Glomerulonephritis in the dog and cat

The glomerulonephritides constitute a group of renal diseases with heterogeneous aetiology. There are primary, secondary and idiopathic forms. The classification is based on the histological features seen by optical microscopy of renal biopsies, combined with the animal’s clinical data. The most significant clinical signs of glomerulonephritis are proteinuria/haematuria, nephrotic syndrome, acute nephritis, oedema and hypertension. Renal failure is the clinical consequence of the progression of the damage to the kidneys.

The primary glomerulonephritides are divided into:

• idiopathic primary forms: these account for most of the primary forms;
• true primary forms: caused by a specific agent capable of stimulating an immune-mediated inflammatory response.

The secondary glomerulonephritides are associated with systemic pathologies in which the glomerular disease is a consequence of disorders of other organs (e.g., heart – hypertension, pancreas – diabetes).

The diagnosis of glomerular disorders is made from examination of biopsy material by optical microscopy, immunofluorescence studies and electron microscopy.

PATHOGENESIS

There are two pathogenic mechanisms underlying the characteristic cascade of reactions occurring in patients with glomerulonephritis:

• deposition of circulating antigen-antibody immune complexes. These immune complexes are defined soluble and are trapped in the glomerular filter at the level of the mesangium and glomerular basement membrane (subepithelial, subendothelial and intramembranous sites);
• deposition of antibodies against self antigens of the cells in the glomerulus and/or against non-self antigens “implanted” in the glomerulus. In this case, the antibody-antigen complexes are referred to as in situ immune complexes.

The formation and deposition of immune complexes activates the cascade of reactions of chemical mediators responsible for inflammation: the complement system, coagulation factors, prostaglandins, cytokines and growth factors. These factors attract inflammatory cells to the glomerulus and interstitium leading to an increase in the production of the mediating systems by resident cells and other cells. The vicious cycle that is established in this way is responsible for progression of the chronic renal disease, characterized by glomerulosclerosis and interstitial fibrosis.

The progression of the damage occurring in glomerulonephritis is manifested by:

• proteinuria: this is a consequence of the loss of correct function and of the selective capacity of the filtration barrier formed of the fenestrated endothelium / basement membrane /vascular foot processes (pedicels) of the podocytes. The clinical course of the animal is related to the amount of protein lost. In the case of mild to moderate proteinuria, compensatory mechanisms are put into play, such as increased hepatic synthesis of proteins and reduced protein catabolism. In the case of moderate to severe proteinuria the compensatory mechanisms are lost and the condition is associated with an increase in urea, hypoalbuminaemia and nephrotic syndrome.
• alterations in clotting factors: these predispose affected animals to thromboembolism as a result of a decrease in antithrombin III (lost in the urine) and increases in other factors (V, VII, VIII and X).
• systemic hypertension: this complication can be found in the phase of chronic renal failure in which a decrease in functioning glomerular volume leads to an increase in the entry pressure to make up for the reduction in the area of glomerular filtration. The kidney responds with compensatory mechanisms mediated by the renin-angiotensin-aldosterone system. Prolonged states of hypertension give rise to the typical lesions of glomerulosclerosis.

Table 1. Outline of the progression of primary glomerular damage.

AETIOLOGY

Classification
A full classification of glomerulonephritides has yet to be made, but the system used for human kidney disease can be taken as a starting point. In veterinary medicine, various classes have been recognized on the basis of histological and electron microscopy findings:

• minimal lesion disease: a primary lesion characterized exclusively by the fusion of podocyte pedicels detectable by electron microscopy. This condition is considered idiopathic in dogs, although it has been described after experimentally induced Ehrlichia canis infection.
• membranous glomerulonephritis: this is characterized histologically by diffuse thickening of the glomerular basement membrane caused by deposition of immune complexes, associated with reduced proliferation of mesangial cells (Fig. 1). Immunofluorescence studies can show positivity for IgG and C3 antibodies and the variable presence of IgM (Fig. 2). Positivity is manifested as a granular pattern along the glomerular capillaries. In the dog, a primary/idiopathic form and secondary forms have been described. These latter are secondary to infestation by parasites belonging to the genus Dirofilaria, protozoan infections (leishmaniasis) and the presence of neoplasm.
• membrano-proliferative glomerulonephritis: this is characterized by an increase in mesangial (endothelial and mesangial) cells and irregular thickening of the glomerular basement membrane (Fig. 3). Depending on the site of the deposits, this type of glomerulonephritis can be distinguished into having a:
  • predominantly sub-endothelial and mesangial localisation
  • predominantly sub-epithelial and mesangial localisation.

Immunofluorescence reveals the presence of IgG and C3 deposits in the mesangium and along the basement membrane, distributed in a granular membrane. Membrano-proliferative glomerulonephritis has been widely described in dogs with Leishmania infantum infection, systemic lupus erythematosus and Lyme disease (Fig. 4).

• mesangio-proliferative glomerulonephritis: this is characterized by an increase in mesangial cells. The thickness of the glomerular basement membranes is within the norm in most areas. Immunofluorescence reveals intense deposition of IgM in the mesangium. This type of glomerulonephritis has been described in dogs following Adenovirus (CAV1) infection, with characteristic inclusion bodies in the mesangial cells, and during infections by Leishmania infantum.
• focal segmental glomerulosclerosis: this disorder is characterized by areas of adhesions of the glomerular tuft with Bowman’s capsule (synechiae), which undergoes segmental glomerular sclerosis. Only some glomeruli are affected (focal disease) and mainly at the level of the vascular pole. Immunofluorescence studies show positivity for IgM and C3 corresponding with the areas of glomerular sclerosis. The condition is idiopathic in the dog.      

DIAGNOSIS

Signalment: dogs of all ages and all breeds can show the clinical signs of glomerulonephritis, although the incidence increases in dogs aged between 5-7 years old. Breeds that have been described to be affected more frequently are the Labrador, Golden Retriever and Schnauzer. 

History: a careful history and thorough clinical examination are necessary to differentiate the different types of glomerulonephritis which, in many cases, are secondary to other disorders.

Clinical examination: Some clinical signs of glomerular damage are non-specific (anorexia, weight loss, etc.)  or not present until the uraemic stage has been reached.  Some dogs present at the clinical examination with nephrotic syndrome (oedema, ascites). At ultrasound examination, the kidneys may have a normal size and morphology, be enlarged (acute glomerulonephritides) or have a decreased volume (chronic glomerulonephritides and/or glomerulosclerosis) with a hyperechoic cortex. Rarely there may be signs related to pulmonary thromboembolic complications and paresis of the posterior limbs; rare cases of retinal detachment caused by chronic hypertension have also been reported.

Various aetiological agents are able to trigger primary renal inflammatory disorders. Those described in the literature include: 

• Immune-mediated forms secondary to:
  • Bacteria:  pyometra, bacterial endocarditis, discospondylitis, brucellosis
  • Viruses:  infectious canine hepatitis virus (canine adenovirus type 1)
  • Parasites:  dirofilariasis
  • Neoplasms:  lymphoma, mastocytosis, carcinoma
  • Degenerative/inflammatory phenomena: pancreatitis, cirrhosis, chronic dermatitis, polyarthritis, cholangio-hepatitis, stomatis
• Autoimmune forms
  • oystemic lupus erythematosus;
  • onti-glomerular basement membrane antibodies.

TREATMENT

There are often multiple pharmacological choices for the treatment of the different types of glomerulonephritis. In cases of true, primary glomerulonephritis, the gold standard treatment is an aetiologically targeted drug. It is not, however, always possible to identify the primary trigger and/or eliminate its cause; in these cases the use of immunosuppressive drugs is fundamental. The effects of corticosteroids, azathioprine, cyclophosphamide, chlorambucil and cyclosporine are known from human medicine. Angiotensin-converting enzyme (ACE) inhibitors are drugs used for their capacity to reduce hypertension following the loss of protein. Their mechanism of action is related to a reduction in the area of the pores of the fenestrated endothelium. In stages of nephrotic syndrome, ACE-inhibitors also seem to reduce the levels of circulating triglycerides and cholesterol.

In some cases the treatment of choice should be accompanied by supportive therapy:

• diet: restriction of sodium in diet and only high-quality proteins
• diuretics: to control oedema/ascites
• plasma transfusion
• aspirin – anticoagulant drugs

Suggested readings

1. Center, S.A., Smith, C.A., Wilkinson, E., Erb, H.N., Lewis, R.M., 1987 Clinicopathologic, renal immunofluorescent, and light microscopic features of glomerulonephritis in the dog: 41 cases (1975-1985). Journal of the American Veterinary Medical Association190, 81-90.
2. Choi, E.W., Lee, C.W., 2004 Development of canine nephrotic syndrome model. The Journal of Veterinary Medical Science 66, 169-174.
3. Finco, D.R., Brown, S.A., Brown, C.A., Crowell, W.A., Cooper, T.A., Barsanti, J.A., 1999 Progression of chronic renal disease in the dog. Journal of Veterinary Internal Medicine 13, 516-528.
4. Remuzzi G, Bertani T. Pathophysiology of progressive nephropathies. N Engl J Med 1998; 339: 1448-1456.
5. Rodriguez-Iturbe B, Johnson RJ, Herrera-Acosta J. Tubulointerstitial damage and progression of renal failure. Kidney Int Suppl 2005; 99: S82-S86.
6. Smith, L.H. Jr., Wilson, C.B., 1972 Immunological mechanisms of glomerulonephritis. California Medicine 116, 47-52.
7. Trautwein, G. and Trautwein-Hewicker, M. (2000). Immunopathological mechanisms of glomerulonephritis in domestic animals. European Journal of Veterinary Pathology, 6, 83-94.