Proteinuria is usually taken to mean a pathologic increase in the quantity of protein present in the urine. It is considered a hallmark of glomerular disease. However, protein is normally present in the urine in small quantities, and while mild proteinuria may not require specific treatment, it may serve as a valuable marker in clinical research. In particular, quantification of urinary protein excretion has been investigated as a noninvasive marker for glomerular hypertension and as such may serve as an important prognostic marker.

Urine dipsticks have both poor sensitivity and specificity for detection of proteinuria in the cat, unless it is severe. As a result, measurement of the urine protein-to-creatinine (UPC) ratio is most often employed for the quantification of proteinuria. Tests that quantify albumin in the urine, rather than total protein, have also been developed.

If proteinuria is documented, it is very important to consider its origin. Proteinuria may occur due to the filtration of an excessive amount of small proteins that usually are reabsorbed by the proximal tubule; this is sometimes referred to as prerenal proteinuria. The classical situation in which this occurs is in multiple myeloma; however, this is an uncommon cause of proteinuria in the cat. Postrenal causes of proteinuria are much more common and can include any infectious or inflammatory disease of the lower urinary tract, most often urinary tract infection (UTI) or urolithiasis. Although gross haematuria may increase UPC measurements, microscopic haematuria typically does not unless caused by an underlying infection.

Primary Glomerular Disease

Primary glomerular disease is uncommon in the cat. When it does occur it is most often seen in young males and is histologically characterised as membranous glomerulonephritis. Cats with renal lymphoma may also be proteinuric. Renal amyloidosis has been described as a familial syndrome in Abyssinian cats, but the deposition is usually exclusively in the medulla and as a consequence these cats are usually nonproteinuric. Patients with primary glomerular disease may develop nephrotic syndrome; this is the constellation of proteinuria, hypoalbuminaemia, hypercholesterolaemia, and subcutaneous oedema and/or ascites. It is uncommon, even in patients with documented protein-losing nephropathy (PLN).

Patients with PLN should have a diagnostic workup to try to identify a potential underlying cause for their glomerular disease. If none is found, then renal biopsy should be considered. There is currently a WSAVA sponsored scheme for the assessment of renal biopsies in dogs and cats with PLN; this includes examination of specimens by light microscopy, immunofluorescence and electron microscopy. If a potential candidate is identified, further details can be obtained by emailing either kidney.vpdc@uu.nl or glees@cvm.tamu.edu.

Treatment of PLN may be directed at the underlying cause and/or aimed at management of the proteinuria (low protein diet, ACE-inhibitors, aspirin). It is currently unclear whether immune-suppressive therapy is beneficial in treatment of cats with primary glomerular disease; cases should be considered on an individual basis.

Glomerular Hypertension

Following loss of a critical amount of renal mass, hyperfiltration occurs in the remaining functional nephrons. Hyperfiltration occurs due to an increase in pressure applied to the glomerular filtration barrier, and this results in proteinuria. Ultimately, over time, this adaptive change may be detrimental ('maladaptive') and may result in interstitial fibrosis and inflammation resulting in further nephron loss, even in the absence of any extrinsic factors which damage the kidney (the so-called intact nephron hypothesis).

Evidence for Glomerular Hypertension in the Cat

In an epidemiological study (Syme et al. 2006) of 94 cats at initial diagnosis of their chronic kidney disease and 42 nonazotaemic aged cats, urine protein excretion was shown to be highest in patients with higher initial plasma creatinine concentration and increased systolic blood pressure (as shown in the graph, below left). These observations provide circumstantial evidence to support the hypothesis that cats with naturally occurring chronic kidney disease develop proteinuria due to development of glomerular hypertension, since hyperfiltration would be expected to be more severe in cats with fewer functioning nephrons, and consequently, more marked elevation of plasma creatinine concentration and also in those with higher systemic blood pressure.

The cats included in the cross-sectional epidemiological study were also enrolled in a longitudinal study of survival time. Proteinuria proved to be significantly and independently associated with survival, as were age and plasma creatinine concentration. No association was found between gender or systolic blood pressure and survival. For illustrative purposes, the survival curves for cats with variable magnitude of proteinuria and adjusted for any influence of creatinine concentration and age are depicted in the figure (above right).

The results of these studies demonstrate that proteinuria is associated with shortened survival times in cats with naturally occurring kidney disease. However, because only about half of the cats suffering from CKD in our clinic population die or are euthanatized because of progressive renal failure or an acute uraemic crisis, rapid decline in renal function may not be the sole reason for the decreased survival times in cats with proteinuria. In human beings with renal disease, proteinuria has been found to predict morbidity and mortality due to a number of diseases in addition to progressive renal failure. Subsequently, proteinuria has also been shown to be of prognostic significance in hypertensive cats (Jepson et al. 2007) and in nonazotaemic geriatric cats (Jepson et al. 2009).

One might conclude from these studies that interventions designed to reduce urinary protein excretion would slow progressive renal injury and, therefore, improve survival in cats with CKD. This conclusion assumes that protein in the urine in these animals is damaging to the remaining functioning nephrons and so leads to progressive renal injury. Another interpretation of these findings, however, is that the appearance of protein in the urine is merely a marker that progressive renal injury is occurring. In this case, whilst renoprotective interventions might be expected to reduce protein excretion because they slow progressive renal injury, reducing urine protein excretion per se will not necessarily prove to be renoprotective.

Treatment of CKD with ACE-Inhibitors

The rationale for treatment of renal disease with angiotensin-converting enzyme (ACE) inhibitors is that these drugs cause preferential dilatation of the efferent arterioles, resulting in reduction of glomerular capillary pressure and reduction of glomerular capillary permeability to protein, thus reducing proteinuria and preventing the development of glomerulosclerosis.

As you are probably aware, benazepril has a licensed indication for the treatment of cats with CKD in Europe, New Zealand, and many other areas of the world. The study that supported the license application has been published (King et al. 2007). In it, almost 200 cats were enrolled in a placebo-control study of benazepril treatment (0.5–1.0 mg/kg), which was given for up to 3 years or until death occurred. The treatment was found to decrease proteinuria in all subgroups, although an improvement in survival time was not actually demonstrated in any group. Examining rationally the evidence provided, it is apparent that the cats that are most likely to benefit from treatment are those with higher UPCs and those cats that are likely to live for at least a few months. Treating cats that are severely azotaemic or that have prerenal azotaemia with ACE-inhibitors may actually speed their demise.

References

1.  Jepson RE, et al. Effect of control of systolic blood pressure on survival in cats with systemic hypertension. J Vet Intern Med. 2007;21(3):402–409.

2.  Jepson RE, et al. Evaluation of predictors of the development of azotemia in cats. J Vet Intern Med. 2009;23(4):806–813.

3.  King JN, et al. Prognostic factors in cats with chronic kidney disease. J Vet Intern Med. 2007;21(5):906–916.

4.  Syme HM, et al. Survival of cats with naturally occurring chronic renal failure is related to severity of proteinuria. J Vet Intern Med. 2006;20(3):528–535.