Acute kidney injury and chronic kidney disease are common names for disease states, that affect renal function. Both acute kidney injury and chronic kidney disease may result from multiple etiologies. Acute kidney injury is typically caused by acute renal insult, such as reduced renal blood flow or nephrotoxicants.

Chronic kidney disease is a slowly progressing disorder, and a common cause of death in dogs. It can be caused by multiple etiologies, but glomerular diseases are the most typical underlying pathology. In glomerular diseases, protein, especially albumin, leaks into urine through damaged glomeruli. A prolonged proteinuric condition with severe hypoalbuminemia, hypercholesterolemia and ascites/edema, is called nephrotic syndrome.

Reduction of renal filtration capacity is the most characteristic metabolic change observed in chronic kidney disease. However, chronic kidney disease can lead to a wide range of other metabolic derangements from impaired renal enzymatic activity to increased muscle catabolism.

 

Creatinine as a biomarker of kidney filtration

Creatinine is the most commonly evaluated biomarker of kidney function. In IRIS recommendations for chronic kidney disease and acute kidney injury, blood creatinine plays a major role in determining the stage and the treatment of the disease. In international recommendations, creatinine concentrations are recommended to be evaluated against the dog’s previous results instead of the reference values in the early stages of the disease, since the inter-individual variation of blood creatinine concentration is high. For example, muscle mass affects the amount of released creatinine. In the early stages of renal failure, a slight change in blood creatinine concentration already indicates a relatively high loss of kidney capacity.

Hyperalbuminemia can be caused by dehydration

Fluid loss due to polyuria and vomiting can lead to severe dehydration especially in acute kidney injury. Dehydration causes relative hyperalbuminemia, since the blood fluid content drops in a dehydrated animal. Correction fluid balance is a vital treatment goal in these patients, since dehydration can cause ischemic kidney damage.

Altered kidney energy metabolism can cause hyperlactatemia

Lactate is formed when cells use anaerobic glycolysis for energy production. In normal conditions, around 30% of circulating lactate is removed by the kidneys via gluconeogenesis and urinary excretion. Renal insufficiency can cause elevated blood lactate concentrations, probably due to decreased renal elimination of lactate. Dehydrated patients can have hyperlactatemia because of increased lactate formation, since in severe renal hypoperfusion, the kidneys change from lactate-consuming organs into lactate-forming organs.

Renal enzymatic activity may be impaired

Phenylalanine and tyrosine are aromatic amino acids. Phenylalanine is an essential amino acid, which means that it needs to be sufficiently supplied in the diet. In contrast, tyrosine is considered a non-essential amino acid in normal conditions, since it can be sufficiently formed from phenylalanine. However, in chronic renal failure, conversion of phenylalanine to tyrosine is reduced because renal enzymatic activity is reduced. Plasma levels of phenylalanine may thus slightly rise and the tyrosine plasma levels decrease, leading to a higher phenylalanine/tyrosine ratio. It has been suggested that when tyrosine formation is inadequate, tyrosine should be supplemented in the diet. Tyrosine is needed for example as a precursor of adrenaline, thyroid hormones and melanin.

Branched chain amino acids are associated with muscle catabolism

Branched chain amino acids are so-called essential amino acids, which means that they need to be sufficiently supplied in the diet. Branched chain amino acids are required for maintaining muscle mass, repairing injuries, and formation of hemoglobin. Advanced chronic renal failure may cause circulatory leucine levels to fall. Both reduced protein intake and increased catabolism of muscle and branched chain amino acids are behind this phenomenon. In humans, this condition is treated by supplementing the diet with branched chain amino acids or their keto analogues. In dogs, a similar approach has been suggested for hypoalbuminemic and hypoaminoacidemic patients, whose condition is not adequately controlled by conventional treatments.

Fatty acids are used for treating renal failure

Omega-3 fatty acids are used in the treatment of renal failure. Omega-3 fatty acids have been found to reduce proteinuria, reduce blood pressure, reduce the formation of pro-inflammatory cytokines and to correct hyperlipidemia. Feeding has been shown to affect the plasma levels of these fatty acids, but the association between symptoms and plasma fatty acid concentration is not yet known.

Protein and lipoprotein concentrations change because of proteinuria

Albumin is the most abundant protein in the blood. Albumin is largely responsible for the maintenance of blood oncotic pressure. Severe hypoalbuminemia causes fluid to leak out of the blood vessels into the surrounding tissues, causing edema. Urinary leakage of albumin due to nephrotic syndrome is the most common cause of hypoalbuminemia in renal failure. Clinical symptoms associated with nephrotic syndrome include fatigue, muscle atrophy and edema. Urinary protein loss is confirmed by a urine sample. Proteinuria is one the assessed features in the IRIS staging of chronic kidney disease and it also affects the treatment of the disease.
Lipid metabolism also typically changes as a result of proteinuria. Hypercholesterolemia is one of the components of nephrotic syndrome. Hypertriglyceridemia is less common, but has also been reported. The cause of hyperlipidemia is suspected to be multifactorial; it is thought to develop due to both reduced fat catabolism and increased hepatic lipoprotein formation to correct low oncotic pressure caused by hypoalbuminemia. Monitoring of hyperlipidemia is important in these patients for preventing complications of hyperlipidemia. In humans, hyperlipidemia is also seen in chronic kidney disease patients without proteinuria. The occurrence of hyperlipidemia in non-proteinuric dogs has not yet been thoroughly studied, but indications of similar changes have been reported.

Renal glucosuria occurs in certain kidney diseases, but the patient is rarely hypoglycemic

Certain tubular kidney diseases cause renal glucose loss. However, circulatory glucose levels are so well regulated that only a small proportion of glucosuric dogs are hypoglycemic. Loss of glucose in the urine is confirmed by a urine sample.

 

Possible metabolic changes in renal diseases:

Biomarker
Direction of change
Syy
Creatinine

Reduced renal filtration
Albumine

Dehydration
Lactate

Altered energy metabolism
Leucine

Muscle wasting
Phenylalanine

Reduced renal enzyme activity
Tyrosiini

Reduced renal enzyme activity
Fenyylialaniini/tyrosiini

Reduced renal enzyme activity
Albumine

Proteinuria
Cholesterol

Altered lipid metabolism
Triglycerides

Altered lipid metabolism
LDL

Altered lipid metabolism
VLDL

Altered lipid metabolism
Glucose

Renal glucosuria

 

 

Additional information

IRIS. Grading of Acute Kidney Injury. (2016).
IRIS. IRIS Staging of CKD. (2017).
Thrall, M. A., Weiser, G., Allison, R. W. & Campbell, T. W. Veterinary Hematology and Clinical Chemistry. (Wiley-Blackwell, 2012).
Pang, D. S. & Boysen, S. Lactate in veterinary critical care: pathophysiology and management. J. Am. Anim. Hosp. Assoc. 43, 270–279 (2007).
Allen, S. E. & Holm, J. L. Lactate: physiology and clinical utility. J. Vet. Emerg. Crit. Care 18, 123–132 (2008).
Kopple, J. D. Phenylalanine and tyrosine metabolism in chronic kidney failure. J. Nutr. 137, 1586S–1590S; discussion 1597S–1598S (2007).
Parker, V. J., Fascetti, A. J. & Klamer, B. G. Amino acid status in dogs with protein-losing nephropathy. J. Vet. Intern. Med. 33, 680–685 (2019).
Zatelli, A., D’Ippolito, P., Roura, X. & Zini, E. Short-term effects of dietary supplementation with amino acids in dogs with proteinuric chronic kidney disease. Can. Vet. J. = La Rev. Vet. Can. 58, 1287–1293 (2017).
Holecek, M. Branched-chain amino acids in health and disease: metabolism, alterations in blood plasma, and as supplements. Nutr. Metab. (Lond). 15, 33 (2018).
Bauer, J. E. Therapeutic use of fish oils in companion animals. J. Am. Vet. Med. Assoc. 239, 1441–1451 (2011).
Bauer, J. E. The essential nature of dietary omega-3 fatty acids in dogs. J. Am. Vet. Med. Assoc. 249, 1267–1272 (2016).
Behling-Kelly, E. Serum lipoprotein changes in dogs with renal disease. J. Vet. Intern. Med. 28, 1692–1698 (2014).
Xenoulis, P. G. & Steiner, J. M. Canine hyperlipidaemia. J. Small Anim. Pract. 56, 595–605 (2015).
Thompson, M. F., Fleeman, L. M., Kessell, A. E., Steenhard, L. A. & Foster, S. F. Acquired proximal renal tubulopathy in dogs exposed to a common dried chicken treat: retrospective study of 108 cases (2007-2009). Aust. Vet. J. 91, 368–373 (2013).