Feline renal proteinuria

Introduction

The etiology of proteinuria in cats is multifactorial and can be due to pre-renal, renal, or post-renal disease, or it can occur as an outcome of transient altered renal physiology (functional proteinuria). Proteinuria is a concern for both veterinarians and cat owners as it is associated with the development of azotemia in geriatric cats, and is an independent risk factor for survival in cats with chronic kidney disease (CKD) 1 2. Persistent renal proteinuria is of particular clinical importance and is defined as abnormal quantities of proteins in the urine that occur secondary to disease in the renal tubules, glomeruli and/or interstitial space. Because proteinuria is associated with negative outcomes in cats, it is important for veterinarians to diagnose and treat proteinuria in a strategic manner. This paper offers an update on the current understanding of the etiology of renal proteinuria in cats, outlines the clinical approach to diagnosis, and presents the current management strategies available.

Documentation of proteinuria

Two urine samples taken at different time points should be used to confirm persistent proteinuria; for accuracy, it is essential that the samples have an inactive urine sediment and that the patient is stable at the time of collection. In some instances, proteinuria may be noted alongside clinical signs for hypoalbuminemia (peripheral edema, cavitary effusion) and in this scenario immediate evaluation and treatment may be necessary. In most cases, once the persistence of proteinuria is confirmed by urine dipstick or the sulfosalicyclic turbidimetric test, then the magnitude of the proteinuria should be determined using the urine protein to creatinine ratio (UPC), a quantitative test that measures total urine protein. Based on the International Renal Interest Society (IRIS) guidelines, cats are identified as either non-proteinuric (UPC < 0.2), borderline proteinuric (UPC 0.2-0.4), or proteinuric (UPC > 0.4), again ideally based on two or more urine samples 3. Cats with persistent proteinuria (UPC > 0.4) should always be investigated.

Diagnosis of proteinuria

After determining the degree of proteinuria, the clinician should evaluate for the different causes of pre-renal, post-renal, and functional proteinuria (Table 1). Pre-renal proteinuria occurs when there are increased amounts of small proteins in the systemic circulation that overload the glomeruli and are unable to be completely resorbed in the renal tubules. Post-renal proteinuria occurs when the tissue barrier of the ureters, bladder, urethra, or genital tract is disrupted, allowing plasma proteins to leak into the urine. Functional proteinuria is due to altered renal physiology, with the most well-documented cause in cats being systemic hypertension, either secondary to disease or idiopathic in senior cats 4.

If pre-renal, post-renal, and functional proteinuria causes have been excluded, then this should point clinicians towards pathologic renal proteinuria. Renal proteinuria is described as either tubular or glomerular in origin, or it can be a mixture of both. Glomerular proteinuria is the most common form in proteinuric cats 5 and should be suspected in animals with UPC > 1.0, although a lower UPC value does not exclude glomerular disease 6. Glomerular proteinuria can be further classified as immune-complex glomerulonephritis (ICGN) or non-immune-complex glomerulonephritis (non-ICGN) based on the presence or absence of immune-complex deposits in the glomeruli; these can be identified by submitting renal biopsies for immunofluorescence and transmission electron microscopy.

CKD is the most common cause of non-ICGN renal proteinuria. Based on gel electrophoresis, glomerular proteinuria is most common in CKD cats, followed by mixed proteinuria and tubular proteinuria 7. These findings are consistent with non-specific changes that affect both the tubules and glomeruli found on renal histopathology in cats with CKD 8. Importantly, tubular proteinuria can occur in cats with non-azotemic (IRIS stage 1) CKD, which is consistent with tubular damage that occurs early in the disease process. Other causes of renal proteinuria include renal neoplasia, dysplasia, glomerulosclerosis or atrophy and acute kidney injury (AKI) secondary to hypoxic injury, toxin ingestion (e.g., ethylene glycol, lilies), or pyelonephritis. Inherited renal disorders such as amyloidosis or polycystic kidney disease should be considered differentials for renal proteinuria based on signalment and clinical suspicion.

ICGN is an immune-mediated disease where immune complexes are deposited within the kidney glomeruli. The location of the deposition varies and can occur in the glomerular basement membrane (membranous glomerulonephropathy), in the luminal surfaces of capillary walls (membranoproliferative glomerulonephritis), and the mesangium (mesangioproliferative glomerulonephritis) (Figure 1). Cats with ICGN should be tested for infectious disease, and especially retroviral infections. In a recent retrospective study, cats with ICGN were found to have high UPC ratios (> 2) and to be younger compared to cats with non-ICGN. In addition, a UPC ratio > 3.8 is both sensitive (91.9%) and specific (93.5%) for ICGN in cats 9. In contrast to cats with CKD, cats with ICGN often suffer from hypoalbuminemia and can subsequently develop cavitary effusions or pitting edema 5.

(Table 1) summarizes diagnostic tests to consider during the evaluation of feline proteinuria. The diagnostic approach to cases will depend on history, signalment, physical examination, and clinical suspicion. In particular, a renal biopsy with transmission electron microscopy and immunofluorescence (as well as traditional light microscopy) is required for diagnosis of ICGN, and should be considered in cats with rapidly progressive and/or marked proteinuria. Contraindications to renal biopsy include uncontrolled hypertension, hydronephrosis, anemia, coagulopathy, renal cystic disease, and end-stage CKD with creatinine > 5 mg/dL (442 µmol/L).

Treatment

For pre-renal, post-renal, and functional proteinuria, the underlying condition should be addressed. In cases of renal proteinuria, treatment may include a combination of inhibition of the renin-angiotensin-aldosterone system (RAAS), dietary management, and (when appropriate) immunosuppressive medications.

Inhibition of RAAS

The renin-angiotensin-aldosterone hormone system regulates vascular resistance, blood pressure, and fluid and electrolyte balance in the body (Figure 2). The two drug classes that are most commonly used to inhibit RAAS in cats are angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB), and while both drugs inhibit RAAS and improve proteinuria, their specific mechanism of action differs.

As the name suggests, ACE inhibitors inhibit the angiotensin converting enzyme in the RAAS cascade. Drugs most commonly used in cats within this class include enalapril and benazepril, but note enalapril may accumulate where there is severe kidney disease and should be used cautiously in cats with end-stage CKD. ARBs inhibit the action of angiotensin II by blocking its binding to tissue receptors; telmisartan is the most common ARB used in cats and selectively binds and blocks the angiotensin II type 1 receptor whilst sparing the renoprotective benefits provided by the angiotensin II type 2 receptor. The renoprotective benefits of telmisartan makes it an attractive treatment option in cats with renal proteinuria; in some countries it is also licensed for the treatment of hypertension in cats and is formulated as an oral liquid. In addition, telmisartan may be more efficacious for the treatment of proteinuria in cats compared to ACE inhibitors, especially when used long term 10.

Both ACE inhibitors and ARBs should be started at the recommended dose which is then increased over time until the treatment goal has been achieved (Table 2). Side effects of RAAS inhibition include hyperkalemia, and at high doses hypotension can occur. In addition, AKI is a reported side effect, although the incidence of this in both azotemic and non-azotemic cats treated with telmisartan was rare in a recent study 11.

Because both drug classes can reduce glomerular filtration rate, they should only be used in patients with stable azotemia and euvolemia.

Dietary management

There is limited information as to the efficacy of dietary management in cats with proteinuria 12, although a study showed that a moderate-protein (27.6% dry matter basis) wet diet fed for one year to cats limited proteinuria and glomerular injury in comparison to those fed a high-protein (51.7% dry matter basis) wet diet 13. A modified-protein diet is generally recommended in cats with proteinuria, but they should be monitored for signs of protein malnutrition (anemia, hypoalbuminemia, weight loss, muscle wasting), especially where appetite is reduced.

Daily caloric intake should also be monitored closely to prevent muscle wasting and weight loss, which can develop if energy malnutrition is present. An esophagostomy feeding tube should be considered early on in the disease process if a cat is unable to consume sufficient calories on its own. If necessary it may also be pertinent to review an animal's hydration status, and address this as necessary, either by using canned diets (> 70% moisture), subcutaneous or intravenous fluid therapy, or an esophagostomy tube.

Immunosuppressive drugs

Based on the benefit in dogs, immunosuppressive therapy is recommended in cases of ICGN confirmed on renal biopsy with severe, persistent, or progressive proteinuria and no contraindication to immunosuppression 14. In one study, there was a statistical trend showing ICGN cats that received immunosuppression lived longer, with a median survival time of 204 days compared to 34 days 5. Mycophenolate mofetil monotherapy (8-10 mg/kg PO q12H) is the preferred drug of choice, and can be used in combination with a short tapering course of prednisolone in severe cases. Mycophenolate mofetil is well tolerated in cats, although animals should be closely monitored for side effects, which may include gastrointestinal signs (in particular, diarrhea), bone marrow suppression, and infection 15. Treatment effect may take up to 8-12 weeks.

Monitoring proteinuria

After initiating RAAS inhibition, or after a dose change, indirect blood pressure, serum creatinine and potassium levels should be measured within 7 days. A urinalysis and UPC should be checked 4-6 weeks later to monitor treatment efficacy. After establishing the maintenance dose, routine monitoring every 3-6 months in a stable patient is encouraged.

Although the biological variation of the UPC ratio in cats is unknown, based on studies in dogs it can vary over time by 35-80%, depending on the severity of the proteinuria. UPC values tend to be higher in samples collected in the hospital compared to samples collected at home 16. Additionally, the UPC can be falsely increased by macroscopic red blood cell contamination, which can occur during cystocentesis in cats. UPC should therefore be performed on a urine sample with an inactive sediment collected using a consistent method (free catch or cystocentesis). Because of the significant day-to-day variations, trends in the UPC may be necessary to determine efficacy of treatment, but the treatment goal for proteinuria is a consistent reduction in UPC by at least 50%.

Proteinuria is a clinically relevant finding and the origin of the proteinuria should be explored prior to treatment. Chronic kidney disease is the most common cause of renal proteinuria in cats and can occur in early stage disease. Immune-complex glomerulonephritis is commonly seen in proteinuric cats, especially in younger cats and those with significant proteinuria or retroviral infections. Monitoring the UPC with a consistent urine sample collection method repeatedly over time is necessary to determine treatment efficacy.