Hypertension and Proteinuria: Frequent Complications of Cushing's Disease in Dogs

Long-Term Follow-Up of Renal Function in Dogs after Treatment for ACTH-Dependent Hyperadrenocorticism

P.M.Y. Smets, H.P. Lefebvre, B.P. Meij, S. Croubels, E. Meyer,
I. Van de Maele, and S. Daminet

Journal of Veterinary Internal Medicine 2012;26:565–573

Hyperadrenocorticism (Cushing’s syndrome) is a common endocrine disorder in dogs and is characterized by chronically elevated circulating concentrations of the steroid hormones (e.g., cortisol) produced by the adrenal cortex (1,2). The multi-systemic effects of long-term hypercortisolism in dogs results in a variety of medical complications including hypertension and proteinuria (3-7).

Over 75% of dogs with untreated Cushing’s syndrome have systemic arterial hypertension and half have proteinuria. Unfortunately, both hypertension and proteinuria may persist despite successful treatment of the hypercortisolemia (3-7).

In dogs without Cushing's syndrome, it is well known that systemic hypertension and proteinuria are major risk factors for the development and progression of chronic kidney disease (CKD); both morbidity and mortality are increased in dogs with CKD when either hypertension and proteinuria are present (8). Therefore, since hypertension and proteinuria are so common in dogs with Cushing's syndrome, these dogs might also be at increased risk for renal complications. However, the effects of canine Cushing’s syndrome on renal function and progression of CKD are poorly understood.

In this prospective study by Smets et al (9), the investigators carefully evaluated the renal function in dogs with ACTH-dependent Cushing's syndrome before and after medical or surgical treatment of hypercortisolemia. Routine serum chemistry, urine protein excretion, glomerular filtration rate, and urine markers for renal tubular function were investigated.

Background
Systemic hypertension and proteinuria are frequent complications in dogs with Cushing’s syndrome and do not always resolve after treatment of hypercortisolemia. Therefore, dogs with Cushing’s syndrome may be at risk for renal dysfunction before and after treatment.

Hypothesis and Objectives
To assess renal function in dogs with ACTH-dependent hyperadrenocorticism (ADHAC) before and after treatment.

Dogs
A total of 19 dogs with ACTH-dependent hyperadrenocorticism (followed for at least 6 months) and 12 control dogs were studied.

Methods
Renal function was assessed before and at 1, 3, 6, and 12 months after treatment. Twelve dogs were treated with trilostane and 7 dogs were treated by transsphenoidal hypophysectomy.

Routine renal markers were measured and urinary albumin, immunoglobulin G, and retinol-binding protein were assessed by ELISA. Urinary N-acetyl-b-D-glucosaminidase (NAG) was determined colorimetrically. All urinary markers were indexed to urinary creatinine concentration. Plasma clearance of creatinine, exo-iohexol, and endo-iohexol was used to measure glomerular filtration rate (GFR).

Results
Serum creatinine and urea concentrations increased post-treatment, but remained within reference ranges. Plasma clearance of creatinine and endo-iohexol were significantly lower post-treatment, whereas the plasma clearance of exo-iohexol was not different. Urinary protein-to-creatinine ratio (UPC), urinary albumin-to-creatinine, urinary IgG, and urinary retinol-binding protein were decreased post-treatment, but at 12 months 5 of the 13 dogs remained proteinuric. Urinary NAG did not change significantly.

Conclusions and Clinical Importance
A decrease in GFR and persistent proteinuria post-treatment may warrant the clinician’s attention. Future research including renal histopathology of dogs with persistent proteinuria or low GFR is needed to further assess renal outcome.

Overview of the Problem:

Systemic hypertension
Results of this study confirm that systemic hypertension is common in dogs with Cushing's disease, present in 7 (37%) of the 19 dogs prior to treatment (9).  This prevalence is similar to one recent study (7), but less than that previously reported in 2 other studies, in which 53-86% of dogs with untreated Cushing's syndrome were hypertensive (3,6).

The mechanisms underlying the hypertension potentially include excessive secretion of renin, activation of the renin–angiotensin system, enhanced vascular sensitivity to catecholamines and a reduction of vasodilator prostaglandins (1,2,5). In most dogs with Cushing's syndrome, the degree of hypertension is mild to moderate and not associated with overt clinical signs of blindness (i.e., retinal detachment or hemorrhage is extremely rare). However, this moderate hypertension can exa­cerbate left ventricular hypertrophy and congestive heart failure and may lead to glomerular damage and pro­teinuria.

In general, hypertension does not resolve following treatment of hyperadrenocorticism (1-3,6,7). In support of that statement, hypertension persisted in most of the dogs of this report despite treatment for their Cushing's disease, with 5 (38%) of 13 dogs remaining hypertensive at the 12-month follow-up (9). The explanation for why hypertension persists in many dogs despite successful treatment of their Cushing's disease is not clear.

Proteinuria
About half of dogs with untreated Cushing's syndrome have proteinuria, defined as a urine protein:creatinine ratio (UPC ratio) >0.5-1.0, in the absence of UTI (1-4).   Although such a protein-losing glomerulopathy is common in dogs with Cushing’s syndrome, the severity of proteinuria is generally less than that typically seen in dogs with hypoalbuminemia or hypoproteinemia. Hypertension and proteinuria are common in dogs with Cushing’s syndrome, and they may represent a “cause-and-effect” relationship.

Results of this study also confirm that proteinuria is common in canine Cushing's disease, with high pretreatment UPC ratios found in 68% of dogs of this study (9). However, as with hypertension, proteinuria sometimes fails to completely resolve despite treatment of Cushing's disease (1-4). In agreement with that, results of the present study found that the median levels of proteinuria decreased after treatment, but proteinuria persisted in 5 of 13 (38%) dogs after 12 months of treatment.

Glomerular Filtration Rate (GFR)
Prior to treatment, over half the dogs in this study had high values for GFR (9). The GFR decreased significantly after successful treatment.  The clinical relevance of GFR changes in dogs with Cushing's disease currently is unclear. However, the high pretreatment GFR may be the result of increased renal blood flow and decreased renal vascular resistance, as described in dogs treated with exogenous glucocorticoids (10).

My Bottom Line:

In the workup and management of dogs with Cushing's syndrome, we can never forget that systemic hypertension and proteinuria are extremely common complications of this disease.

Even after successful treatment of Cushing's disease with trilotane or mitotane, many dogs with remain hypertensive and have persistent proteinuria. This suggests that underlying glomerular disease is present in many of these dogs. The new finding in this study (9) that GFR fell is also consistent with the fact that underlying renal disease is present in many of these dogs.

Therefore, it is prudent to continue to monitor blood pressure and urinary protein excretion in all dogs with Cushing's syndrome. If hypertension or proteinuria (or both) persist, one should institute treatment with angiotensin-converting enzyme (AEC) inhibitors (e.g., enalapril or benazepril) and add amlodipine, if needed (11-15).

And a side-note: remember that about half of dogs with Cushing's disease will have a urinary tract infection (UTI). However, because of the immunosuppressive action of excess cortisol, these dogs may not show clinical signs of UTI or have an active urine sediment (1,2). Therefore, a urine culture is recommended in all dogs with newly diagnosed Cushing's syndrome and again at 6-month intervals while on treatment with trilostane or mitotane.

A number of questions remain to be answered to better manage this renal issues in dogs with Cushing's disease:

1. First of all, what's the best protocol to follow with regard to dealing with the proteinuria and hypertension? 
2. Should one treat the Cushing's disease first and see what happens over the next couple months? (That's what I do now, but is this the best protocol?)
3. Or should we be more proactive and treat the proteinuria and hypertension right out of the starting gate, as we start trilostane or mitotane therapy? 
4. Finally, because of the renal issues and overt proteinuria, should we address dietary therapy in these dogs? 

As always, the more we learn, the more we realize how little we really know!

References:

1. Melián C, M. Pérez-Alenza, D, Peterson ME. Hyperadrenocorticism in dogs, In: Ettinger SJ (ed): Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat (Seventh Edition). Philadelphia, Saunders Elsevier, 2010;1816-1840.
2. Herrtage ME, Ramsey IK. Canine hyperadrenocorticism. In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. 4th ed. Quedgeley, Gloucester: British Small Animal Veterinary Association; 2012:167-189.
3. Ortega TM, Feldman EC, Nelson RW, et al. Systemic arterial blood pressure and urine protein-creatinine ratio in dogs with hyperadrenocorticism. Journal of the American Veterinary Medical Association 1996;209:1724–1729. 
4. Hurley KJ, Vaden SL. Evaluation of urine protein content in dogs with pituitary-dependent hyperadrenocorticism. Journal of the American Veterinary Medical Association 1998;212:369–373. 
5. Goy-Thollot I, Pechereau D, Keroack S, et al. Investigation of the role of aldosterone in hypertension associated with spontaneous pituitary-dependent hyperadrenocorticism in dogs. Journal of Small Animal Practice 2002;43:489–492. 
6. Novellas R, de Gopegui RR, Espada Y. Determination of renal vascular resistance in dogs with diabetes mellitus and hyperadrenocorticism. Veterinary Record 2008;163:592-596.
7. Lien YH, Hsiang TY, Huang HP. Associations among systemic blood pressure, microalbuminuria and albuminuria in dogs affected with pituitary- and adrenal-dependent hyperadrenocorticism. Acta Veterinaria Scandinavica 2010;52:61. 
8. Jacob F, Polzin DJ, Osborne CA, et al. Evaluation of the association between initial proteinuria and morbidity rate or death in dogs with naturally occurring chronic renal failure. Journal of the American Veterinary Medical Association 2005;226:393–400. 
9. Smets PM, Lefebvre HP, Meij BP, et al. Long-term follow-up of renal function in dogs after treatment for ACTH-dependent hyperadrenocorticism. Journal of Veterinary Internal Medicine 2012;26:565-574. 
10. Hall JE, Morse CL, Smith MJ, et al. Control of arterial pressure and renal function during glucocorticoid excess in dogs. Hypertension 1980;2:139-148.
11. Brown S, Atkins C, Bagley R, et al. Guidelines for the identification, evaluation, and management of systemic hypertension in dogs and cats. Journal of Veterinary Internal Medicine 2007;21:542-558. 
12. Lefebvre HP, Toutain PL. Angiotensin-converting enzyme inhibitors in the therapy of renal diseases. Journal of Veterinary Pharmacology and Therapeutics 2004;27:265-281. 
13. Lees GE, Brown SA, Elliott J,et al. Assessment and management of proteinuria in dogs and cats: 2004 ACVIM Forum Consensus Statement (small animal). Journal of Veterinary Internal Medicine 2005;19:377-385. 
14. Lefebvre HP, Brown SA, Chetboul V, et al. Angiotensin-converting enzyme inhibitors in veterinary medicine. Current Pharmaceutical Design 2007;13:1347-1361. 
15. Chew DJ, DiBartola SP, Schenck PA. Chronic renal failure. In: Canine and Feline Nehrology and Urology. Second Ed. Elsevier Saunders, St. Louis. 2011;145-196.