Rosanne E. Jepson, BVSc, MVetMed, PhD, DACVIM, DECVIM, MRCVS
Renal proteinuria can be identified in both dogs and cats. It can be part of a primary renal disease process (e.g., primary glomerular or tubular disease) or may represent a manifestation of renal disease in association with another underlying condition. In health, the concentration of protein in the urine is typically low with urine protein to creatinine ratios (UPC) typically <0.2 in cats (up to 0.4 in entire male cats) and <0.5 in dogs.1-3
For any patient where proteinuria is identified, it is important to establish the origin of proteinuria, which may be prerenal, renal or postrenal. Prerenal proteinuria is typically the result of increased circulating plasma proteins and is most often identified in relation to elevated circulating immunoglobulins, for example Bence Jones proteinuria in patients with multiple myeloma. Indication for the presence of a prerenal proteinuria may therefore come from assessment of a biochemical profile. Mild increase in proteinuria can also be identified in certain physiological states such as after extreme exercise or in association with pyrexia. Postrenal proteinuria results from protein originating from the lower urinary tract, for example in association with urinary tract infection or inflammation. In the investigation for any renal cause of proteinuria, exclusion of both pre- and postrenal proteinuria is necessary.
Renal proteinuria can be either tubular or glomerular in origin although the magnitude of proteinuria is typically more significant in patients with glomerular than tubular disease. A number of methods are available for the assessment. An initial assessment is usually made on the basis of dipstick evaluation. This should be interpreted in light of urine specific gravity (USG), given that 2+ protein is more likely to be of significance with a USG of 1.012 than 1.045. However, ultimately if assessment of proteinuria is required, this should be quantified with a UPC.4,5 Studies have evaluated the day-to-day variability in UPC for assessment of proteinuria and particularly for patients that are more markedly proteinuric (UPC>2), consideration should be given to pooling equivolumes of urine from 3 consecutive days for submission rather than a single spot urine sample.6 It is also important to appreciate that this day-to-day variability means that in order for a significant change in UPC to be identified for a patient with UPC∼0.5 the change must be in around 80%, whilst for more markedly proteinuric patients (UPC∼4) a 50% reduction is required for the change to be deemed significant.7 Free catch samples are suitable for assessment of UPC and samples obtained from a home environment may be preferable.8 Haematuria is unlikely to substantially alter the UPC of a urine sample unless there is gross haematuria.9 Historically, there has been interest in assessment of specific urinary proteins (e.g., albuminuria), although, to date, there have not been studies that support superiority of this over assessment of UPC in clinical practice.
In patients with renal tubular disease (e.g., tubulointerstitial nephritis), the presence of proteinuria reflects both altered haemodynamics due to loss of functioning nephrons and altered tubular reabsorption of proteins. In these conditions, proteins are typically low molecular weight and the overall magnitude of proteinuria is low (UPC<2.0). Nevertheless, even this low magnitude of proteinuria has been associated with the development of azotaemia, survival and progression of disease in cats with CKD and outcome in dogs with CKD.10,11 Given the potential for proteinuria to play a role in the progression of disease, antiproteinuric therapy forms part of the recommended treatment plan for both dogs and cats with persistent proteinuria (UPC>0.4) with many clinicians also considering institution of antiproteinuric therapy even for those patients with borderline proteinuria (UPC 0.2–0.4). It is important to appreciate that in end-stage disease proteinuria may fall due to a reduced number of nephrons and therefore reduction in proteinuria late in the disease process is not always a positive indication if azotaemia is deteriorating.
In patients with glomerular disease, structural or function change at the glomerulus results in increased filtration of proteins that can be low, medium or high molecular weight. Glomerular disease is identified more often in dogs than cats. Here the magnitude of proteinuria is typically higher (UPC>2.0) and may be associated with biochemical changes such as hypoalbuminaemia and hypercholesterolaemia, which together with the presence of effusions and/or peripheral oedema may be referred to as nephrotic syndrome. Patients with glomerular disease particularly early in the disease cause will not necessarily demonstrate azotaemia as renal function (i.e., GFR) may be normal. Clinical presentation of such patients may therefore range from the clinically asymptomatic (e.g., detected due to hypoalbuminaemia on a routine preanaesthetic screen) through to clinical signs referable to renal disease or proteinuria.
In cats, primary glomerular disease is most often the result of either amyloidosis or membranous nephropathy with the latter condition typically affecting male cats (7:1 male:female) that are younger than the normal demographic of cats with CKD (median 6 years). In dogs, primary glomerular disease can be largely considered as either immune-mediated or non-immune-mediated disease with the latter category encompassing a number of breed-specific, familial and congenital conditions affecting the structure of the glomerular filtration barrier [e.g., amyloidosis (Shar-Pei), COL4 mutation (cocker spaniel)]. For patients with immune-mediated glomerular disease, diagnostic investigations must determine whether the condition is primary or secondary to another underlying disease process (e.g., systemic immune-mediated disease, infectious disease, neoplasia).12
In key situations, renal biopsy may be required in order to determine the exact aetiology of glomerular disease with submission to the International Veterinary Renal Pathology Service (IVRPS http://vet.osu.edu/vmc/international-veterinary-renal-pathology-service-ivrps) permitting evaluation of renal tissue by transmission electron microscopy and immunofluorescence in addition to routine histopathology. Based on a recent pathology study from this centre, approximately 50% of dogs with proteinuria will have an immune-mediated aetiology for their glomerular disease.
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