7 ug/dl in ISACHC III dogs. There was close correlation of serum Cys-C and SDMA concentrations to serum creatinine, urea nitrogen and the severity of HF. Our study demonstrated that the GFR was decreased in dogs with CMVI having earlier stages of HF.

Symmetric Dimethylarginine: Improving the Diagnosis and Staging of Chronic Kidney Disease in Small Animals. Roberta Relford, Jane Robertson, Celeste Clements. Small Animal Pract. November 2016;46(6):941-960. Quote: Symmetric dimethylarginine (SDMA) is a new kidney biomarker that accurately reflects glomerular filtration fate (GFR). SDMA level increases earlier in chronic kidney disease (CKD), on average with 40% reduction of GFR, compared with up to 75% reduction needed to increase creatinine level. Unlike creatinine, SDMA is not affected by lean body mass so it is a more sensitive indicator of kidney function in patients with muscle loss. ... In a group of Cavalier King Charles spaniels, SDMA level was not affected by age or asymptomatic mitral regurgitation. [citing this 2006 article above] ... The validated immunoassay for SDMA, the IDEXX SDMA test, is a clinically relevant and reliable tool for diagnosing early CKD in small animals when creatinine level is still within the reference interval. SDMA was added to the International Renal Interest Society CKD guidelines to complement creatinine testing in staging early and advanced disease.

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