Rosanne E. Jepson, BVSc, MVetMed, PhD, DACVIM, DECVIM, FHEA, MRCVS
The kidney has many important functions including excretion of toxic wastes, water, electrolyte and acid base homeostasis and hormonal synthesis. At its simplest, kidney disease can therefore be defined as any condition that alters one or more of these functions of the kidney. In canine and feline medicine we most often consider conditions affecting the kidney as being either tubular or glomerular in origin, relating to the primary site of altered function although conditions that affect both tubules and the glomeruli are possible. It is common for kidney disease to be classified as either acute or chronic depending on the duration of changes being present in the kidney although it is certainly also possible for patients to experience an acute kidney injury (AKI) on top of a pre-existing chronic kidney disease (CKD), often termed 'acute on chronic.' Differentiation of acute from chronic disease is important in terms of differences in the likely underlying aetiology, diagnostic and therapeutic management planning and prognostic information. Chronic disease usually implies that there has been an alteration in structure or function of the kidney present for at least 2–3 months. Recent studies have also begun to explore the potential relationship between AKI insults and the development of CKD, hypothesizing that serial small AKI episodes may be stimuli for the cascade of proinflammatory and profibrotic events that mediate the development of tubulointerstitial nephritis.
Diagnosis of kidney disease is usually a multifactorial process requiring integration of clinical signs, historical information, findings on physical examination and assessment of renal function and structure. The clinical presentation of patients with kidney disease and indeed the results of diagnostic investigations will be dependent on the location of disease within the kidney (e.g., tubular versus glomerular disease). It must be remembered that the clinical presentation of patients with kidney disease may range from those that are clinically asymptomatic (e.g., a cat with IRIS stage 1 CKD or dog with primary glomerular disease that is detected due to identification of hypoalbuminaemia and proteinuria on a biochemical profile) to those with more typical clinical signs referable to loss of the functional nephrons (e.g., polyuria, polydipsia, decreased appetite, nausea, vomiting) or glomerular disease (e.g., peripheral oedema, pleural or abdominal effusions). Physical examination findings can elude to the duration of disease with findings such as poor body condition and small irregular kidneys supporting chronic disease whilst good body condition and palpably normal to enlarged kidneys may support an acute disease process. However, an unremarkable physical examination does not preclude the presence of kidney disease.
Ultimately, the diagnosis of kidney disease and localization of the disease process will be made on the basis of the diagnostic investigation, including assessment of renal function, urinalysis, assessment of proteinuria, and potentially diagnostic imaging. The gold standard for assessing renal function is direct assessment of glomerular filtration rate (GFR). Although GFR measurements using techniques such as iohexol clearance are not difficult to perform, it is more common for surrogate markers of GFR to be used in clinical practice (e.g., urea, creatinine, and symmetric dimethylarginine [SDMA]). Interpretation of results of these surrogate markers requires an understanding of the potential biological and laboratory variability and in particular factors that are likely to influence results, such as recent feeding for urea and body or muscle condition for creatinine. A key advantage of the novel GFR marker, SDMA, is that it is not influenced by body muscle mass, meaning that it may provide a more accurate representation of renal function, particularly in patients with appreciable muscle loss (e.g., geriatric cat with CKD). Assessment of routine biochemistry for parameters that may influence management (e.g., phosphorus, potassium, calcium) and for patients with proteinuria, albumin concentration is also important. A minimum of a packed cell volume and total solids is of use for identification of anaemia and where this occurs, a complete blood count may be considered.
In any patient where azotemia is identified, it is fundamental to establish whether the azotaemia is prerenal, renal or postrenal in origin. The latter is often easily excluded on the basis of clinical presentation (i.e., obstructive urinary tract disease). However, establishing the presence of a prerenal component involves assessment of hydration status of the patient and interpretation of renal function (i.e., creatinine) together with urine concentrating ability. In the dog, azotaemia combined with a urine specific gravity (USG) of >1.030 may be indicative of a prerenal azotaemia, whilst for the cat USG should exceed 1.035–40 although is frequently much higher in young cats. Dogs and cats with tubular disease will often have reduced concentrating ability but it is possible for both to retain a degree of concentrating ability particularly in the early stages of disease and therefore isosthenuria (USG 1.008–1.015) is not a requirement for a diagnosis of renal disease. For patients with primary glomerular disease, urine concentrating ability may be normal given the location of the pathology.
Urinalysis including dipstick evaluation and sediment examination is an important component of assessing for renal disease. Dipstick assessment may give information relating to proteinuria but should be interpreted in light of the urine specific gravity and may also be informative in terms of tubular function (e.g., glucosuria and pH). Sediment examination can be important for identification of an active sediment (e.g., urinary tract infection or pyelonephritis), but may also reveal changes such as crystalluria or cast formation. Ultimately, if proteinuria is suspected or staging for proteinuria (see below) is being performed, it is important to ensure that pre- and postrenal causes of proteinuria have been excluded and that quantitative assessment with a urine protein to creatinine ratio (UPC) is performed.
Diagnostic imaging may also form part of the diagnostic investigation of a patient with suspected kidney disease. Ultrasound is of particular use for evaluating the size, shape and architecture of the kidney. This may provide supporting evidence for whether a disease process is acute or chronic and may identify complicating factors such as nephro- or ureterolithiasis. However, again normal renal architecture does not preclude the presence of kidney disease; for example, in patients with primary glomerular disease renal ultrasound may be considered unremarkable. Abdominal radiographs may be useful for patients where there is a suspicion for urolithiasis and contrast imaging may sometimes be performed (e.g., anterograde pyelogram) where there is concern regarding ureteral obstruction.
Having made a diagnosis of kidney disease, it is widely recommended that staging according to the International Renal Interest Society (IRIS) is performed for patients with chronic disease. It is fundamental that staging is only performed after the diagnosis of CKD has been made and that patients are considered to have stable disease at the time of staging. Any pre-renal azotaemia should be corrected before staging is performed. IRIS have also recently released a grading system that is used for classification of AKI. Further details can be found at www.iris-kidney.com/guidelines/grading.html
Having made a diagnosis of CKD, individuals will be placed into a stage based on their plasma creatinine concentration. Note that patients in IRIS stage 1 and early IRIS stage 2 CKD may have substaging should then be performed using both proteinuria (UPC evaluation) and blood pressure. Phosphorus targets are also available in terms of optimal stage-specific management of CKD-mineral and bone disorder. The criteria for IRIS staging can be found here: www.iris-kidney.com/guidelines/grading.html
Reflecting the evidence that SDMA may be able to identify an earlier stage of disease than creatinine concentration and that it may be of particular use in assessing GFR in patients with poor muscle condition, IRIS have recently released guidelines for the use of SDMA within their CKD staging system: www.iris-kidney.com/pdf/3_staging-of-ckd.pdf (VIN editor: the original link http://www.iris-kidney.com/pdf/staging-of-ckd.pdf was modified on 3/8/18). For example, a persistently elevated SDMA in a patient where creatinine is within reference interval is supportive of IRIS stage 1 disease. Note the importance of documenting that the elevation of SDMA is persistent in this situation with at least two samples obtained ideally 2–4 weeks apart. Similarly, the addition of SDMA to the staging system allows patients with poor muscle condition to be more accurately classified in a potentially higher stage for management and treatment recommendations. It is likely that the use of SDMA for the management of both CKD and AKI will evolve as we become more familiar as clinicians with the utility of this marker.
1. Relford R, Robertson J, Clements C. Symmetric dimethylarginine: improving the diagnosis and staging of chronic kidney disease in small animals. Vet Clin North Am Small Anim Pract. 2016;46(6):941–60.
2. Hall JA, Yerramilli M, Obare E, Yerramilli M, Almes K, Jewell DE. Serum concentrations of symmetric dimethylarginine and creatinine in dogs with naturally occurring chronic kidney disease. J Vet Intern Med. 2016;30(3):794–802.
3. Hall JA, Yerramilli M, Obare E, Yerramilli M, Jewell DE. Comparison of serum concentrations of symmetric dimethylarginine and creatinine as kidney function biomarkers in cats with chronic kidney disease. J Vet Intern Med. 2014;28(6):1676–83.
4. Nabity MB, Lees GE, Boggess MM, Yerramilli M, Obare E, Yerramilli M, et al. Symmetric dimethylarginine assay validation, stability, and evaluation as a marker for the early detection of chronic kidney disease in dogs. J Vet Intern Med. 2015;29(4):1036–44.
5. Jepson RE, Syme HM, Vallance C, Elliott J. Plasma asymmetric dimethylarginine, symmetric dimethylarginine, l-arginine and nitrite/nitrate concentrations in cats with chronic kidney disease and hypertension. J Vet Intern Med. 2008;22:317–24.
6. Hall JA, Yerramilli M, Obare E, Yerramilli M, Yu S, Jewell DE. Comparison of serum concentrations of symmetric dimethylarginine and creatinine as kidney function biomarkers in healthy geriatric cats fed reduced protein foods enriched with fish oil, L-carnitine, and medium-chain triglycerides. Vet J. 2014;202(3):588–96.