In glomerular disease, the structure and/or function of the glomerulus is altered. The hallmark clinical sign of glomerular disease is proteinuria, which can be severe. Glomerular disease often causes or occurs in conjunction with chronic kidney disease. Diagnosis involves characterizing the nature of the disease via a renal biopsy, when practical, and carefully evaluating potential underlying disease triggers and sequelae. Treatment of glomerular disease includes pharmacological and dietary intervention to decrease proteinuria and therapies to manage or prevent sequelae. When the underlying etiology is known, specific treatment to address etiology is indicated.
In glomerular disease, the structure and/or function of the glomerulus is altered. Glomerular disease is a well-recognized cause of chronic kidney disease (CKD) in dogs, can produce acute kidney injury (AKI) in dogs, and occasionally occurs in cats.
Etiology of Glomerular Disease in Dogs and Cats
Damage to the glomerular basement membrane results in proteinuria, which can lead to clinical abnormalities relating primarily to protein loss (hypoalbuminemia, muscle wasting, edema, etc). Proteinuria is also damaging to the renal tubule, resulting in loss of urine-concentrating ability and progression to azotemic CKD.
With more sophisticated techniques for evaluating renal biopsies, including the use of transmission electron microscopy and immunofluorescence, in addition to standard light microscopy, understanding of glomerular diseases is evolving. Currently, the most common glomerular diseases affecting dogs are immune complex glomerulonephritis (ICGN), glomerulosclerosis, and amyloidosis. Cats are much less commonly affected by glomerulopathies in general; however, ICGN appears to be the most common glomerular disease in cats as well.
Familial glomerulopathies as a primary cause of CKD have been reported in several breeds of dogs, including Bernese Mountain Dogs, English Cocker Spaniels, English Springer Spaniels, Doberman Pinschers, Greyhounds, Lhasa Apsos, Poodles, Rottweilers, Samoyeds, Shih Tzus, and Soft Coated Wheaten Terriers. Compared to other forms of glomerular disease, familial glomerulopathies tend to present earlier in life.
Most cases of amyloidosis in dogs and cats, including familial amyloidosis in Chinese Shar-Pei and Abyssinian cats, are reactive, or secondary, amyloidosis. In this form of the disease, amyloid A protein is deposited in various tissues after serum levels increase as a result of chronic inflammation.
When the kidneys are affected, amyloid deposition in nonfamilial forms of amyloidosis in dogs usually occurs in the glomerulus. However, in Shar-Pei, at least 25% of Abyssinian cats, and many domestic cats with the nonfamilial form of this disease, amyloid is found primarily in the medullary interstitium, where it interferes with the renal concentrating mechanism and is more likely to produce nonproteinuric CKD than protein-losing glomerular amyloid deposition.
In contrast, glomerular amyloidosis usually leads to marked proteinuria. The nonfamilial form of amyloidosis usually affects middle-aged to older dogs and cats. Beagles, Collies, and Walker Hounds are reported to be at increased risk. The familial form of the disease is usually diagnosed at a younger age.
Clinical Findings of Glomerular Disease in Dogs and Cats
Glomerular disease occurs most often in middle-aged to older dogs. It is far less common in cats than in dogs.
The hallmark clinical sign of glomerular disease is proteinuria, which can be severe. Otherwise, animals can develop nonspecific clinical signs such as lethargy, inappetence, and weight loss; signs attributed to concurrent renal tubule injury, such as uremic signs and polyuria/polydipsia; or signs attributable to severe glomerular damage, such as thromboembolism, edema secondary to hypoalbuminemia, or systemic hypertension.
Protein wasting can produce preferential loss of lean body mass that may be apparent on physical examination. Severe or chronic glomerular disease is a cause of CKD; most dogs and many cats with glomerular disease eventually develop stage 3 or 4 CKD. Systemic hypertension can be more prevalent in proteinuric CKD and can occur at any stage.
Either loss of urine-concentrating ability or azotemia can be present in animals with glomerular disease.
Animals with primary glomerular disease as a cause of CKD could have clinical and laboratory abnormalities somewhat different from those with primary tubulointerstitial disease. Uncommonly, urine specific gravity is inappropriately high for the degree of renal dysfunction—a condition referred to as "glomerulotubular imbalance."
Diagnosis of Glomerular Disease in Dogs and Cats
Laboratory evaluation
Screening for underlying infectious, inflammatory, and neoplastic etiologies
Renal biopsy
Glomerular disease can be detected incidentally when persistent renal proteinuria is found on urinalyses. Animals with glomerular disease typically have persistent proteinuria in the absence of any postrenal causes of proteinuria (hematuria, pyuria, bacteriuria).
A urine protein:creatinine ratio > 2 suggests (but is not definitive for) a glomerular origin. Marked proteinuria can occur in the presence or absence of azotemia. Furthermore, marked proteinuria can occur before loss of tubular function is sufficient to decrease urine-concentrating ability.
Azotemia is often present in cases of glomerular disease, because severe or chronic proteinuria damages the renal tubule and ultimately leads to a decrease in glomerular filtration rate (GFR) and CKD. Patients should be staged and substaged as for CKD, including evaluation for systemic hypertension, which is a common complication of glomerular disease with or without azotemia.
Severe proteinuria can also lead to hypoalbuminemia, which can be accompanied by hypercholesterolemia and third-space fluid sequestration. The combination of these findings is called nephrotic syndrome.
Although most cases of glomerular disease in dogs and cats do not have a known underlying etiology, a thorough search for potential causes of proteinuria (infectious and inflammatory diseases and neoplasia) should be completed, because identification and specific treatment of an underlying trigger have the potential to greatly improve outcome.
A careful physical examination should be undertaken, including a thorough search for ocular, oral, and cutaneous lesions, as well as testing for relevant endemic infectious etiologies. A more aggressive diagnostic investigation, including renal biopsy and advanced imaging of chest and abdomen to screen for neoplasia, is indicated in more severe or progressive cases.
Renal biopsy is required to determine the type of glomerular disease. Because of the risk and expense of renal biopsy, it is not appropriate in all circumstances. Biopsy should be seriously considered in cases of severe or progressive disease, particularly those that do not respond to nonspecific treatment of proteinuria. Untreated hypertension and coagulopathy are contraindications to renal biopsy, because of bleeding risk.
Because transmission electron microscopy and immunofluorescence are essential for complete evaluation of glomeruli, samples must be carefully collected and prepared for this purpose and should be sent to an experienced nephropathologist.
Treatment of Glomerular Disease in Dogs and Cats
RAAS blockade
Dietary management
Thromboprophylaxis
Management of sequelae
Specific therapy, such as immunosuppression
RAAS Blockade as Treatment for Glomerular Disease
Pharmacological blockade of the renin-angiotensin-aldosterone system (RAAS) can lower glomerular hydrostatic pressure, thereby decreasing proteinuria.
Angiotensin-converting enzyme inhibitors (ACE inhibitors) are effective for RAAS blockade (benazepril or enalapril: 0.5–2 mg/kg, PO, every 24 hours; daily dose can be divided every 12 hours; start at the low end and increase incrementally every 2 weeks to effect).
Alternatively, the angiotensin receptor blocker telmisartan is effective (1–3 mg/kg, PO, every 24 hours; daily dose can be divided every 12 hours; start at the low end and increase incrementally every 2 weeks to effect).
Patients being administered ACE inhibitors or angiotensin receptor blockers should be monitored for hyperkalemia, hypotension, and marked worsening of azotemia.
Dosage should be increased as tolerated to target a normal urine protein:creatinine ratio (< 0.5). Because this is often not feasible, however, published guidelines recommend a decrease of 50% or more from baseline as an alternative target.
Thromboprophylaxis as Treatment for Glomerular Disease
Dogs with substantial proteinuria are at risk for thromboembolic complications and should be treated with antithrombotics.
The optimal protocol is not known; however, clopidogrel (1–4 mg/kg, PO, every 24 hours) is often selected because of its known efficacy as an antiplatelet drug in small animals, as well as its availability and ease of use.
Aspirin (1–5 mg/kg, PO, every 24 hours) can also be used for its antiplatelet effects.
Treatment of Systemic Hypertension in Glomerular Disease
Animals with glomerular disease are at high risk for systemic hypertension. If present, hypertension should be managed as described for CKD.
Nutrition in the Treatment of Glomerular Disease
Dietary modification is indicated in glomerular disease. Even in the absence of azotemic CKD, lowering dietary protein content can decrease proteinuria by altering glomerular hemodynamics.
Other aspects of nutritional management include decreasing dietary sodium and adding omega-3 fatty acids.
Immunosuppressive Therapy as Treatment for Glomerular Disease
Immunosuppressive therapy is indicated in severe or progressive disease when a biopsy diagnosis of ICGN has been confirmed. Immunosuppressive therapy is a reasonable consideration in severe or progressive cases without biopsy confirmation because ICGN is believed to be responsible for approximately half of glomerulopathies in dogs and cats. In such cases, risks and potential benefits of immunosuppressive therapy should be carefully evaluated. Patients should be monitored closely for response to therapy and the development of adverse effects.
The ideal immunosuppressive protocol is not known; however, mycophenolate mofetil (10–15 mg/kg, PO, every 12 hours) is anecdotally used with success in ICGN cases.
Other options include cyclosporine (5 mg/kg, PO, every 12 hours) and azathioprine (dogs only: 2 mg/kg, PO, every 24 hours for 14 days, then decreased to every 48 hours).
Prednisone in dogs only or prednisolone in dogs or cats (2 mg/kg, PO, every 24 hours) is usually reserved for rapidly progressive cases that require quick effect, and then can be replaced with an alternative immunosuppressant after the disease has stabilized.
Prognosis of Glomerular Disease in Dogs and Cats
The prognosis of glomerular disease is highly variable and depends on the underlying disease process, response to therapy, and time of diagnosis. Many animals experience life-limiting progressive disease; others can have a normal lifespan with appropriate management. Nephrotic syndrome and severe azotemia are associated with a poor prognosis.
Key Points
Glomerular diseases are common causes of CKD in dogs. They are characterized by proteinuria that can be severe and can progress to azotemia, hypoalbuminemia, and nephrotic syndrome.
Diagnostic workup of animals with glomerular disease includes documentation and quantification of persistent renal proteinuria, evaluation of other renal laboratory parameters, and a thorough investigation, including possible renal biopsy, of the underlying cause.
Glomerular diseases are treated with a combination of nonspecific therapies intended to minimize urinary protein loss and associated sequelae. When possible, the underlying disease process is identified and treated.
For More Information
IRIS Canine GN Study Group Standard Therapy Subgroup, Brown S, Elliott J, Francey T, Polzin D, Vaden S. Consensus recommendations for standard therapy of glomerular disease in dogs. J Vet Intern Med. 2013;27(s1):S27-S43.
IRIS Canine GN Study Group Diagnosis Subgroup, Littman MP, Daminet S, Grauer GF, Lees GE, van Dongen AM. Consensus recommendations for the diagnostic investigation of dogs with suspected glomerular disease. J Vet Intern Med. 2013;27(s1):S19-S26.
Cianciolo RE, Mohr FC, Aresu L, et al. World Small Animal Veterinary Association Renal Pathology Initiative: classification of glomerular diseases in dogs. Vet Pathol. 2016;53(1):113-135.
Also see pet owner content regarding noninfectious diseases of the urinary system in dogs and cats.
