Canine glomerular disease


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Canine glomerulonephritis: new thoughts on proteinuria and treatment
Glomerular disease in the dog is not only a common form of renal disease but also an important cause of chronic renal failure. The presence of immune complexes in glomerular capillary walls is a major cause of canine glomerular disease and is commonly referred to as glomerulonephritis. Leakage of plasma proteins, principally albumin, across the damaged glomerular capillary walls results in persistent proteinuria – the clinicopathological hallmark of glomerulonephritis. Recent evidence suggests that, in addition to being a marker of disease, persistent proteinuria is associated with progressive glomerular and tubulointerstitial lesions and loss of additional nephrons. Perhaps the best treatment for glomerulonephritis is the identification and correction of any underlying inflammatory, immune-mediated or neoplastic disease that results in the deposition or formation of glomerular immune complexes. In cases of idiopathic glomerulonephritis, angiotensin-converting enzyme inhibitors have been shown to decrease proteinuria and potentially slow disease progression.
Journal of Small Animal Practice (2005) 46, 469-478

Until relatively recently, canine glomerular disease was thought to be uncommon and unimportant. It is now recognised that glomerular disease is not only common but can also lead to chronic renal insufficiency or failure in the dog. For example, in a study of 76 dogs with chronic renal disease, 40 (52 per cent) had glomerular disease rather than non-glomerular disease as the underlying pathological process (MacDougall and others 1986). In another study of dogs with naturally occurring end-stage renal disease that received renal allografts, glomerular disease was judged to be the underlying pathology in seven of 15 cases (Mathews and others 2000). It is interesting to note that a urine protein:creatinine ratio (UP/C) of less than five was required for a dog to be eligible for transplantation. This helped exclude underlying glomerular disease, which might have adversely affected the

Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas 66506, USA

allograft. Even though the inclusion criteria were biased against proteinuric disease, 47 per cent of the dogs studied had glomerular disease (Mathews and others 2000). The magnitude of this problem is emphasised by additional studies that have shown the prevalence of glomerular disease in randomly selected dogs to be as high as 70 per cent (Rouse and Lewis 1975, Muller-Peddinghaus and Trautwein 1977). Most canine glomerular disease is thought to be associated with the presence of immune complexes in glomerular capillary walls (DiBartola and others 1980b, Jaenke and Allen 1986, Center and others 1987, Cook and Cowgill 1996). However, structural abnormalities (for example, type IV collagen defects in hereditary nephritis in Samoyed dogs), haemodynamic abnormalities (such as intraglomerular hypertension) and glomerular amyloid deposition are examples of additional types of glomerular disease in dogs. This review will focus on immune complex glomerulonephritis (GN). Persistent proteinuria (principally albuminuria) with inactive urine sediment has long been the clinicopathological hallmark of glomerular disease in dogs. However, confirmation of GN requires histological examination of renal biopsy specimens. Use of the UP/C to quantitatively estimate proteinuria has greatly facilitated the diagnosis of GN in veterinary medicine. Beyond the diagnostic utility of proteinuria, pathophysiological consequences of persistent proteinuria in dogs may include decreased plasma oncotic pressure, hypercholesterolaemia, systemic hypertension, hypercoagulability, muscle wasting and weight loss. The potential for proteinuria to be associated with renal disease progression has also been recognised, stimulating a discussion about what level of proteinuria is normal. Development of canine-specific albumin ELISA technology that enables the detection of very low concentrations of albumin (microalbuminuria) has helped drive this reevaluation.lllll

• VOL 46 • OCTOBER 2005

a smooth. decreasing the angiotensin and aldosterone response. When antibodies present in plasma react with an antigen in situ. and that heartworm-associated immune complexes can form in situ within the glomerulus (Grauer and others 1989). immune complexes formed when a large antigen excess exists do not readily bind complement and have a reduced capacity to produce immunological injury. TXB. Proposed glomerular pathophysiology subsequent to immune complex deposition or in situ formation JOURNAL OF SMALL ANIMAL PRACTICE ➞ Production of growth factor and matrix promoting substances Intraglomerular hypertension ➞ ➞ ➞ Endothelial damage ➞ ➞ ➞ Platelet aggregation ➞ ➞ ➞ ➞ Coagulation system activation ➞ ➞ Fibrin production ➞ ➞ Ang II Angiotensin II TXB Thromboxane ET-1 Endothelin-1 • VOL 46 • OCTOBER 2005 . Autoimmune GN. Immune complexes formed when a large antibody excess exists tend to be large. the condition in which antibodies are directed against endogenous glomerular basement membrane material. Conversely. glomerular filtration may be decreased resulting in azotaemia and renal failure. AETIOLOGY AND PATHOPHYSIOLOGY Soluble circulating antigen-antibody complexes may be deposited or trapped in the glomerulus when a mild antigen excess occurs. Glomerular deposition of preformed immune complexes usually results in a lumpy or granular immunofluorescent or immunocytochemical pattern along capillary walls. linear pattern of immune complexes is often produced. Soluble Dirofilaria immitis antigens contain carbohydrate moieties (Weil and others 1985) and therefore the adherence of these antigens to the glomerular capillary wall may Immune complex deposition or in situ formation ➞ ➞ ➞ ➞➞ Complement activation Production of proinflammatory molecules Production of vasoactive substances (Ang II. in many cases the antigen source or underlying disease process is not identified. For example. insoluble and rapidly removed from the circulation by phagocytic cells. or when antigen and antibody molecules are present in approximately equal numbers in the plasma. immune complexes may also form in situ in the glomerular capillary wall. and supportive care. Irreversible damage to the glomerulus renders the entire nephron unable to function and. Diseases associated with glomerulonephritis in dogs Infectious Canine adenovirus I Bacterial endocarditis Brucellosis Dirofilariosis Ehrlichiosis Leishmaniosis Pyometra Borelliosis Chronic bacterial infections (gingivitis. which can lead to glomerular hyalinisation and sclerosis. and the glomerular disease is referred to as idiopathic (Cook and Cowgill 1996). However. Specific treatment objectives include: identification and elimination of any underlying disease process that may be producing antigen-antibody complexes. has not been documented in dogs with naturally occurring GN. This occurs when circulating antibodies react with endogenous glomerular antigens or ‘planted’ non-glomerular antigens in the glomerular capillary wall. as the disease progresses. studies of dogs with dirofilariosis have shown that heartworm antigens have an affinity for glomerular capillary walls. pyoderma) Rocky Mountain spotted fever Trypanosomosis Septicaemia Helicobacter* Neoplasia Inflammatory Pancreatitis Systemic lupus erythematosus Other immune-mediated diseases Prostatitis Hepatitis Inflammatory bowel disease Others Hyperadrenocorticism and long-term high-dose corticosteroids* Idiopathic Familial Non-immunological hyperfiltration* Diabetes mellitus* *Uncertain or questionable causes The presence of immune complexes in glomerular capillary walls often stimulates glomerular cell proliferation and thickening of capillary walls. General treatment objectives for GN include attenuation of the proteinuria and disease progression. non-glomerular antigens may localise in the glomerular capillary wall as a result of electrical charge interaction or biochemical affinity with the glomerular capillary wall. decreasing the platelet/thromboxane response. Several infectious and inflammatory diseases have been associated with glomerular deposition of immune complexes (Table 1). However.Canine glomerular disease 10/6/05 5:46 PM Page 470 Table 1. but identification of exogenous antigens within glomerular tissue is rarely accomplished. ET-1) Proliferative and/or membranous response resulting in proteinuria FIG 1. Identification 470 of endogenous immunoglobulin or complement within the glomerulus using various immunological techniques is not difficult. In contrast to the glomerular deposition of preformed complexes.

in turn. and result in progressive nephron loss. exacerbate glomerular damage by releasing vasoactive and inflammatory substances. Reprinted with permission (Grauer 1991) ➞ ➞ ➞ Renal vasodilatation Intraglomerular hypertension Glomerular hyperfiltration FIG 3. Adhesions to the Bowman’s capsule and periglomerular fibrosis are also present. In pro- Decreased number of nephrons ➞ Systemic hypertension ➞ ➞ Proteinuria ➞ ➞ Protein depletion Weight loss 471 . As more and more nephrons become involved. may contribute to glomerular hyalinisation and sclerosis (Brenner and others 1982).Canine glomerular disease 10/6/05 5:46 PM Page 471 FIG 2. Remaining viable nephrons compensate for the decrease in nephron numbers with increased individual glomerular filtration rates (Fig 3). Henson 1971. For example. fibrosis and cell death (Tang and others 1999). Kincaid-Smith 1972. The glomerulus responds to this injury by cellular proliferation. These substances may be produced by endogenous glomerular cells or by recruited platelets. Platelets. which can contribute to the injury (Johnson 1997) (Fig 1). There is increasing evidence in laboratory animals and humans that proteinuria can cause glomerular and tubular damage. This increased hydrostatic pressure within the glomerular capillaries helps drive glomerular proteinuria. Albumin and other proteins accumulate in lysosomes and are then degraded into amino acids. Fibrosis and scarring of irreversibly damaged nephrons may give the appearance of interstitial inflammation. The immune-mediated pathophysiology associated with either deposition or in situ formation of immune complexes stresses the importance of identification and correction of any underlying or concurrent disease process. also contribute to glomerular damage (Vassalli and McCluskey 1964. several factors. They are also capable of releasing growth-stimulating factors that promote proliferation of vascular endothelial cells (Hayslett 1984). This ‘hyperfiltration’. 200. treatment is focused on decreasing this glomerular response to immune complexes (for example. In addition.ll Once a glomerulus has been irreversibly damaged by GN. In addition to the RAAS. platelet aggregation. resulting in intraglomerular hypertension. growth factors. Proximal tubular cells normally resorb protein from the glomerular filtrate by endocytosis. and extracellular matrix proteins and proteases. Plasma proteins that have crossed the glomerular capillary wall can accumulate within the glomerular tuft and stimulate mesangial cell proliferation and increased production of mesangial matrix (Jerums and others 1997). the entire nephron becomes non-functional. coupled with systemic hypertension and high dietary protein. Platelet activation and aggregation occur secondarily to endothelial damage or antigen-antibody interaction (Hayslett 1984). and by the facilitation of the coagulation cascade. Angiotensin and aldosterone are also proinflammatory and can stimulate glomerular cell proliferation and fibrogenesis. Although it has not been documented in dogs with naturally occurring GN. if the injury persists. hyperfiltration and proteinuria in remnant nephrons may result in progressive nephron loss independent of the previously discussed immunemediated GN. The large glomerulus shows hypercellularity with prominent focal accumulations of mesangial matrix material and thickened glomerular capillary walls. vasoactive substances. Clark and others 1976). glomerular filtration as a whole decreases. The glomerulus provides a unique environment for injurious immune complexes to stimulate production of bioactive mediators like proinflammatory cytokines. activation of the coagulation system and fibrin deposition. hyalinisation and sclerosis (Fig 2). Periodic acid-Schiff. activation of the renin-angiotensinaldosterone system (RAAS) can have haemodynamic and non-haemodynamic effects on the kidneys (Hilgers and Mann 1996). The small glomerulus is irreversibly damaged and obsolescent. excessive amounts of protein in glomerular filtrate can be toxic to human tubular epithelial cells and can lead to interstitial inflammation. angiotensin and platelet antagonists). thickening of the glomerular basement membrane and. In cases where identification and correction of an underlying disease process is not possible. Proposed pathogenesis of nephron loss in progressive renal disease Glomerular cell proliferation Glomerulosclerosis JOURNAL OF SMALL ANIMAL PRACTICE • VOL 46 • OCTOBER 2005 ➞ be caused by a carbohydrate-glycoprotein interaction. Advanced membranoproliferative glomerulonephritis. if present. and for many years renal interstitial inflammation or ‘chronic interstitial nephritis’ was thought to be the primary lesion that caused chronic renal insufficiency or failure in dogs. including activation of the complement system. The main haemodynamic effect is vasoconstriction of the efferent glomerular arteriole. macrophages and neutrophils. A hyaline cast is present in a tubule (arrow).

mild weight loss. Based on this evidence in other species. in one study. Transferrin increases iron uptake by epithelial cells. such as albumin. and increased hepatic synthesis of proteins and lipoproteins (Wheeler and others 1989). which are not as easily lost through the damaged capillary wall as the proteins with smaller molecular weights. Exposure to plasma proteins at the apical surface of the tubular cell results in a basolateral release of growth factors. blindness may be the presenting sign in hypertensive dogs. vomiting. fibronectin and monocyte chemoattractant protein-1 (MCP-1) (Harris and others 1996). was thought to be the cause of ascites and oedema. coupled with increased responsiveness to normal vasopressor mechanisms. ET-1 also binds to receptors on interstitial fibroblasts. independent of aldosterone. 84 per cent of dogs with glomerular disease were found to be hypertensive (Cowgill 1991).1 (TGF. Another mediator of tubulointerstitial damage related to excessive tubular cell protein resorption is the upregulation of tubular-derived endothelin-1 (ET-1) (Benigni and others 1995). causing sodium retention. Systemic hypertension has been commonly associated with immune-mediated GN. This process may also induce excessive tubular expression of transforming growth factor. Retinal changes. weight loss. nausea and vomiting may occur. and hypercholesterolaemia. clinical signs associated with an underlying infectious. The hypercholesterolaemia associated with the nephrotic syndrome probably occurs because of a combination of decreased catabolism of proteins and lipoproteins. as a result of oedema or ascites Depression. rarely. hyperphosphataemia. polyuria-polydipsia Acute dyspnoea or severe panting Clinicopathological findings Serum albumin (1·5-3·0 mg/dl) Serum albumin (<1·5 mg/dl) hypercholesterolaemia Azotaemia. anorexia. Resorbed lipoproteins can release lipid moieties that can accumulate into lipid droplets or be oxidised to toxic radicals (Ong and Moorhead 1994). Complement proteins can be activated on the brush border of proximal tubular cells. non-regenerative anaemia Hypoxaemia. normal or low PCO2. In addition to these clinical signs. This results in the accumulation of cholesterol-rich lipoproteins with large molecular weights. complement and lipoproteins. causing enzymatic damage to the cytoplasm (Olbricht and others 1986). nausea. polyuria. fibrinogen (>300 mg/dl). causing interstitial cel472 Pulmonary thromboembolism Retinal haemorrhage and/or detachment Acute blindness *Microalbuminuria may precede proteinuria and therefore be an early diagnostic tool PCO2 Carbon dioxide in the blood lular proliferation and extracellular matrix production (Benigni and others 1995).1) that can result in the interstitial inflammation and scarring typical of end-stage kidney disease (Remuzzi 1995). Increased glomerular permeability to plasma proteins allows tubular cell contact with transferrin. Hypercoagulability and thromboembolism associated with nephrotic • VOL 46 • OCTOBER 2005 JOURNAL OF SMALL ANIMAL PRACTICE . Rarely. All of these processes can irreversibly damage the proximal tubule and interstitium and result in nephron loss. hypoalbuminaemia. including haemorrhage. Blood pressure measurement should be included in evaluating and managing glomerular disease as it is probable that controlling systemic hypertension will attenuate the disease’s progression. decreased muscle mass Severe muscle wasting Weight gain may occur. but also a mediator of progressive renal injury. CLINICAL SIGNS The clinical signs associated with mild to moderate urinary protein loss are usually non-specific and include weight loss and lethargy. systemic hypertension and hypercoagulability are frequent complications in dogs with nephrotic syndrome. dogs may be presented with acute dyspnoea or severe panting caused by a pulmonary thromboembolism. detachment and papilloedema. isosthenuria or minimally concentrated urine. excessive lysosomal processing can result in swelling and rupture of lysosomes. Hypertension probably occurs because of a combination of activation of the RAAS and decreased renal production of vasodilators. if protein loss is severe (serum albumin concentration of less than 10 to 15 g/l). anorexia. antithrombin III (<70 per cent of normal) Systolic blood pressure >180 mmHg teinuric conditions. polydipsia. If the glomerular disease process causes loss of greater than threequarters of the nephrons. can be consequences of systemic hypertension and. Classically. renal failure and resultant azotaemia. Persistent proteinuria may lead to clinical signs of the nephrotic syndrome that is a combination of proteinuria. Tubular injury may also occur as a consequence of proteinaceous casts obstructing the tubules (Bertani and others 1986). Attenuating proteinuria should be a major treatment objective in dogs with GN. Tubular ET-1 formed in response to increasing concentrations of albumin presented to the proximal tubular epithelium is secreted towards the basolateral cellular compartment and accumulates in the interstitium causing ischaemia. oedema and/or ascites often occur (Table 2). may contribute to sodium retention (Brown and others 1982). a combination of decreased plasma oncotic pressure and hyperaldosterone activity. Occasionally.Canine glomerular disease 10/6/05 5:46 PM Page 472 Table 2. However. it is possible that proteinuria is not only a marker of glomerular disease in the dog. Once inside the cell the iron ions catalyse the formation of reactive oxygen species that can cause peroxidative injury (Alfrey and others 1989). inflammatory or neoplastic disease may be the reason why owners seek veterinary care. It has been hypothesised that intrarenal mechanisms. glomerulosclerosis and amyloidosis and. resulting in insertion of a membrane attack complex followed by cytoskeletal damage and cytolysis (Camussi 1994). ascites or oedema. Signs associated with different manifestations of glomerular disease Manifestation Mild to moderate proteinuria* Marked proteinuria (>3·5 g/day) Renal failure Clinical signs Lethargy.

Ideally. MDB Minimum database (complete blood count. regardless of urine concentration. SSA Sulfosalicylic acid. often expensive and frequently unrewarding. complete MDB. The pulmonary arterial system is the most common location for a thromboembolus to lodge. such collections require the use of a metabolism 473 • VOL 46 • OCTOBER 2005 . IX. any positive result for proteinuria. blood pressure No abnormalities Continue to monitor proteinuria Determine the need to treat versus continued monitoring and investigation. not all dogs with haematuria and pyuria have albuminuria (Vaden and others 2002).Canine glomerular disease 10/6/05 5:46 PM Page 473 Positive dipstick result for proteinuria Evaluate results in light of urine sediment findings Confirm positive results with SSA or ERD ➞ ➞ ➞ ➞ ➞ syndrome occur secondarily to several abnormalities in the clotting system. urine protein excretion should be quantified (Fig 4). a positive dipstick reading for proteinuria in the presence of haematuria or pyuria was often attributed to urinary tract haemorrhage or inflammation. Dogs with pulmonary thromboembolisms are usually dyspnoeic and hypoxic. may be normal. Brief algorithm for the diagnosis of proteinuria. Finally. haematuria and pyuria have an inconsistent effect on urine albumin concentrations. these screening tests are performed concurrently as the SSA test has increased sensitivity for proteinuria and the dipstick method often lacks specificity. most likely renal proteinuria. the traditional interpretation may not be correct. ERD Heska’s Early Renal Damage point-of-care microalbuminuria assay. a hypoalbuminaemia-related platelet hypersensitivity has been found to increase platelet adhesion and aggregation proportionately to the magnitude of hypoalbuminaemia (Green and others 1985). Therefore. which can result in false positives (Grauer and others 2004). Similarly. ‘antigen hunt’. Treatment of pulmonary thromboembolism is difficult. XI and XII) and normally plays a vital role in modulating thrombin and fibrin production. PE Physical examination. either glomerular or tubular FIG 4. This helps evaluate the severity of renal lesions and assess response to treatment or progression of disease. In addition to a mild thrombocytosis. may be abnormal. transient or early renal proteinuria ➞ Recheck in two to four weeks ➞ UP/C=>2·0. Although 24-hour collection of urine and measurement of urine protein excretion in mg/kg/day has been the gold standard for quantitating proteinuria. X. altered fibrinolysis and increases in the concentration of clotting factors with large molecular weights may lead to a relative increase in clotting factors compared with regulatory proteins. Proteinuria detected by these screening methods has historically been interpreted in the light of urine specific gravity and the urine sediment findings. Likewise. most likely glomerular proteinuria UP/C=<0·5 to 2·0. PE. serum biochemistry profile and complete urinalysis) ➞ ➞ Abnormalities Pursue further diagnostics and appropriate treatment ➞ ➞ ➞ Reassess patient’s history. Persistent proteinuria was recently defined in a consensus statement commissioned by the American College of Veterinary Internal Medicine as three positive urinalyses each separated by at least two weeks. Loss of antithrombin III in urine also contributes to hypercoagulability (Green and Kabel 1982). Confirm proteinuria is persistent Obtain UP/C UP/C=<0·5. For example. early prophylactic treatment is important. with few pulmonary parenchymal radiographic abnormalities. based on the magnitude of the proteinuria and whether or not it increases over time ➞➞ ➞ DIAGNOSIS Detecting and quantifying proteinuria Proteinuria is routinely detected by semiquantitative methods including the urine dipstick colorimetric test and the sulfosalicylic acid (SSA) turbidometric test. Antithrombin III works in concert with heparin to inhibit serine proteases (clotting factors II. UP/C Urine protein:creatinine ratio. In both examples. One of the hallmarks of glomerular proteinuria is persistence. If the results of screening tests for proteinuria are persistently positive. Given the limits of conventional dipstick sensitivity (greater than 0·30 g/l). in a hypersthenuric animal a positive dipstick JOURNAL OF SMALL ANIMAL PRACTICE result of trace or +1 proteinuria has often been attributed to urine concentration rather than abnormal proteinuria.

Biewenga and others 1983. genetically at risk of developing protein-losing enteropathy and nephropathy. including infectious. Bianchi and others 1999. 82 per cent were positive for microalbuminuria (Grauer and others 2002). Other conditions have been reported in dogs with microalbuminuria. At the end of the study. The observation that persistent microalbuminuria develops in dogs with this type of protein-losing nephropathy at approximately the same time that mesangial hypercellularity and segmental glomerular sclerosis occur is of interest. Most studies have shown that normal urine protein excretion in dogs is less than 10 to 15 mg/kg/day (Barsanti and Finco 1979. In these dogs. although it was more rigidly defined as albumin levels of between 2 and 20 mg/dl (Pressler and others 2001). PintoSietsma and others 2000. a statistically significant correlation was found between increasing age and microalbuminuria. In 86 dogs whose owners were not seeking veterinary care the prevalence of microalbuminuria was 19 per cent (Jensen and others 2001). Grauer and others 1985). all developed microalbuminuria. Although the health status of this study population of dogs was not reported. elective procedures and evaluation of health problems at a veterinary teaching hospital (Jensen and others 2001). lesions in the glomerular basement membrane became apparent by eight weeks of age. This is a rapidly progressive glomerular disease occurring secondarily to a defect in type IV collagen.Canine glomerular disease 10/6/05 5:46 PM Page 474 cage. The onset of microalbuminuria corresponded to the onset of antigenaemia. The initially recommended normal values for canine UP/Cs of less than 1·0 were likely to have been conservative and have recently been lowered. which is a structural component of the glomerular basement membrane (Lees and others 2002a). In 3041 dogs owned by staff from over 350 veterinary clinics. Weir 2002). Renal proteinuria of either tubular or glomerular origin is indicated by a ratio greater than 0·5. Center and others 1985. In dogs evaluated at another veterinary teaching hospital for health problems. was 76 per cent (Vaden and others 2001). metabolic and cardiovascular disease (Pressler and others 2001. Persistent microalbuminuria was detected between eight and 23 weeks of age. Whittemore and others 2003). Heska). Concurrent inflammatory bowel disease may account for microalbuminuria in some of the dogs that did not progress to overt proteinuria. up to 16 weeks before the onset of overt proteinuria. DiBartola and others 1980a.ll Whenever possible. even the very low single nephron proteinuria that occurs secondarily to intraglomerular hypertension in hypertrophied nephrons in chronic renal disease is abnormal compared with what frequently would be considered normal whole-body or whole-kidney proteinuria. The prevalence of microalbuminuria in 20 soft-coated wheaten terriers. In 12 healthy dogs that were experimentally infected with D immitis L3 larvae and longitudinally evaluated. Results of an ongoing study of • VOL 46 • OCTOBER 2005 JOURNAL OF SMALL ANIMAL PRACTICE . McCaw and others 1985). the prevalence of microalbuminuria was 30 per cent. the prevalence was higher (36 per cent) in 159 dogs whose owners were seeking veterinary care for routine health screening. A ratio greater than 2·0 is strong evidence of glomerular disease. Muller-Peddinghaus and Trautwein 1977). be used to establish baseline proteinuria in individual patients. separated by at least 24 hours. Of all the samples collected over the 14 to 23 month postinfection period of study. The magnitude of microalbuminuria increased over time and it preceded the development of overt proteinuria. or indwelling or repeated urinary catheterisation. The magnitude of microalbuminuria increased over time and 43 per cent of the dogs with microalbuminuria eventually developed abnormal UP/Cs. it is recommended that more than one UP/C. neoplastic. White and others 1984. and that normal UP/Cs are less than 0·2 to 0·3. Albuminuria was evaluated in 36 male dogs with X-linked hereditary nephropathy. the prevalence of microalbuminuria was 25 per cent (Radecki and others 2003). The prevalence of microalbuminuria in dogs has been evaluated in several studies. However. particularly those diseases that involve the glomerulus. Grauer and others 1985. inflammatory. Microalbuminuria Recently a point-of-care immunoassay for the detection of low levels of albumin (microalbuminuria) in the urine of dogs has become commercially available (ERDHealthScreen. microalbuminuria appears to be a good indicator of early renal disease in dogs. there was histological evidence of glomerular disease by light microscopy (n=11) or electron microscopy (n=12). and it has also been observed in humans with systemic diseases that are associated with glomerulopathy (Gosling 1995. Microalbuminuria is usually defined as a urine albumin concentration of between 0·01 and 0·30 g/l. Based on recent studies. For example. The UP/C in spot urine samples from dogs has been shown to accurately reflect the quantity of protein excreted in the urine over a 24-hour period (White and others 1984. These are abnormal concentrations too small to be routinely detected by standard dipstick screening tests. as measured by UP/C. Today ratios of less than 0·5 are considered normal and it is likely that the definition of normal will continue to decrease with time. which occurred at 14 to 30 weeks of age. It is interesting to 474 note that microalbuminuria has been shown to be an accurate predictor of subsequent renal diseases in humans with both systemic hypertension and diabetes mellitus. The increasing prevalence of glomerular lesions in dogs as they age tends to corroborate the age-related prevalence of microalbuminuria (Rouse and Lewis 1975. It was concluded that microalbuminuria was a reliable early marker of developing nephropathy. making the procedure cumbersome and expensive.

In a recent retrospective study of 106 dogs with GN. Histopathological evaluation of renal tissue will help to establish a diagnosis (for example. and electron microscopy should be used to maximise the information gained from the biopsy specimen. Caution: volume contraction and reduced glomerular filtration rate may result Paracentesis for patients with tense ascites and/or respiratory distress Plasma transfusions† *Denotes treatments thought most important by the author †Controversial treatments or treatments with questionable efficacy • VOL 46 • OCTOBER 2005 475 . Further study is necessary to determine if microalbuminuria is an accurate predictor of overt proteinuria and various additional types of renal disease in dogs. GN versus amyloidosis or glomerulosclerosis) and form a prognosis. and abdominal radiographs or renal ultrasonography) have been conducted and an assessment of blood clotting ability has been performed. its treatment has received substantially less attention in veterinary medicine than has the treatment of chronic renal failure. Whittemore and others 2003). and reduction of the glomerular response to the immune complexes. even though UP/Cs may not be increased above the reference range (Pressler and others 2003). urine albumin concentrations did not consistently decrease with decreased tumour burden. immunofluorescent and/or immunocytochemical staining. As has been reported in humans with acute inflammatory conditions. Unfortunately. enalapril 0·5 mg/kg every 12 to 24 hours)* Oedema/ascites: Dietary sodium reduction Cage rest Furosemide 1 to 2 mg/kg as needed if necessary. However. thin sections. proteinuria associated with dirofilariosis in dogs often improves or resolves after successful treatment of the parasitic infection. transient microalbuminuria occurred in some of these dogs. A biopsy of the cortical region of the kidney should be obtained to assure an adequate number of glomeruli in the specimen. and to avoid the major vessels and renal nerves in the medullary region. and overt haematuria is not uncommon. neoplasia). Infection. the best way to obtain a renal biopsy is by laparotomy in which both kidneys can be visualised. and adequacy of the biopsy specimen is assured. Consultation with the histopathology laboratory before the biopsy is important to ensure appropriate fixatives are used. A large percentage of animals that were euthanased or died had microalbuminuria suggesting that. Most animals will exhibit microscopic haematuria for one to three days postbiopsy. For example. Biopsies indicated by persistent proteinuria If persistent proteinuria of renal origin is identified. with n-3 fatty acid supplementation* Hypertension: Dietary sodium reduction Angiotensin-converting enzyme inhibition (eg. Renal biopsies can be obtained percutaneously using the keyhole technique or by JOURNAL OF SMALL ANIMAL PRACTICE laparoscopic (Grauer and others 1983) or ultrasonographic guidance (Hager and others 1985). elimination of the antigen source is often not possible because the antigen source or underlying disease may not be identified or may be impossible to eliminate (for example. as in humans. a renal biopsy is indicated. postbiopsy haemorrhage can be accurately assessed and treated. urinalysis. serum biochemistry profile. its presence may be a negative prognostic indicator. renal biopsy should be considered only after less invasive tests (complete blood count. Special stains. Eliminating the source of antigenic stimulation is the treatment of choice for GN. The prevalence of microalbuminuria in dogs admitted to intensive care units is higher than in other reported patient populations and appears to vary with different classifications of disease (Pressler and others 2001. high quality/low quantity protein. this early detection tool should increase the ability to alter disease progression. poly- Table 3.Canine glomerular disease 10/6/05 5:46 PM Page 475 microalbuminuria in dogs with lymphosarcoma and osteosarcoma demonstrated that urine albumin concentrations were significantly increased in these animals. If microalbuminuria does predict overt proteinuria and/or renal disease. Treatment guidelines for glomerulonephritis Identify and correct any underlying disease processes* Immunosuppressive treatment† Haemodynamic/antiproteinuric treatment (angiotensin-converting enzyme inhibitors)* Antiplatelet-hypercoagulability treatment Aspirin 0·5 mg/kg every 12 to 24 hours* Coumadin – titrate dose based on prothrombin time Supportive care Dietary: sodium reduced. As immune complexes usually initiate GN. However. quantitation of proteinuria. TREATMENT Even though GN is a major cause of chronic renal disease in the dog. Frequently. Severe haemorrhage occurs in less than 3 per cent of cases (Jeraj and others 1982) and is almost always caused by poor technique. primary treatment objectives include identification and elimination of causative/associated antigens. 43 per cent had no identifiable concurrent disease or disorder and 19 per cent had neoplasia (Cook and Cowgill 1996).

there has been only one controlled veterinary clinical trial assessing the effects of immunosuppressive therapy. treatment with corticosteroids appeared to be detrimental. immunosuppressive drugs have been recommended in dogs with GN. Immunosuppressive agents Based on results in humans. Because fibrin accumulation within the glomerulus is a frequent and irreversible consequence of GN. once or twice daily) may selectively inhibit platelet cyclo-oxygenase without preventing the beneficial effects of prostacyclin formation (vasodilation. multicentre. which can occur with glomerular disease (Reddi and others 1991). After six months of treatment the change in UP/C from baseline was different between groups. Appropriate dosage is important if non-specific cyclooxygenase inhibitors such as aspirin are used to decrease glomerular inflammation and platelet aggregation. Dogs were randomly assigned to receive either enalapril (n=16. and platelet depletion attenuates the disease. In a retrospective study of dogs with naturally occurring GN. hyperadrenocorticism and immune-mediated anaemia are additional commonly identified concurrent medical problems (Cook and Cowgill 1996). In another study. anticoagulant treatment may serve a dual purpose. • VOL 46 • OCTOBER 2005 JOURNAL OF SMALL ANIMAL PRACTICE . Furthermore.Canine glomerular disease 10/6/05 5:46 PM Page 476 arthritis. In dogs with unilateral nephrectomy and experimentally induced diabetes mellitus. Low-dose aspirin is easily administered on an outpatient basis and does not require extensive monitoring. as well as the lack of consistent therapeutic response to corticosteroids. An extremely low dosage of aspirin (0·5 mg/kg orally. When data were adjusted for changes in glomerular filtration rate (UP/C stable serum creatinine [SrCr]) a similar significant reduction was noted. In rats. no progression (<50 per cent reduction in UP/C with stable SrCr). Similarly. aspirin may be a valuable substitute (Grauer and others 1992b). systemic lupus erythematosus). Treatment with ACEIs probably decreases proteinuria and preserves renal function associated with glomerular disease by several mechanisms. Twentynine adult dogs with membranous (n=16) and membranoproliferative (n=13) GN were identified. leading to azotaemia and worsening of proteinuria (Center and others 1987). Hills).ll Thromboxane synthetase inhibitors decreased proteinuria. The change in systolic blood pressure after six months of treatment was also significantly different between groups. Angiotensin-converting enzyme inhibitors There is a growing body of evidence indicating that angiotensin-converting enzyme inhibitors (ACEIs) reduce protein excretion and disease progression in dogs with GN. prednisone increased the UP/C from 1·5 to 5·6 in carrier female dogs with X-linked hereditary nephropathy (Lees and others 2002b). raises questions about the use of corticosteroids in dogs with GN. The response to treatment was significantly better in dogs treated with enalapril compared with those given a placebo (Grauer and others 2000). Despite widespread use of immunosuppressive agents. Thromboxane is thought to arise primarily from platelets attracted to the glomerulus in immune 476 complex disease. as does treatment with coumadin (Bristol-Myers Squibb). administration of lisinopril decreases efferent glomerular arteriolar resistance. These findings suggest that platelets and thromboxane have an important role in the pathogenesis of GN. 0·5 mg/kg orally. neutrophil infiltration and fibrin deposition in dogs with experimental GN (Longhofer and others 1991. treatment may be aimed at decreasing the glomerular response to the presence of immune complexes. the routine use of corticosteroids to treat GN in dogs is not recommended. decreased glomerular basement membrane splitting and prolonged survival compared with control dogs (Grodecki and others 1997). ACEI administration reduced glomerular transcapillary hydraulic pressure and glomerular cell hypertrophy. Grauer and others 1992a). which results in decreased glomerular transcapillary hydraulic pressure and decreased proteinuria (Brown and others 1993). a double-blinded. hepatitis. In dogs. Response to treatment was categorised as: improvement (>50 per cent reduction in UP/C with stable SrCr). improved renal excretory function. Recently. and progression (>50 per cent increase in UP/C and/or SrCr or euthanasia due to renal failure). All dogs were treated with low-dose aspirin (0·5 to 5 mg/kg orally. treatment with corticosteroids would be indicated if the underlying disease process was known to be steroid-responsive (for example. Grauer and others 1992a).lll Reducing glomerular response to immune complexes Alternatively. idiopathic GN (Grauer and others 2000). The association between hyperadrenocorticism or long-term exogenous corticosteroid administration and GN and thromboembolism in the dog. prospective clinical trial assessed the effects of enalapril versus standard care in dogs with naturally occurring. Consequently. In the absence of specific thromboxane synthetase inhibitors. Ciclosporin treatment was found to be of no benefit in reducing proteinuria associated with idiopathic GN in dogs (Vaden and others 1995). as well as proteinuria (Brown and others 1993). platelet survival is decreased in several types of GN in human patients. Increased urinary excretion of thromboxane has been detected in dogs with experimentally induced GN (Longhofer and others 1991. ACEI treatment of Samoyed dogs with X-linked hereditary nephritis decreased proteinuria. glomerular cell proliferation. The enalapril treatment group had significantly reduced UP/Cs. administration of enalapril prevents the loss of glomerular heparan sulfate. inhibition of platelet aggregation). However. once to twice daily) and fed a prescription diet (Canine k/d. once to twice daily) or a placebo (n=14) for six months (one dog was treated first with the placebo and then with enalapril).

A. In dogs with surgically reduced remnant kidneys. G. 537-546 DIBARTOLA. MEYER. BROGGINI. M. If hypertension is not controlled with dietary sodium reduction alone. (1976) The platelet as a mediator of tissue damage in immune complex GN. W. A. M. L. (1994) Alternative pathway activation of complement by cultured human proximal tubular epithelial cells. R. 366-374 BOHLE. N. C. V. H. PROGNOSIS The prognosis for dogs with GN is variable and is best made based on a combination of the severity of dysfunction (the magnitude of proteinuria and presence or absence of azotaemia). M. (1996) Clinical and pathologic features of protein-losing glomerular disease in the dog: a review of 137 cases.. I.. MARKANDU. 81-90 CENTER. (1980b) Urinary protein excretion and immunopathologic findings in dogs with glomerular disease. H. M. A. W. JOURNAL OF SMALL ANIMAL PRACTICE dietary supplementation with fish oil reduced proteinuria. I. L. 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(1980a) Quantitative urinalysis including 24-hour protein excretion in the dog. 1210-1218 BURKHOLDER. A. pathophysiology and therapeutic implications. A. will undoubtedly provide valuable information and increase vets’ ability to treat this disease. W. Administration of ACEIs in dogs slows glomerular mesangial cell growth and proliferation. & REMUZZI. & MACGREGOR. dietary protein supplementation has been recommended to offset the effects of proteinuria.. References ALFREY.Canine glomerular disease 10/6/05 5:46 PM Page 477 Administration of ACEIs is also thought to attenuate proteinuria in humans by decreasing the size of glomerular capillary endothelial cell pores (Wiegmann and others 1992). A morphological and clinical analysis of 1747 cases. diagnosis and management of systemic hypertension in dogs and cats. K. E. Journal of Laboratory Clinical Medicine 131. 165-175 CAMUSSI. CHEW. & LINDSAY. M. Journal of the American Veterinary Medical Association 190. E. KASHTAN.. 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