Diagnostic Approach to Proteinuria
Article posted with permission from the Author
Diagnostic approach to Proteinuria
Date: Tuesday, July 20 @ 11:58:32 SAST
Topic: VetMed Magazine
Protein losing nephropathy is a common but under diagnosed form of renal disease in the dog and cat. Unfortunately the disease is often clinical silent and can only be determined on urine analysis. Although evaluation of protein in the urine should be a standard diagnostic method, it is too rarely done.
Lobetti RG
BVSc (Hons), MMedVet (Med), Dipl ECVIM
Bryanston Veterinary Hospital, PO Box 67092, Bryanston, 2021, South Africa, rlobetti@mweb.co.za
Abstract
Protein losing nephropathy is a common but under diagnosed form of renal disease in the dog and cat. Unfortunately the disease is often clinical silent and can only be determined on urine analysis. Although evaluation of protein in the urine should be a standard diagnostic method, it is too rarely done. If diagnosed early, both the therapeutic options and the prognosis are much better. Urine analysis should be performed routinely in animals and all animals with an unexplained proteinuria should be thoroughly investigated as to the cause of the proteinuria. This paper will address the pathophysiology, causes and consequences of proteinuria, as well the diagnostic approach to an animal that has unexplained proteinuria on routine urine analysis.
Introduction
The hallmark of glomerular diseases is abnormal protein loss in the urine. From a diagnostic standpoint the clinical finding of proteinuria must first be localized as pre-renal, renal, or post-renal.
Pre-renal
This is were protein loss occurs in the normal kidneys as a consequence of abnormal small molecular weight proteins present in the blood passing through the filtration barrier (e.g. haemoglobinuria, light-chain proteinuria in myeloma, myoglobinuria). Transient pre-renal proteinuria can result from increased intraglomerular capillary pressure. The increased pressure favours transport of small proteins normally present in plasma through the filtration barrier, which may accompany strenuous exercise, fever, or seizures.
Renal
Glomerular proteinuria occurs when there is disruption of the filtration barrier causing altered permselectivity and resulting in molecules normally retained within the plasma space being lost in the urine. Because albumin is relatively small (65,000 daltons), it is the predominant protein lost from the glomerulus. The renal tubule can also result in proteinuria and occurs when the proximal tubule fails to reabsorb normally filtered proteins, which may be present in generalized tubulopathies such Fanconi syndrome or acute tubular necrosis.
Post-renal
Post-renal proteinuria occurs when protein enters the urine because of haemorrhage or inflammation within the lower urinary tract or genital tract.
Pre-renal proteinuria can usually be ruled out by history and with a normal serum protein and spinning the urine to distinguish haemoglobinuria and myoglobinuria from haematuria. Post-renal proteinuria can often be diagnosed on the basis of active urine sediment - haematuria, pyuria, and bacteruria.
Glomerular Structure And Function
The glomerulus is a tuft of highly branched capillaries, which together with Bowman's capsule form the renal corpuscle of the nephron. The glomeruli are confined to renal cortex. The components of the glomerulus include the capillary endothelial cells, the visceral epithelial cells, mesangial cells, mesangial matrix, and capillary basement membranes.
Glomerular capillary endothelial cells are similar to those in capillaries throughout the body except that they contain numerous large pores called fenestrae. Glomerular capillaries are covered by visceral epithelial cells called podocytes because they contain cytoplasmic foot process that extend to the glomerular basement membrane (GBM). The spaces between the cytoplasmic foot processes are all called slit pores and they are covered with split pore membranes. This is where filtration is believed to occur. The visceral epithelium is covered with sialoprotein, which is negatively charged and tends to inhibit the passage of negatively charged macromolecules. The permselectivity of the glomerulus is thus both a charge- and sized-based barrier. Mesangial cells occupy spaces in the tuft between the capillary loops and produce the mesangial matrix. Mesangial cells have phagocytic capabilities. The mesangial matrix provides the structural support for the glomerulus. The GBM is located between the endothelial and visceral epithelial cells although it does not completely surround the capillary lumen.
Glomerular Injury
Glomerular injury is an important cause of renal disease in companion animals and appears to be more common in dogs than in cats. Because the components of the nephron are functionally interdependent, disease in the glomerulus if progressive and unresolved will eventually lead to damage to the tubules, interstitium, and vasculature, resulting in chronic renal failure.
In both dogs and cats, immune complex glomerulonephritis (GN) and amyloidosis are the most common primary glomerular disease syndromes. A hereditary susceptibility to certain types of GN has been demonstrated in humans but to date, not in companion animals.
Causative factors that are associated with GN in the dog and cat include the following:
Because the inciting cause of glomerulonephritis is rarely known, it is usually characterized by its histological description:
Amyloid is deposited mainly in the glomeruli, although in cats, it may be deposited in the interstitium of the medulla. Amyloid is produced by mononuclear-macrophage cells from amyloidogenic glycoproteins (serum amyloid protein A from hepatocytes in chronic inflammation and amyloid AL from the light chains of immunoglobulins in plasma cell dyscrasia). Glomerular amyloidosis can result in proteinuria, the nephrotic syndrome and ultimately renal failure. Medullary amyloidosis in cats produces no clinical signs but may cause renal medullary necrosis.
Consequences of Glomerular Dysfunction
A careful history and full clinical examination are required because many cases of GN are secondary to occult disease. In one report of dogs with GN, approximately 50% of the dogs had a concurrent neoplastic, infectious, inflammatory, or immune-mediated disease at post mortem. Specific clinical abnormalities associated with glomerular injury may be subtle (weight loss, poor hair coat) or absent unless the animal is in renal failure. Oedema, ascites, or pleural effusion is present in animals with the nephrotic syndrome. Renal size may be normal, increased (amyloidosis, acute GN), or decreased (chronic GN or glomerulosclerosis). Haematuria with RBC casts may be evident in animals with GN.
Shar Pei dogs with amyloidosis may have pyrexia, swollen hocks, and/or a swollen muzzle. Clinical signs of hepatic involvement may be present in affected Shar Pei dogs and Abyssinian, Oriental Shorthair, and Siamese cats.
Occasionally animals may present with signs attributable to the thromboembolism: dyspnoea because of pulmonary thromboembolism and hind limb paresis from aortic thromboembolism. Some animals may present for acute blindness associated with hypertensive retinal detachment.
Persistent proteinuria with a negative sediment or accompanied by hyaline or granular casts on urine sediment is suggestive of glomerular disease. In early cases the urine dipstick may in fact be negative for proteinuria, as the concentration of protein is extremely low. This can be overcome by determining micro-albuminuria, which at this point is only available for dogs.
Animals with glomerular amyloidosis generally have the highest urine protein creatinine ratio. Animals with medullary amyloidosis may lack significant proteinuria early in the course of their disease.
Diagnostic Workup
In summary a full investigation into the aetiology of renal proteinuria would include:
_Very few studies of companion animal patients are published. When an underlying disease is found, correction of that disorder is often the most critical aspect of therapy. Unfortunately, such as underlying disorder is rarely found. Supportive care for patients with renal failure, hypertension, ascites, or oedema is always indicated.
High-quality, low protein diets have been recommended for many years because higher protein diets promoted a greater magnitude of proteinuria, which depleted the body albumin pool. Recently, the practice of protein restriction has been questioned in certain types of GN in humans. It may be that higher protein diets can be fed without inducing a greater magnitude of proteinuria if they are used together with an angiotensin-converting-enzyme (ACE) inhibitor or an anti-thrombin antagonist.
ACE inhibitors have been shown to reduce proteinuria in both dogs and humans with GN. In humans, improvements in lipid abnormalities (hypercholesterolemia, hyperlipoproteinaemia) are also clearly demonstrated.
Mini-dose aspirin is used routinely to minimize risks of hypercoagulability. Thromboxane inhibitors have been studied on a limited basis in dogs with some success and omega-3 fatty acids may also be of benefit.
Immunosuppressive Therapy
The use of immunosuppressive agents, and which type, is perhaps the most controversial and difficult aspect of therapy for GN. Use of corticosteroids is indicated when an underlying corticosteroid-responsive disease is identified (e.g. SLE).
The current view is that idiopathic GN in humans does not appear too responsive to glucocorticoids, which contradicts early studies suggesting otherwise. In contrast, there is convincing evidence that cytotoxic therapy with cyclophosphamide or chlorambucil has benefit in idiopathic membranous GN, especially when instituted early in the disease. Other drugs that can be used are chlorambucil, cyclophosphamide, or cyclosporine. Many of the human studies evaluating chlorambucil also involved some months of treatment with pulsed methylprednisolone to reduce of the risk of leukopaenia from chlorambucil.
Further reading
Article posted with permission from the Author
Diagnostic approach to Proteinuria
Date: Tuesday, July 20 @ 11:58:32 SAST
Topic: VetMed Magazine
Protein losing nephropathy is a common but under diagnosed form of renal disease in the dog and cat. Unfortunately the disease is often clinical silent and can only be determined on urine analysis. Although evaluation of protein in the urine should be a standard diagnostic method, it is too rarely done.
Lobetti RG
BVSc (Hons), MMedVet (Med), Dipl ECVIM
Bryanston Veterinary Hospital, PO Box 67092, Bryanston, 2021, South Africa, rlobetti@mweb.co.za
Abstract
Protein losing nephropathy is a common but under diagnosed form of renal disease in the dog and cat. Unfortunately the disease is often clinical silent and can only be determined on urine analysis. Although evaluation of protein in the urine should be a standard diagnostic method, it is too rarely done. If diagnosed early, both the therapeutic options and the prognosis are much better. Urine analysis should be performed routinely in animals and all animals with an unexplained proteinuria should be thoroughly investigated as to the cause of the proteinuria. This paper will address the pathophysiology, causes and consequences of proteinuria, as well the diagnostic approach to an animal that has unexplained proteinuria on routine urine analysis.
Introduction
The hallmark of glomerular diseases is abnormal protein loss in the urine. From a diagnostic standpoint the clinical finding of proteinuria must first be localized as pre-renal, renal, or post-renal.
Pre-renal
This is were protein loss occurs in the normal kidneys as a consequence of abnormal small molecular weight proteins present in the blood passing through the filtration barrier (e.g. haemoglobinuria, light-chain proteinuria in myeloma, myoglobinuria). Transient pre-renal proteinuria can result from increased intraglomerular capillary pressure. The increased pressure favours transport of small proteins normally present in plasma through the filtration barrier, which may accompany strenuous exercise, fever, or seizures.
Renal
Glomerular proteinuria occurs when there is disruption of the filtration barrier causing altered permselectivity and resulting in molecules normally retained within the plasma space being lost in the urine. Because albumin is relatively small (65,000 daltons), it is the predominant protein lost from the glomerulus. The renal tubule can also result in proteinuria and occurs when the proximal tubule fails to reabsorb normally filtered proteins, which may be present in generalized tubulopathies such Fanconi syndrome or acute tubular necrosis.
Post-renal
Post-renal proteinuria occurs when protein enters the urine because of haemorrhage or inflammation within the lower urinary tract or genital tract.
Pre-renal proteinuria can usually be ruled out by history and with a normal serum protein and spinning the urine to distinguish haemoglobinuria and myoglobinuria from haematuria. Post-renal proteinuria can often be diagnosed on the basis of active urine sediment - haematuria, pyuria, and bacteruria.
Glomerular Structure And Function
The glomerulus is a tuft of highly branched capillaries, which together with Bowman's capsule form the renal corpuscle of the nephron. The glomeruli are confined to renal cortex. The components of the glomerulus include the capillary endothelial cells, the visceral epithelial cells, mesangial cells, mesangial matrix, and capillary basement membranes.
Glomerular capillary endothelial cells are similar to those in capillaries throughout the body except that they contain numerous large pores called fenestrae. Glomerular capillaries are covered by visceral epithelial cells called podocytes because they contain cytoplasmic foot process that extend to the glomerular basement membrane (GBM). The spaces between the cytoplasmic foot processes are all called slit pores and they are covered with split pore membranes. This is where filtration is believed to occur. The visceral epithelium is covered with sialoprotein, which is negatively charged and tends to inhibit the passage of negatively charged macromolecules. The permselectivity of the glomerulus is thus both a charge- and sized-based barrier. Mesangial cells occupy spaces in the tuft between the capillary loops and produce the mesangial matrix. Mesangial cells have phagocytic capabilities. The mesangial matrix provides the structural support for the glomerulus. The GBM is located between the endothelial and visceral epithelial cells although it does not completely surround the capillary lumen.
Glomerular Injury
Glomerular injury is an important cause of renal disease in companion animals and appears to be more common in dogs than in cats. Because the components of the nephron are functionally interdependent, disease in the glomerulus if progressive and unresolved will eventually lead to damage to the tubules, interstitium, and vasculature, resulting in chronic renal failure.
In both dogs and cats, immune complex glomerulonephritis (GN) and amyloidosis are the most common primary glomerular disease syndromes. A hereditary susceptibility to certain types of GN has been demonstrated in humans but to date, not in companion animals.
Causative factors that are associated with GN in the dog and cat include the following:
- Infectious
- FeLV
- FIP
- Bacterial endocarditis
- Adeno virus
- Pyometra
- Ehrlichiosis
- Leptospirosis
- Chronic bacterial infections
- Inflammatory
- Pancreatitis
- SLE
- Chronic inflammatory skin disease
- Polyarthritis
- Chronic hepatopathies
- Chronic gastro-enteropathies
- Neoplasia
- Lymphoma
- Mast cell tumours
- Other
- Metabolic/toxic
- Corticosteroids
- Diabetes mellitus
- Captopril
- Pencillamine
- Sulphonamides
- Vaccines Mercury
- Bee stings
- Idiopathic
- Familial? Potential mechanisms involved in glomerular injury include:
- Deposition of preformed circulating immune complexes into the GBM.
- In situ reaction of antibody with exogenous (planted) antigens or intrinsic glomerular antigens.
- Cell-mediated immune reactions.
- Complement-mediated damage.
- Deposition of amyloid protein.
- Haemodynamic forces (altered renal blood flow, systemic or glomerular hypertension).
- Hyperlipidaemia.
- Intra-renal coagulation. Pathogenesis of Glomerulonephritis
The most common inciting cause of GN is the deposition of preformed circulating immune complexes into the GBM. In certain instances immunoglobulins can combine with antigens previously planted in the GBM. Primary autoimmune GN occurs with antibodies reactive against native GBM proteins, but this has not been reported in companion animals. Any infectious, inflammatory, parasitic, neoplastic, or degenerative disease process that results in sustained antigenic stimulation can lead to immune-mediated glomerular damage. However, in the vast majority of animal cases the antigen source or underlying disease process cannot be identified and the glomerular disease is thus labelled as idiopathic.
Because the inciting cause of glomerulonephritis is rarely known, it is usually characterized by its histological description:
- Membranous GN.
- Proliferative GN - increased glomerular cellularity.
- Membranoproliferative GN - combination of the above 2.
- Glomerulosclerosis - glomerular scarring associated with increased mesangial matrix deposition Membranous GN is the most common type and is generally associated with heavy proteinuria and frequently an insidiously progressive course leading to renal failure. Membranoproliferative (mesangiocapillary) glomerulonephropathy is also common in the dog. Late stage membranous GN is difficult to definitively distinguish membranoproliferative GN without electron microscopy. Proliferative glomerulopathy generally presents with a fulminating course. Glomerulosclerosis is an end-stage of chronic inflammatory or degenerative renal diseases in which the glomeruli are replaced by hyaline or fibrotic material.
Amyloid is deposited mainly in the glomeruli, although in cats, it may be deposited in the interstitium of the medulla. Amyloid is produced by mononuclear-macrophage cells from amyloidogenic glycoproteins (serum amyloid protein A from hepatocytes in chronic inflammation and amyloid AL from the light chains of immunoglobulins in plasma cell dyscrasia). Glomerular amyloidosis can result in proteinuria, the nephrotic syndrome and ultimately renal failure. Medullary amyloidosis in cats produces no clinical signs but may cause renal medullary necrosis.
Consequences of Glomerular Dysfunction
A careful history and full clinical examination are required because many cases of GN are secondary to occult disease. In one report of dogs with GN, approximately 50% of the dogs had a concurrent neoplastic, infectious, inflammatory, or immune-mediated disease at post mortem. Specific clinical abnormalities associated with glomerular injury may be subtle (weight loss, poor hair coat) or absent unless the animal is in renal failure. Oedema, ascites, or pleural effusion is present in animals with the nephrotic syndrome. Renal size may be normal, increased (amyloidosis, acute GN), or decreased (chronic GN or glomerulosclerosis). Haematuria with RBC casts may be evident in animals with GN.
Shar Pei dogs with amyloidosis may have pyrexia, swollen hocks, and/or a swollen muzzle. Clinical signs of hepatic involvement may be present in affected Shar Pei dogs and Abyssinian, Oriental Shorthair, and Siamese cats.
Occasionally animals may present with signs attributable to the thromboembolism: dyspnoea because of pulmonary thromboembolism and hind limb paresis from aortic thromboembolism. Some animals may present for acute blindness associated with hypertensive retinal detachment.
Persistent proteinuria with a negative sediment or accompanied by hyaline or granular casts on urine sediment is suggestive of glomerular disease. In early cases the urine dipstick may in fact be negative for proteinuria, as the concentration of protein is extremely low. This can be overcome by determining micro-albuminuria, which at this point is only available for dogs.
Animals with glomerular amyloidosis generally have the highest urine protein creatinine ratio. Animals with medullary amyloidosis may lack significant proteinuria early in the course of their disease.
Diagnostic Workup
In summary a full investigation into the aetiology of renal proteinuria would include:
_Very few studies of companion animal patients are published. When an underlying disease is found, correction of that disorder is often the most critical aspect of therapy. Unfortunately, such as underlying disorder is rarely found. Supportive care for patients with renal failure, hypertension, ascites, or oedema is always indicated.
High-quality, low protein diets have been recommended for many years because higher protein diets promoted a greater magnitude of proteinuria, which depleted the body albumin pool. Recently, the practice of protein restriction has been questioned in certain types of GN in humans. It may be that higher protein diets can be fed without inducing a greater magnitude of proteinuria if they are used together with an angiotensin-converting-enzyme (ACE) inhibitor or an anti-thrombin antagonist.
ACE inhibitors have been shown to reduce proteinuria in both dogs and humans with GN. In humans, improvements in lipid abnormalities (hypercholesterolemia, hyperlipoproteinaemia) are also clearly demonstrated.
Mini-dose aspirin is used routinely to minimize risks of hypercoagulability. Thromboxane inhibitors have been studied on a limited basis in dogs with some success and omega-3 fatty acids may also be of benefit.
Immunosuppressive Therapy
The use of immunosuppressive agents, and which type, is perhaps the most controversial and difficult aspect of therapy for GN. Use of corticosteroids is indicated when an underlying corticosteroid-responsive disease is identified (e.g. SLE).
The current view is that idiopathic GN in humans does not appear too responsive to glucocorticoids, which contradicts early studies suggesting otherwise. In contrast, there is convincing evidence that cytotoxic therapy with cyclophosphamide or chlorambucil has benefit in idiopathic membranous GN, especially when instituted early in the disease. Other drugs that can be used are chlorambucil, cyclophosphamide, or cyclosporine. Many of the human studies evaluating chlorambucil also involved some months of treatment with pulsed methylprednisolone to reduce of the risk of leukopaenia from chlorambucil.
Further reading
- Grauer GF, Dibartola SP. 2000. Glomerular disease. In: Ettinger SJ, Feldman EC (eds). Textbook of Veterinary Internal Medicine. WB Saunders, Philadelphia: 1662-1677
- Finco DR. 1995. Urinary protein loss. In: Osborne CA, Finco DA (eds) Canine and Feline Nephrology and Urology. Lea and Febiger, Baltimore: 211-215
- Lulich J, Osborne C. 1990. Interpretation of urine protein-creatinine ratios in dogs with glomerular and non-glomerular disorders. Compendium on Continuing Education for the Practising Veterinarian 12: 59-73
- Jergens AE. 1987. Glomerulonephritis in dogs and cats. Compendium on Continuing Education for the Practising Veterinarian 9: 903-912
- Adams LG, Polzin DJ, Osborne CA. 1992. Correlation of urine protein/creatinine ratio and 24 hour urinary protein excretion in normal cats and cats with surgically induced CRF. Journal of Veterinary Internal Medicine 6: 36-40
- Grauer GF. 1992. Glomerulonephritis. Seminars in Veterinary Medicine and Surgery (Small Animal) 7: 187-197
