Hypertriglyceridemia-associated proteinuria in Miniature Schnauzers

Introduction

Primary hypertriglyceridemia, also known as familial idiopathic hypertriglyceridemia, is a common yet under-recognized condition in Miniature Schnauzers. This metabolic disorder has an age-dependent manifestation, with a prevalence that increases from 15% of Miniature Schnauzers less than 3 years of age to more than 75% of dogs older than 9 years of age 1.

Hypertriglyceridemia is typically associated with increased risk for pancreatitis, gallbladder mucoceles, and elevated liver enzymes 2 3 4; more recently, hypertriglyceridemia has also been found to be associated with proteinuria and glomerular pathology in Miniature Schnauzers 5 6 7.

Approximately 50% of Miniature Schnauzers with primary hypertriglyceridemia have proteinuria, and fasting serum triglyceride concentrations have a strong positive correlation with urinary protein-to-creatinine ratios (UPC) in the breed 5 6. Furthermore, renal biopsies of proteinuric Miniature Schnauzers with hypertriglyceridemia contain lipid thromboemboli (Figure 1a) (Figure 1b) (Figure 1c) (Figure 1d) 7. These findings suggest that hypertriglyceridemia is the cause rather than the consequence of glomerular disease. This paper presents the features and consequences of hypertriglyceridemia-associated proteinuria in Miniature Schnauzers and provides information on how to diagnose and manage the condition. 

Clinicopathologic features 

The clinical presentation of hypertriglyceridemia-associated proteinuria is outlined in (Table 1). As noted above, the condition is most common in middle aged and older Miniature Schnauzers 5. Males and females are affected at similar frequency; no sex predisposition has been reported. Unless comorbidities are present, affected dogs do not have any clinical signs 5 6; for example, polyuria and polydipsia have not been reported. There are also no physical examination findings specifically associated with the condition, although hypertriglyceridemia can result in ocular lipid deposits 8. Thus, hypertriglyceridemia-associated proteinuria is often detected incidentally when urinalysis is performed for routine health screening or for comorbidities.

The laboratory findings seen with hypertriglyceridemia-associated proteinuria are also presented in (Table 1). The extent of proteinuria is strongly correlated to fasting serum triglyceride concentrations 5 6. Proteinuria occurs in 25-41% of Miniature Schnauzers with mild hypertriglyceridemia (100-400 mg/dL, 1.1-4.5 mmol/L), and the degree of UPC elevation is generally mild (i.e., < 2). In contrast, proteinuria occurs in 85-88% of Miniature Schnauzers with moderate to severe hypertriglyceridemia (> 400 mg/dL, > 4.5 mmol/L), and the UPC is greater than 2 in most dogs, with values > 5 reported. Urine specific gravity (USG) is variable and similar to age-matched Miniature Schnauzers without hypertriglyceridemia-associated proteinuria. The urine sediment is inactive on examination. 

Hypertriglyceridemia-associated proteinuria is not associated with hypoalbuminemia or azotemia 6. It is important to note that there are inter-breed differences in serum creatinine concentration, and the median in healthy Miniature Schnauzers is < 1.0 mg/dL, < 88 μmol/L 6 9.

Hypercholesterolemia is rare in Miniature Schnauzers with mild primary hypertriglyceridemia, but common in those with moderate to severe hypertriglyceridemia, at around 40% of dogs where the serum triglyceride level is > 400 mg/dL, > 4.5 mmol/L 1. Moderate to severe hypertriglyceridemia is also associated with elevations in liver enzymes; 60% of Miniature Schnauzers with serum triglyceride > 400 mg/dL, > 4.5 mmol/L show elevation in alkaline phosphatase plus at least one other enzyme 4. This is thought to be due to hepatic lipid accumulation. No hematologic abnormalities have been associated with hypertriglyceridemia-associated proteinuria, but mild thrombocytosis (platelet count of 400-500 x 10³/μL) is common in older Miniature Schnauzers 6.

Diagnosis 

The presence of hypertriglyceridemia and proteinuria in a Miniature Schnauzer is necessary for a diagnosis of hypertriglyceridemia-associated proteinuria, but in itself not sufficient to confirm the disorder; other causes of these disturbances must first be ruled out. A simple diagnostic approach is presented in (Table 2). A serum biochemistry profile (Figure 2) and urinalysis are critical to exclude pre- and post-renal causes of proteinuria and for detecting abnormalities (e.g., hypoalbuminemia, azotemia) that could indicate that a more severe form of glomerular disease is present 11 12. It is also important to rule out treatment with medications associated with hyperlipidemia (e.g., corticosteroids, phenobarbital) and to evaluate for metabolic disorders that can cause secondary hyperlipidemia 13. These include diabetes mellitus, hyperadrenocorticism, and hypothyroidism, all of which can also be associated with proteinuria 14 15 16.

Hyperadrenocorticism can be particularly difficult to differentiate from primary hypertriglyceridemia, as similar patterns of liver enzyme elevations occur with both conditions. If clinical signs (e.g., polyuria, polydipsia, polyphagia) and physical exam findings (e.g., alopecia, abdominal distension, hyperpigmentation) consistent with hyperadrenocorticism are present, a low-dose dexamethasone suppression test is recommended as a diagnostic test for hyperadrenocorticism 17. If signs are absent, a urine cortisol-to-creatinine ratio can be used to rule out hyperadrenocorticism. Obesity, pancreatitis, and cholestasis are also associated with mild hypertriglyceridemia in dogs 13 18. 

Ultimately, hypertriglyceridemia-associated proteinuria is a diagnosis of exclusion. The final step in the diagnostic process is the evaluation of a renal biopsy with comprehensive examination of the tissue by thin sections, special stains, and transmission electron microscopy (Figure 1a) (Figure 1b) (Figure 1c) (Figure 1d) 7. Glomerular lipid thromboemboli with or without focal segmental glomerulosclerosis are characteristic for lipid-induced injury. If no lipid deposits are present, or if other lesion types are detected, the dog’s proteinuria should be assumed to have another origin. Importantly, one in five Miniature Schnauzers undergoing renal biopsy for proteinuria are found to have immune-complex mediated glomerulonephritis 7 and could benefit from treatment with immunosuppressive therapy 19. The decision to proceed with a renal biopsy in a dog with presumed hypertriglyceridemia-associated proteinuria should weigh the likelihood of another disease process against the risk of complications from the biopsy, such as severe hemorrhage 20.

Treatment

No studies have investigated the optimal therapy for Miniature Schnauzers with hypertriglyceridemia-associated proteinuria. However, based on data from humans and rodents, management of the hypertriglyceridemia is important. Dietary management should first be instituted, and feeding a low-fat diet (containing less than 25 grams of total fat per 1,000 kcal) is recommended 13. Reduced dietary protein intake is recommended for dogs with glomerular disease 21, but it is unknown if this is beneficial for dogs with hyperlipidemia-associated proteinuria. If the fasting serum triglyceride concentration remains elevated after two months of exclusively feeding this type of diet, a fibrate should be administered. This is especially important if the serum triglyceride concentration is > 400 mg/dL (> 4.5 mmol/L), as the risks for proteinuria and pancreatitis are greatest with this degree of hypertriglyceridemia 2 5 6. Bezafibrate is effective at normalizing triglyceride concentrations in dogs within 30 days of treatment 22 and has a recommended dose of 50 mg PO q24H for dogs weighing < 12 kg, 100 mg for 12.1-25 kg, and 200 mg for > 25 kg. Bezafibrate is manufactured as a 200 mg sustained-release tablet; although it must be split for dogs weighing less than 25 kg, it remains effective at treating hypertriglyceridemia in animals under this weight. If bezafibrate is not available, other options include fenofibrate at 2-4 mg/kg q24H 23, or clinofibrate at 10 mg/kg q12H 24. In humans, major side effects of fibrates include myopathy and hepatotoxicity, but these have not yet been reported in dogs at the dosages recommended above. Other proposed medications for hyperlipidemia in dogs are omega-3 fatty acids and niacin, but evidence of efficacy is lacking 13.

Treatment of proteinuria with an inhibitor of the renin‐angiotensin‐aldosterone system is recommended for dogs with a UPC consistently > 0.5 21. Examples include angiotensin converting enzyme inhibitors such as enalapril or benazepril (both given at 0.5 mg/kg q24H), or angiotensin receptor blockers such as telmisartan (1 mg/kg once daily). The UPC, serum creatinine, serum potassium, and blood pressure should be rechecked 1-2 weeks after starting these drugs 21. Antithrombotic agents are also a component of the general recommendations for dogs with proteinuric glomerular disease, but a prothrombotic tendency was not found in a limited evaluation of Miniature Schnauzers with hypertriglyceridemia-associated proteinuria 6. Given the paucity of data, the decision to start an antithrombotic agent can be made at the discretion of the clinician. Antihypertensive therapy should be administered to dogs with persistent hypertension (> 150 mmHg) according to consensus guidelines for management of glomerular disease (Figure 3) 21. 

Prognosis

Longitudinal data on Miniature Schnauzers with hypertriglyceridemia-associated proteinuria is limited to one study that followed 8 affected dogs for a median of 18 (range 3-31) months 6. During this time there was no evidence of progressive renal disease, and no deaths were attributed to the hypertriglyceridemia-associated proteinuria. Dogs with hypertriglyceridemia-associated proteinuria also have no evidence of cardiac damage or hypercoagulability, as assessed by antithrombin III activity 6. 

Primary hypertriglyceridemia is prevalent in middle-aged and geriatric Miniature Schnauzers and often associated with glomerular-range proteinuria. There is evidence that the proteinuria is a consequence of lipid-induced glomerular injury, and glomerular lipid emboli have been detected in renal biopsies obtained from hypertriglyceridemic, proteinuric Miniature Schnauzers. The disease is subclinical, and serious consequences of glomerular disease (hypoalbuminemia, azotemia, or thromboembolic disease) have not been reported. When hypertriglyceridemia and proteinuria are detected concurrently in this breed, other possible causes, such as hyperadrenocorticism, should be ruled out before making the presumptive diagnosis of hypertriglyceridemia-associated proteinuria. Treatment consists of management of hypertriglyceridemia with diet, and if needed, fibrate administration. Inhibition of the renin-angiotensin-aldosterone system is also recommended to reduce proteinuria. Based on limited data, prognosis is excellent, but if hypoalbuminemia, azotemia, or persistent isosthenuria develops, other underlying disease processes should be investigated.