Harriet M. Syme, BSc, BVetMed, PhD, FHEA, DACVIM, DECVIM-CA, MRCVS
Traditionally, in veterinary medicine we have only paid attention to proteinuria when it is severe enough to result in hypoalbuminaemia or overt nephrotic syndrome (proteinuria, hypoalbuminaemia, hypercholesterolemia and ascites/oedema). However, this situation is changing and there is increasing evidence of the importance of proteinuria as a prognostic factor in patients with CKD even when the proteinuria is relatively mild. In this lecture we will briefly review protein losing nephropathy in dogs and cats but will then focus on the prognostic significance of proteinuria and its potential as a therapeutic target.
Protein Losing Nephropathy (PLN)
Gross proteinuria is considered to be the hallmark of glomerular disease. Although there is no convention in veterinary medicine about the level of proteinuria that this constitutes, in general we consider proteinuria severe enough to result in hypoalbuminaemia in this category and usually the urine protein-to-creatinine ratio (UPC) is greater than 2.0 to 5.0 in these animals, but this is quite variable between individual patients.
Broadly speaking the glomerular diseases that cause proteinuria can be divided into those that are inherited defects in the components of the glomerular barrier and the acquired diseases of amyloidosis and glomerulonephritis. Glomerulonephritis, however, is not one disease but many and with the advent of improved diagnostic evaluation due to the WSAVA standardisation scheme for renal histopathology it is hoped that diagnosis of this group of diseases will be refined and treatment will be improved. Glomerular disease is more common in the dog than the cat.
The signs seen in patients with proteinuria are very variable. In some patients proteinuria may be detected as part of a wellness screen in asymptomatic individuals or as part of a work up for non-specific signs such as weight loss, malaise or inappetence. Even if severe, proteinuria does not invariably result in development of nephrotic syndrome (in one study only 15% of dogs with glomerulonephritis had this),1 but some patients will be presented due to development of ascites or oedema. Other secondary clinical signs may develop in patients with PLN such as those related to thromboembolism or systemic hypertension. It is important to recognise that not all patients with PLN, or even those with nephrotic syndrome, will be azotemic--thus although some patients will have signs of chronic kidney disease (CKD) at presentation, and many more will develop these signs as the glomerular disease progresses, these will not invariably be present.
One reason, then, that we should care about proteinuria is to appropriately diagnose, treat and monitor patients with glomerular disease.
Prognostic Significance of Proteinuria in Patients with CKD
Proteinuria has recently been found to be of prognostic significance in cats in numerous different studies. This is somewhat surprising since overt protein losing nephropathy is relatively uncommon in this species. In one study of cats with CKD that used Cox's proportionate hazard model to estimate the relative risks of death or euthanasia during follow-up plasma creatinine concentration and proteinuria were found to be very highly related to survival.2 Indeed, in that study the hazard ratio (95% confidence intervals) for death or euthanasia was 2.9 (1.4-6.3) and 4.0 (2.0-8.0) for UPC ratios of 0.2-0.4 and >0.4 respectively, compared with the baseline group with UPC of <0.2, showing the prognostic significance of proteinuria of a magnitude that would previously have been considered trivial. Results of other studies have been similar. The BENRIC study which investigated the effects of ACE-inhibitor therapy in cats with chronic renal failure also demonstrated an inverse relation between proteinuria and survival time.3,4 A further study demonstrated that UPC was significantly higher (median 1.33, range 0.50-6.47) in cats that died within one month of diagnosis of chronic renal failure, than in cats that survived for longer (median 0.22, range 0.01-1.44).5
Proteinuria has also been shown to be of prognostic significance in dogs with CKD. In one study of 45 dogs with CKD the relative risk of developing a uremic crisis (compared to the reference category with UPC<1.0) was 2.1, 2.7 or 6.4 times greater in dogs with UPC values of 1.0-2.0, 2.0-3.0 or >3.0, respectively.6 For the same groups, the risk of death due to any cause was increased 1.7, 2.9 and 7.7-fold.6 In a second study the survival of dogs with CKD and UPC<1.0 (mean 1053 days) was significantly longer than that of dogs with UPC >1.0 (mean 390 days).7
Prognostic Significance of Proteinuria in Patients with Hypertension
A further population of cats in which the prognostic significance of proteinuria has been studied is those with systemic hypertension.8 In all 141 hypertensive cats were included in the study and all were treated with amlodipine at a dose of 0.625 or 1.25 mg with the aim of maintaining the systolic blood pressure <160 mm Hg. Fifty-eight percent of the cats were azotemic when the hypertension was diagnosed. The only variable in the study that was predictive of survival was proteinuria. The median survival time of the cats that died or were euthanized during the study was 490 (range 217-1169), 313 (range 124-607) and 162 (range 73-406) days for cats that were non-proteinuric (<0.2), mildly proteinuric (0.2-0.4) and proteinuric (>0.4), respectively. Time-averaged blood pressure (calculated from measurements made over the entire period of follow-up), age and plasma creatinine concentration were among the other pre-treatment predictive variables that were investigated but none was significantly associated with survival.
There is less data available to evaluate the prognostic significance of proteinuria in dogs with hypertension per se. However, in Jacob's study of dogs with CKD described above those dogs that had the highest blood pressure also tended to be the most proteinuric and to have the shortest survival times.6
Prognostic Significance of Proteinuria in Non-Azotemic Patients
Proteinuria has also been found to have prognostic value in non-azotemic cats. A study of 61 apparently healthy cats that had been presented for wellness examinations and from which stored urine samples were available for retrospective measurement of UPC showed that proteinuria was associated with reduced survival.9 The median [25th, 75th percentile] UPC of the cats that died (n=15) was 0.30 [0.26, 0.37] compared with 0.11 [0.16, 0.21] in the 46 cats that were lost to follow up (n=10) or still alive at the termination of the study (n=36). In a different study 118 apparently healthy, geriatric (9 years) cats were enrolled and followed for at least a year and monitored for the development of azotaemia. The UPC of those cats that developed azotaemia (n=29; 0.19 [0.14, 0.39]) was significantly greater than those that did not (n=62; 0.14 [0.11, 0.20]).10
Numerous and varied diseases have been associated with proteinuria in dogs.11 However, the prognostic significance of a finding of mild proteinuria in patients without azotaemia is uncertain.
Putative Mechanisms for the Detrimental Effects of Proteinuria
Proteinuria may have prognostic significance for many different reasons and these are not mutually exclusive. Dogs and cats with proteinuria associated with kidney disease are more likely to have glomerular disease which tends to be more rapidly progressive than tubular disease. Proteinuria may also serve as a marker for glomerular hypertension, generalised endothelial dysfunction or loss of functioning tubules any of which may be linked to an increased rate of progression of kidney disease through proteinuria-independent mechanisms. Nonetheless, numerous experimental studies provide evidence that proteinuria might also play a direct role in mediating ongoing renal injury. Urinary proteins may elicit pro-inflammatory and pro-fibrotic effects that contribute directly to tubulointerstitial damage.
Proteinuria as a Therapeutic Target
If proteinuria is directly injurious to the kidney then interventions to reduce proteinuria should be associated with delayed progression of renal disease. This has resulted in recommendations that reduction in proteinuria be used as a primary therapeutic end-point. It is important to recognize however, that if proteinuria is simply a marker for some other injurious process (for example glomerular hypertension) and therapeutic interventions ameliorate that process, a survival benefit may still be evident, even if this is not directly mediated by the reduction in proteinuria.
A number of studies have been performed in humans with chronic kidney disease that indicate that treatment with angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARB) may be superior to treatment with other anti-hypertensive agents and that this is due to the greater reduction in urinary protein excretion that occurs with these drugs. The ACE-inhibitor benazepril has been shown to reduce glomerular capillary pressure and proteinuria in cats with experimentally reduced renal mass.12 The anti-proteinuric effect has also been demonstrated in clinical cases of naturally occurring chronic renal failure.4,5 As might be expected, reduction in proteinuria is greatest in those patients that are most proteinuric before treatment. Unfortunately, despite the demonstrated efficacy of ACE-inhibitors in reducing proteinuria demonstrable benefit in terms of increased survival times,4 or reduction in the number of cats with an increase in the severity of azotaemia over a follow-up period of 6-months,5 could not be demonstrated, although favourable trends were evident in both studies. These results are disappointing. It is possible that clear benefit to ACE-inhibitor therapy could be demonstrated by carefully selecting the population that was studied to include only cats that were grossly proteinuric, had mild azotaemia at the study outset and allowing for a prolonged period of follow-up. However, if this were the case, it would not be representative of many cats with chronic kidney disease.
The ACE-inhibitor enalapril has been used in a placebo-controlled study of dogs with biopsy confirmed glomerulonephritis. Dogs treated with enalapril had a reduction in proteinuria compared with those receiving placebo and progression of renal disease was slowed.13 Although clinical studies have not been performed in dogs with less severe proteinuria dogs subjected to sub-total nephrectomy and treated with enalapril did show a tendency to a reduction in proteinuria compared to control dogs, and a reduction in the glomerular and tubulointerstitial lesions when the study was terminated after 6 months of treatment.14
There are concerns that treatment of hypertension with calcium-channel blockers, such as amlodipine, may exacerbate glomerular hypertension and proteinuria due to afferent arteriolar vasodilation. However, in studies of cats with naturally occurring hypertension proteinuria was actually reduced when cats were treated with amlodipine.8 This presumably was due to the marked reduction in systemic blood pressure that occurred when treatment was implemented. In dogs, where the reduction in blood pressure in response to amlodipine treatment is more modest, worsening of proteinuria may be a more realistic concern, however, no data exists to substantiate or refute this possibility.
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