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Cushing's Disease (Hyperadrenocorticism) in Dogs

Synthesized from Multiple Veterinary Sources

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1. Definition & Terminology

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2. Etiology & Classification

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3. Epidemiology

• Overall prevalence: ~0.20% in general practice; up to 1.46% at specialist referral centers
• Mean age at diagnosis: 9.8 ± 2.5 years (middle-aged to older dogs)
• Sex predisposition: Females > males (OR 1.85); neutered animals at higher risk (OR 2.54)
• Breed predisposition: Standard Schnauzer (OR 58.1), Fox Terrier (OR 20.33), Poodle, Dachshund, Boxer, Boston Terrier, Beagle
• Study population: 21,281 client-owned dogs across 5 veterinary centers in Italy

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4. Clinical Signs

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5. Pathophysiology

• Gluconeogenesis → hyperglycemia, insulin resistance
• Protein catabolism → muscle wasting, poor wound healing, thin skin
• Immunosuppression → susceptibility to infections (UTI, pyoderma, fungal infections)
• Mineralocorticoid effect (at high levels) → sodium/water retention → hypertension, PU/PD
• Lipid metabolism → hepatic lipidosis, hypercholesterolemia, hepatomegaly

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6. Diagnosis

Step 1 — Screening Tests (confirm hypercortisolism)

Key point (Lathan 2023): A flatline post-ACTH stimulation result (<2 µg/dL) confirms hypoadrenocorticism, but not all dogs with naturally occurring Cushing's syndrome (NOCS) have elevated post-ACTH results. LDDST is preferred for diagnosis.

Step 2 — Differentiation Tests (PDH vs. ACT)

Routine Clinicopathological Findings

• CBC: Stress leukogram (neutrophilia, lymphopenia, eosinopenia, monocytosis), erythrocytosis
• Chemistry: Elevated ALP (most consistent — often >5× ULN), elevated ALT, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, hypokalemia (occasionally)
• UA: Low specific gravity, proteinuria, glucosuria (if diabetic), bacteriuria (secondary UTI common despite lack of pyuria due to immunosuppression)

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7. Treatment

A. Medical Management (most common approach)

Trilostane (preferred first-line)

• Mechanism: Competitive inhibitor of 3β-hydroxysteroid dehydrogenase → blocks cortisol and aldosterone synthesis
• Dose: 1–2 mg/kg SID or BID; titrate based on ACTH stimulation test (target post-ACTH cortisol 1.45–9.1 µg/dL / 40–250 nmol/L)
• Monitoring: ACTH stimulation test at 10–14 days, 4 weeks, then every 3–6 months
• Adverse effects: Adrenal insufficiency (overdose), reversible adrenal necrosis, hypotension, hyperkalaemia
• Advantage over mitotane: Simpler dosing, reversible mechanism, less systemic toxicity

Mitotane (o,p'-DDD) — alternative

• Mechanism: Adrenocorticolytic drug → selective destruction of zona fasciculata/reticularis (induction) or total adrenocortical destruction (high-dose)
• Induction (PDH): 25–50 mg/kg/day PO with food until loss of PU/PD, typically 7–10 days; concurrent monitoring for hypoadrenocorticism
• Maintenance: ~50 mg/kg/week
• Monitoring: ACTH stimulation test (target post-ACTH cortisol 1–5 µg/dL)
• Adverse effects: GI signs (anorexia, vomiting, diarrhea), life-threatening addisonian crisis, neurological signs
• Use for ACT: High-dose protocol (75–100 mg/kg/day) — greater risk of complete adrenal destruction
• Reine 2007: Mitotane use is "complicated and comes with many potential side effects, making many practitioners wary of its use"

Ketoconazole

• Mechanism: Inhibits adrenal and gonadal steroidogenesis (P450 enzymes)
• Dose: 5–15 mg/kg BID
• Use: Less effective; considered second-line; useful when trilostane/mitotane unavailable
• Adverse effects: Hepatotoxicity, GI signs

L-Deprenyl (Selegiline)

• Mechanism: MAO-B inhibitor → dopaminergic → suppresses ACTH secretion
• Use: Mild, early PDH only; poor responder rate vs. other drugs; no longer commonly recommended

B. Surgical Treatment

C. Radiation Therapy

• Indicated for pituitary macroadenomas (>1 cm) causing neurological signs
• Does not directly reduce cortisol but shrinks tumor mass
• Rapastella et al. 2023 [PMID 37218395]: Concurrent hypercortisolism affects survival in dogs treated with radiotherapy for pituitary macroadenomas — combined medical + radiation is preferred

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8. Complications & Comorbidities

• Diabetes mellitus: Insulin resistance → concurrent DM in ~10% of Cushing's cases; resolves with successful treatment
• Pulmonary thromboembolism: Hypercoagulable state; can be fatal
• Hypertension: Common; may require antihypertensive therapy (amlodipine)
• Recurrent infections: UTI most common; also pyoderma, demodicosis
• Calcinosis cutis: Mineralization of skin; can be severely pruritic
• Respiratory signs: Panting, exercise intolerance; radiographic abnormalities documented (Mendonça 2024)
• QT interval instability: Cardiac arrhythmia risk documented (Vila et al. 2023 [PMID 35575953])

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9. Prognosis

• PDH (medically managed): Median survival ~2 years with trilostane or mitotane; quality of life significantly improved with treatment
• ACT (adrenalectomy): Adenoma — good prognosis; carcinoma — guarded, metastasis possible
• Macroadenoma with neurological signs: Poor without combined pituitary-directed therapy
• Untreated Cushing's: Progressive deterioration, diabetes, infections, thromboembolic disease

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10. Emerging / Future Treatments

• Pituitary-targeting drugs: Pasireotide (somatostatin analogue), cabergoline (dopamine agonist) — reduce ACTH from tumor
• Novel steroidogenesis inhibitors: Levoketoconazole, osilodrostat — under investigation in dogs
• Machine learning screening: Yoo et al. 2026 [PMID 41431376] demonstrated ML-assisted screening improves early detection accuracy

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Key References by Source

Chronic Kidney Disease (CKD) in Dogs and Cats

A Comprehensive Evidence-Based Review

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1. Definition & Overview

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2. Epidemiology

Cats

• CKD is the most common metabolic disease of domesticated cats, with most affected cats being geriatric (>12 years of age) (Brown et al., Vet Pathol 2016 [PMID 26869151])
• Prevalence: reported in 30–40% of cats >15 years old; increasing with age
• The frequency of CKD diagnosis in cats has increased in recent decades, partly due to improved detection and increased longevity
• Pathological hallmarks: interstitial inflammation, tubular atrophy, fibrosis, and secondary glomerulosclerosis
• Unlike in humans and dogs, primary glomerulopathies with marked proteinuria are remarkably rare in cats

Dogs

• CKD occurs commonly in older dogs (typically >7–9 years); certain small breeds may be affected younger
• Breed predispositions include: Cocker Spaniel, Shih Tzu, Bull Terrier (hereditary nephritis), Bernese Mountain Dog (glomerulonephritis), Samoyed (X-linked hereditary nephritis), and Doberman Pinscher (renal dysplasia)
• Prevalence is lower than in cats but still significant in geriatric populations (Bartges, Vet Clin North Am 2012 [PMID 22720808])

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3. Etiology & Risk Factors

Cats

Dogs

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4. Pathophysiology

A. Progressive Nature of CKD

1. Glomerular hypertension & hyperfiltration: Loss of nephrons forces remaining nephrons to hyperfiltrate → glomerular capillary hypertension → glomerulosclerosis → further nephron loss (Brenner hypothesis)
2. RAAS activation: Decreased renal perfusion activates the renin-angiotensin-aldosterone system (RAAS), causing intraglomerular hypertension, proteinuria, inflammation, and fibrosis. Chronic RAAS activation perpetuates CKD alongside cardiovascular disease (Ames et al., J Vet Intern Med 2019 [PMID 30806496])
3. Proteinuria: Filtered proteins are directly toxic to tubular epithelium; proteinuria drives interstitial inflammation, tubular apoptosis, and fibrosis. Proteinuria is a negative prognostic indicator in both species (Vaden & Elliott, Vet Clin North Am 2016 [PMID 27485278])
4. Phosphorus retention: As GFR declines → phosphorus retention → stimulates FGF-23 secretion and secondary renal hyperparathyroidism (RSHPT) → soft tissue mineralization, further nephron loss, cardiovascular calcification
5. Uremia: Accumulation of uremic toxins (urea, creatinine, indoxyl sulfate, p-cresol sulfate, etc.) → systemic inflammation, GI damage, nausea, anorexia, CNS depression
6. Gut-kidney axis: Gut dysbiosis in CKD leads to accumulation of uremic toxins (indoxyl sulfate, p-cresyl sulfate), disruptions in bile acid and fatty acid profiles, and systemic inflammation that exacerbates renal dysfunction (Summers & Quimby, Vet J 2024 [PMID 38897377])
7. AKI–CKD continuum: Progressive CKD may represent repeated episodes of subclinical acute kidney injury over time (Cowgill et al., Vet Clin North Am 2016 [PMID 27593574])

B. Differences Between Species

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5. IRIS Staging System

IRIS CKD Stages — Dogs

IRIS CKD Stages — Cats

IRIS Sub-staging

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6. Clinical Signs

A. By Stage

B. Specific Signs

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7. Diagnosis

A. Clinicopathological Findings

B. SDMA as a Biomarker

• Rises above the reference interval with smaller reductions in GFR than creatinine (detects ~25–40% loss vs. ~75% loss for creatinine)
• Is not influenced by muscle mass (important in cachectic cats/dogs)
• Should be evaluated together with creatinine for diagnosis and monitoring

C. Imaging

D. Renal Biopsy

• Nephrotic syndrome / marked proteinuria (UPC >2.0)
• Unexplained acute deterioration
• Young animals with CKD (rule out hereditary nephropathy)
• Before immunosuppressive therapy

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8. Comorbidities & Complications

1. Systemic Arterial Hypertension

• Present in >60% of cats and dogs with CKD
• Causes: glomerular hypertension, RAAS activation, sodium retention
• Consequences: retinal detachment/blindness, LVH, stroke, worsens proteinuria and CKD progression
• Treatment: Amlodipine (1st line in cats: 0.625–1.25 mg/cat SID); ACE inhibitors or ARBs (dogs); combination if needed

2. Proteinuria

• UPC >0.5 in dogs and >0.4 in cats is pathological and warrants investigation
• Glomerular proteinuria → tubular damage → fibrosis → progression
• Standard of care: ACE inhibitors (enalapril, benazepril) and/or ARBs (telmisartan preferred in cats; losartan in dogs)
• Telmisartan now preferred over benazepril in cats based on superior antiproteinuric effect (Vaden & Elliott 2016 [PMID 27485278]; ACVIM Consensus 2005 [PMID 15954557])

3. Anemia of CKD

• Non-regenerative, normocytic, normochromic anemia
• Causes: decreased erythropoietin (EPO) production, decreased RBC lifespan, uremic inhibition of erythropoiesis, GI bleeding, iron deficiency
• Treatment:
  • Darbepoetin alfa (preferred; less immunogenic than recombinant human EPO): 1 µg/kg SQ every 1–2 weeks
  • Iron supplementation (oral or IV)
  • Blood transfusion in acute decompensation
  • Novel: AAV-vectored erythropoietin gene therapy (SB-001) — prospective trial showed 86% response rate in cats with IRIS Stage 2–4 CKD anemia; complications included hypertension and encephalopathy (Vaden et al., J Vet Intern Med 2023 [PMID 37847024])

4. Secondary Renal Hyperparathyroidism (RSHPT)

• Decreased phosphorus excretion → hyperphosphatemia → elevated FGF-23 → decreased calcitriol → increased PTH
• Promotes soft tissue mineralization, cardiovascular calcification, and further nephron loss
• Treatment: Phosphate restriction (diet), phosphate binders (aluminum hydroxide, calcium carbonate, lanthanum carbonate, sevelamer)
• Note: Monitor for aluminum toxicity with aluminum-based binders (Sheffler et al., BMC Vet Res 2025 [PMID 40336076])

5. Metabolic Acidosis

• Common in IRIS Stage 3–4
• Bicarbonate <17 mEq/L (dogs) or <17 mEq/L (cats) warrants treatment
• Treatment: Potassium citrate (0.5–1 mEq/kg BID–TID PO) or sodium bicarbonate

6. Hypokalemia (Cats)

• Common in cats with CKD due to anorexia, vomiting, and polyuria-related losses
• Clinical signs: generalized muscle weakness, ventroflexion of the neck, lethargy
• Treatment: Oral potassium gluconate (2–4 mEq/cat/day) or potassium citrate

7. Urinary Tract Infection (UTI)

• Bacteriuria associated with worse survival and disease progression in azotemic cats (Hindar et al., J Vet Intern Med 2020 [PMID 33016500])
• Isosthenuria and reduced immune function predispose to UTI; important to culture urine (often subclinical)

8. Gastrointestinal Signs

• Nausea, vomiting from uremic toxins → H2 blockers or proton pump inhibitors
• Omeprazole improves appetite in cats with CKD — demonstrated in a double-blind RCT (Spencer et al., J Vet Intern Med 2021 [PMID 34590746])
• Maropitant (antiemetic) often used adjunctively

9. Cardiorenal Syndrome (CRS)

• Bidirectional relationship between cardiac and renal disease
• Cardiac disease reduces renal perfusion → worsens CKD; CKD causes hypertension, LVH, and activates RAAS → worsens cardiac disease
• RAAS activation is central to both conditions (Ames et al., J Vet Intern Med 2019 [PMID 30806496]; Orvalho & Cowgill, Vet Clin North Am 2017 [PMID 28669432])

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9. Treatment & Management

A. Stage-Based Management (IRIS Guidelines)

B. Nutritional Management

C. Pharmacological Management Summary

D. RAAS Blockade in CKD

• Reduce intraglomerular pressure
• Decrease proteinuria
• Slow CKD progression
• Reduce cardiovascular remodeling

E. Fluid Therapy & Diuresis

• Subcutaneous fluids (SQ): Widely used in cats with Stage 3–4 CKD for home management; shown to be well-tolerated and valued by owners (Cooley et al., J Feline Med Surg 2018 [PMID 28948902])
• IV fluid diuresis: In-hospital for uremic crises or acute decompensation
• Fluid type: Balanced electrolyte solutions (Ringer's lactate, PlasmaLyte); avoid LRS in severe hyperkalemia

F. Dialysis & Renal Replacement Therapy

• Peritoneal dialysis (PD): Used for acute decompensation; less common long-term
• Hemodialysis (HD): Available at specialist centers; used in acute uremic crisis, toxin removal, bridging therapy before transplantation
• Renal transplantation: Cats — established option at specialty centers (associated with good quality of life; requires lifelong immunosuppression with cyclosporine); dogs — less practiced due to ethical concerns and poorer outcomes

G. Gut Microbiome Targeting (Emerging)

• Intestinal phosphate binders
• Probiotics and prebiotics
• Adsorbents (activated charcoal, AST-120 — binds indole, reducing indoxyl sulfate)
• Dietary fiber to reduce uremic toxin generation

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10. Monitoring Protocol

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11. Prognosis

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12. Species-Specific Differences Summary

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Complete Reference List