Proteinuria: What’s New in the Management of this Silent Killer?

NORMAL RENAL HANDLING OF PROTEIN
The filtration barrier is freely permeable to water and small dissolved solutes, but retains most macromolecules such as proteins. The filtration barrier is comprised of (1) fenestrated endothelium, (2) glomerular basement membrane, (3) specialized epithelial cells, podocytes. The major determinants restricting protein passage into the filtrate are size and charge. A significant amount of albumin is NOT found in urine. However, despite this complex filtration system, the glomerulus normally leaks small quantities of albumin. When this occurs, there is rapid uptake of these proteins by the proximal renal tubular cells. Proximal tubular cells also reabsorb other low molecular weight proteins.

LABORATORY TESTS FOR PROTEINURIA
1) Urine dipstick is widely available, but the least reliable. Primarily albumin is measured. Both false negatives (e.g. Bence-Jones proteins) and false positives (e.g. alkaline urine, contact time, detergents) are possible. The urine dipstick is commonly used as a screening test for proteinuria. Positive results should be confirmed with urine-protein-creatinine ratio.

2) Urine protein to creatinine ratio (UPC) is the current standard to quantify proteinuria. Protein is quantified on a chemistry analyzer, which is more accurate than a dipstick and unaffected by urine concentration (because it is expressed as a ratio).

• Urine samples should be free of pyuria and color change from hematuria.
• A voided sample is reliable as long as no evidence of pyuria/ post-renal proteinuria.
• UPC is higher in urine samples collected in the hospital vs at home.
• There is day-to-day variation in UPC, especially with glomerular disease.
• UPC correlates with 24-hour protein excretion (gold standard), but variability can occur in single UPC results. Therefore, pooled or averaged samples are preferred when the degree of proteinuria is high. There is probably no diagnostic advantage to testing a pooled sample when there is low to moderate proteinuria.
• A significant difference in serial UPC values requires a change of 40% at high UPC values (near 12) and 80% at low UPC values (near 0.5).

Clinical Assessment of proteinuria should consider 1) persistence, 2) localization, and 3) magnitude. Approximately 60% of dogs with glomerular proteinuria will have immunecomplex glomerulonephropathy (ICGN) or amyloidosis.10
Both diseases represent an aberrant or excessive immune or inflammatory response to an infectious, neoplastic, or inflammatory condition.

Protein-losing nephropathy caused by glomerular proteinuria is uncommon in cats. However, based on renal biopsy, more than 70% of cats with primary glomerular disease have ICGN.11 Membranous glomerulonephropathy is the most commonly recognized form of ICGN in cats, followed by membranoproliferative glomerulonephritis; other forms of ICGN are reported less frequently.11,12 In both dogs and cats with glomerular proteinuria, the workup includes a comprehensive investigation for underlying infectious, neoplastic, or inflammatory conditions.10,13 Don’t forget to measure systemic blood pressure and perform a fundic examination in all patients with proteinuria. Management of proteinuria includes treatment of underlying diseases, when present, inhibition of the reninangiotensin- aldosterone system, dietary modification, antithrombotic therapy, and, sometimes, immunosuppression.

1) Inhibition of the Renin-Angiotensin-Aldosterone System (RAAS)- Chronic RAAS activation results in increased glomerular filtration rate, which can exacerbate proteinuria.14 Drugs that decrease the vasoconstrictive effects of angiotensin II on the efferent glomerular arteriole, such as ACE-inhibitors (ACEi) or angiotensin-receptor blockers (ARB) are recommended. For many years, ACEi such as enalapril or benazepril, have been the frontline treatment choice for RAAS-inhibition. However, some dogs can have worsening of proteinuria despite treatment, and ACEi are not always successful.14 In recent years, ARB have been demonstrated to be more effective than ACEi and ARB are now recommended as the frontline treatment.15 There can be a synergistic effect to both drugs together and combination treatment can be considered for difficult cases; side effects can be additive.16

WHERE IS THE EVIDENCE? DOGS:
In a prospective, randomized, double-masked clinical trial, 39 dogs with CKD and UPC > 0.5 (if azotemic) or ≥ 1.0 (if non-azotemic) were randomized to receive telmisartan (1.0 mg/kg PO q 24 h; n=20 dogs) or enalapril (0.5 mg/kg PO q 12 h; n= 19 dogs) and followed for 120 days.17 At day 30, the percentage change in UPC was greater for telmisartantreated dogs (65%) as compared to enalapril-treated dogs (35%). Telmisartan remained superior to enalapril at days 60 and 90.17 Also, of note, combination therapy resulted in concerning azotemia in 4/13 dogs (31%). Side effects of ACEi and ARB are similar (e.g. progressive azotemia, hyponatremia, hyperkalemia, gastrointestinal) and can be synergistic.16 A retrospective study from 2012 to 2018 evaluated blood pressure and UPC for 42 dogs treated with benazepril or enalapril alone, telmisartan alone, or both drugs.18 Dogs treated with a combination of ACEi and ARB had significant reduction in UPC compared to ACEi alone. Additionally, the mean systolic blood pressure was significantly lower in dogs treated with combination therapy as compared to ACEi alone.18 In another retrospective study, 44 dogs with proteinuria (non-azotemic dogs with UPC ≥ 2 and azotemic dogs with UPC ≥ 0.5) were separated into 3 groups: telmisartan alone, and in combination with benazepril or mycophenolate.14 UPC was followed over 12 months; a positive response was considered to be a post-treatment UPC < 0.5 or a decrease of ≥ 50% from baseline. At the 1-month follow-up, 70% of dogs had a favorable response. The average decrease over the study period was 41%.

CATS:
In a prospective, controlled, randomized, parallel group, blinded clinical trial of 224 adult cats with CKD (primarily IRIS stage 2), telmisartan (1 mg/kg PO q 24 h) significantly decreased proteinuria relative to baseline at all assessment points (over 180 days) and was non-inferior to benazepril (0.5-1 mg/kg PO q 24 h).19 Telmisartan can significantly reduce blood pressure in healthy and hypertensive cats.20,21 The average decrease in systolic blood pressure for hypertensive cats is approximately 23 mmHg by day 14 of treatment.20 The dose used to treat hypertension (1.5 mg/kg PO q 12 h) is higher than what is often needed for the treatment of proteinuria, and dose reductions might be needed over time. Also of note, telmisartan has not been evaluated as a single agent treatment for cats with systolic blood pressure >200 mmHg.20, label dosing Telmisartan- starting dose 0.5 to 1 mg/kg PO q 24 h. Increase by 0.5 mg/kg once daily up to 3 mg/kg/d. Monitor: azotemia, hyperkalemia, hypotension Available tablet sizes: 20 mg, 40 mg, 80 mg Liquid (cats only): Semintra® 10 mg/mL is labeled for cats to initially start with a higher dose (1.5 mg/kg PO q 12 h x 14 d), then taper to minimum dose of 0.5 mg/kg PO q 24 h (I usually don’t start so high).

WORSENING RENAL FUNCTION WITH RAAS INHIBITORS
Guidelines from IRIS for acute kidney injury (AKI) bring attention to an increase in serum creatinine ≥ 0.3 mg/dL within 48-hours. A recent retrospective study evaluating risk factors in 156 dogs receiving an ACE-i, found that 17% of dogs had worsening renal function within the first month of treatment.22 Of those dogs, 63% (n=7) were not considered clinically relevant (i.e. grade 1), but 6.4% were significant (grade 2, 7% (n=2); grade 3, 30% (n=8).

Risk factors identified in this study included pre-existing azotemia (odds ratio 3.21) and concurrent furosemide administration (odds ratio 5.05). Be cautious using RAAS-inhibitors in these patient populations (e.g. start at low doses, recheck blood work early ~ 3-5 days).

2. The goal of Nutritional Modification for the treatment of proteinuria is to reduce proteinuria without losing lean body mass. The protein content among commercial diets varies widely. Treats should also be considered in the diet history- chicken breast, rawhides, and chews are all sources of protein. A low-protein diet should be considered for all proteinuric animals, even if the animal is non-azotemic.16 If the animal is already on a low to moderate protein (close to the AAFCO minimum recommendations for adult maintenance), then medical management might be preferable to further protein restriction.23

WHERE IS THE EVIDENCE?
In one study, 44 dogs with proteinuric CKD (Iris stages 1-4) were fed a prescription renal dietb for 30 days and then randomized to receive either enalapril (0.5 mg/kg PO q 12 h; n=22) or benazepril (0.5 mg/kg PO q 24 h; n=22) through day 150.24 After 30 days of diet change alone, UPC decreased in 95.5% (n=42) dogs. Median UPC at admission was 2.9 (range 0.8-19.8) compared to median UPC at 30 days of 2.2 (range 0.6-14.4). The group treated with both renal diet and enalapril had a significant reduction in UPC by day 60; in contrast, the group treated with benazepril did not have additional benefit.24

In another study, 22 proteinuric, non-azotemic dogs (UPC 1) Were treated with benazepril and randomized to either a low protein (3.7g protein/100 kcal metabolizable energy)c or a maintenance (5.5 g protein/100 kcal metabolizable energy) d diet for 60 days. UPC was significantly lower in the group that was eating the lower protein diet.25

3) Thromboembolic complications are described in 6 to 42% of dogs with protein-losing nephropathy.16,26 The mechanisms for hypercoagulability in this population are multifactorial and poorly understood, but are thought to include loss of antithrombin III, and increases in procoagulant factors, factor V and VIII, and fibrinogen.16 Pulmonary thromboembolism is most commonly reported, followed by aortic thromboembolism.26 Unfortunately, there is no reliable predictor for thromboembolic complications and serum albumin concentration cannot be used to guide treatment.15 The 2023 IRIS updated guidelines recommend clopidogrel as the first line drug for thromboprophylaxis in dogs and cats (with aspirin as an alternative).15 A clopidogrel dosage of 1.1-4 mg/kg PO q 24 h appears safe and effective.26 For animals that develop thromboembolic disease, additional treatments might be considered, such as direct Xainhibitors (e.g. rivaroxaban 1-2 mg/kg/d dogs; 0.5-1 mg/ kg/d cats) or low-molecular weight heparin (e.g. enoxaparin 0.8 mg/kg SQ q 6 h).27 There is a risk for hemorrhage with combination therapy.

4) Immunosuppressive Therapy – The 2013 Consensus statement recommendations for when to use immunosuppressive drugs in the treatment of dogs with proteinuria (when histopathology is not available), include (1) there is clearly a glomerular origin (UPC > 2), (2) immunosuppressive drugs are not contraindicated, (3) the dog’s breed and age of disease onset are not suggestive of a familial nephropathy, (4) amyloidosis is considered unlikely, (5) serum creatinine is > 3.0 mg/dL or progressively increasing, (6) serum albumin < 2.0 g/dL.28 Mycophenolate mofetil, with or without short-term administration of glucocorticoids, has been suggested as the first choice. Cyclosporine has also been suggested for dogs with stable or slowly progressive disease. Glucocorticoids should be limited to the short-term because of the association with steroid excess and proteinuria.9 Treatment should be adjusted or discontinued if adverse effects are noted. Otherwise, 8 to 12 weeks of initial therapy should be provided. If there is no therapeutic response after 3 to 4 months, consider discontinuing immunosuppression. If there is a positive response, then taper to the lowest effective dose that maintains the response without worsening proteinuria, azotemia, or clinical signs.9

5) Therapeutic Goals- The goal is to achieve the lowest possible UPC. In 2023, IRIS redefined success to be a reduction in UPC of 50% from baseline and recognized that achieving a UPC < 0.5 is often not possible if glomerular disease is present.15 When UPC is > 2.0, achieving recommended targets within 3 months appears to be associated with a significant survival benefit.29

TARGETS FOR THERAPY:
16 UPC > 50% reduction from baseline and to achieve the lowest UPC possible15 Potassium concentration < 6.0 mmol/L Systolic blood pressure > 120 mmHg Serum creatinine stable or minimally increased*

• Minimally increased means < 30% increase above baseline when stage 1 or 2 CKD; <10% when stage 3 CKD; no increase when stage 4 CKD.

FOOTNOTES
a. Semintra®, Boehringer Ingelheim, Duluth, GA
b. Prescription Diet Canine k/D, Hill’s Pet Nutrition, Topeka, KS
c. Renal Royal Canin SAS, Amargues, France
d. Adult Royal Canin SAS

REFERENCES

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About the Author

SHELLY OLIN | DVM, DACVIM (SAIM)

Dr. Shelly Olin is a board-certified specialist in small animal internal medicine and a proud native of Charleston, South Carolina. She earned her Doctor of Veterinary Medicine (DVM) degree from the University of Georgia before practicing as an emergency veterinarian in Atlanta, Georgia. Following two years in emergency medicine, she pursued advanced specialty training, completing a residency in internal medicine and achieving diplomate status with the American College of Veterinary Internal Medicine (ACVIM). Dr. Olin currently serves as clinical faculty at the University of Tennessee College of Veterinary Medicine, where she continues to play a key role in clinical service and veterinary education. Her professional interests include endocrine disorders, particularly diabetes mellitus and adrenal diseases, urinary tract disease, minimally invasive diagnostic and therapeutic procedures, and endoscopy. She is also passionate about teaching and mentoring the next generation of veterinarians.