Until relatively recently, canine glomerular disease was thought to be uncommon and unimportant. It is now recognized that glomerulonephritis (GN) is common in dogs and can lead to chronic renal insufficiency/failure.¹ The magnitude of this problem is emphasized by studies that have shown the incidence of GN in randomly selected dogs to be as high as 43-90%.^2,3 The majority of canine GN is mediated by immunopathogenic mechanisms associated with the presence of immune complexes in glomerular capillary walls. Circulating immune complexes may be deposited in the glomerulus or immune complex formation may occur in situ. The glomerulus provides a unique environment for injurious immune complexes to stimulate production of bioactive mediators like eicosanoids, cytokines, and growth factors. These substances may be produced by endogenous glomerular cells or by recruited platelets, macrophages, and neutrophils. In addition to production of these bioactive mediators, several factors including activation of the complement system, platelet aggregation, infiltration of neutrophils and macrophages, activation of the coagulation system, and fibrin deposition can contribute to glomerular damage associated with the presence of immune complexes. Histologically, the glomerulus responds to this injury by cellular proliferation, thickening of the capillary walls, and if the injury persists, hyalinization and sclerosis. Once a glomerulus has been irreversibly damaged, the entire nephron becomes nonfunctional and fibrous tissue replacement occurs. Chronic interstitial nephritis is frequently the histopathologic lesion observed in dogs with chronic renal failure, but this end-stage lesion can result from primary glomerular, tubular, or vascular lesions as well as interstitial tissue lesions.

Loss of plasma proteins into the urine is one of the earliest functional defects recognized in GN. Consequences of plasma protein loss may include sodium retention, hypercoagulability, muscle wasting, and weight loss. There does not appear to be a relationship between proteinuria and glomerular filtration rate in dogs with GN.⁴ Azotemia and renal insufficiency/failure occur as more and more nephrons are irreversibly damaged and become nonfunctional. Late in the disease process, proteinuria in total tends to diminish associated with the decreased number affected glomeruli. Plasma protein loss on an individual remaining nephron basis however, may remain significant. Indeed, individual nephron hyperfiltration and proteinuria have been documented in dogs with the remnant kidney model of renal failure.⁵

There is increasing evidence in laboratory animals and human beings that proteinuria can cause glomerular and tubular damage and result in progressive nephron loss. 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 inhuman beings.⁶ In addition, excessive amounts of protein in the glomerular filtrate can be toxic to human tubular epithelial cells and can lead to interstitial inflammation, fibrosis, and cell death.⁷ Proximal tubular cells normally reabsorb protein from the glomerular filtrate by endocytosis. Albumin and other proteins accumulate in lysosomes and are then degraded into amino acids and returned to the circulation. In proteinuric conditions, excessive lysosomal processing can result in swelling and rupture of lysosomes causing enzymatic damage to the cytoplasm in rat kidneys.⁸ Tubular injury may also occur in rats as a consequence of tubular obstruction with proteinaceous casts.⁹ Increased glomerular permeability to plasma proteins allows tubular contact with transferrin, complement, and lipoproteins in addition to albumin. Transferrin increases iron uptake by epithelial cells. Once inside the cell the iron ions catalyze the formation of reactive oxygen species that can cause peroxidative injury in rats.¹⁰ Complement proteins can be activated on the brush border of proximal tubular cells cultured from human beings resulting in insertion of a membrane attack complex followed by cytoskeletal damage and cytolysis.¹¹ Reabsorbed lipoproteins can release lipid moieties that can accumulate into lipid droplets or be oxidized to toxic radicals.¹² All of these processes can irreversibly damage the proximal tubule and result in nephron loss. Exposure to plasma proteins at the apical surface of cultured human tubular cell results in a basolateral release of growth factors, fibronectin, and monocyte chemoattractant protein-1.¹³ This process may also induce excessive tubular expression of tranforming growth factor-ß1 that can result in the interstitial inflammation and scarring typical of end-stage kidney disease.¹⁴ Osteoponin has been detected in protein congested proximal tubular cells from rats in 2 different models of renal disease.¹⁵ By virtue of its chemoattractant action, osteopontin is a likely mediator of a proximal tubule-dependent inflammatory pathway in response to an excessive protein load. Another mediator of tubulointerstitial damage related to excessive tubular cell protein reabsorption is the up-regulation of tubular-derived endothelin-1 (ET-1).¹⁶ Tubular ET-1 formed in response to increasing concentrations of albumin presented to the proximal tubular epithelium is secreted toward the basolateral cellular compartment and accumulates in the interstitium causing ischemia. Endothelin-1 also binds to receptors on interstitial fibroblasts and causes interstitial cellular proliferation and extracellular matrix production.¹⁶

Several studies in human patients with proteinuric renal disease suggest that proteinuria is linked to renal disease progression. In 176 patients with non-insulin dependent diabetes mellitus that were studied over 5 years, baseline albuminuria was a predictor for the development of incipient nephropathy.¹⁷ Similarly, in people with insulin-dependent diabetes mellitus and established diabetic nephropathy, higher levels of proteinuria at baseline predicted progression of the nephropathy over a median period of 3 years.¹⁸ In another study of people with chronic GN, the decrease in proteinuria via several different treatments predicted the change in the slope of the reciprocal of the serum creatinine over 6 months.¹⁹ Paired renal biopsies taken 5.8 years apart in people with insulin-dependent diabetes mellitus showed that mesangial expansion was linked to microalbuminuria and that tubulointerstitial changes occurred as a result of advanced glomerular injury.²⁰ Finally, in a study of 7728 nondiabetic people, macroalbuminuria was independently associated with decreased glomerular filtration.²¹

Evidence linking proteinuria to progression of renal disease in dogs is less convincing. As stated earlier, individual nephron hyperfiltration and proteinuria have been documented in dogs with the remnant kidney model of renal failure.⁵ However, treatments that have slowed the functional decline and/or histologic changes associated with this model have had variable effects on proteinuria. Angiotensin converting enzyme inhibition and w-3 fatty acid supplementation have decreased proteinuria and slowed progression,^22,23 however calcium blockade treatment resulted in increased mesangial cell proliferation despite decreasing proteinuria.²² Other treatments, such as reduction of dietary phosphorus, decreased renal disease progression in remnant kidney dogs but had no effect on proteinuria.²⁴ In dogs with experimentally induced immune complex GN, treatment with a thromboxane synthetase inhibitor decreased proteinuria and attenuated the development of glomerular lesions but had no effect on established lesions.^25,26 Finally, reduction of proteinuria via angiotensin converting enzyme inhibition treatment slowed progression of renal disease in dogs with 2 different types of naturally occurring glomerulopathies.^27,28

In summary, a direct pathogenetic link between proteinuria and renal damage has not been established in the dog but the evidence is accumulating in other species. We need to increase our understanding of the effects of proteinuria on the glomerulus, the tubule, and the interstitium in the dog. It is possible that proteinuria may be much more than a diagnostic marker of glomerular disease.

References

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