Proteinuric Disease Flashcards
Causes of proteinuria
Altered glomerular permeability
- immune complex deposition
- vascular inflammation
- altered RBF
(can be functional in fever or with exercise)
- Intraglomerular hypertension
Excessive filtered load of albumin in glomerular disease –> secondary interstitial tubulonephritis
Impaired tubular handling
- decreased absorption of LMW proteins that are filtered (lower severity than for glomerular disease)
DDx: Fanconi Syndrome, Renal ischemia, nephrotoxins
- Overload proteinuria (multiple myeloma, Hgb, colostrum)
- Urinary tract inflammation
False positives in high concentrated or alkaline urine
If the urine remains yellow (microscopic haematuria), then there is negligible chance that a UPC >0.5 will be solely due to the added blood.
Clinical significance of proteinuria
Proteinuria is associated with increased risk of mortality (3x in dogs) and complications (1.5x) even when renal function is good
Markedly proteinuric dogs and cats treated with ACEi show renoprotective effects (ie, effects that decrease or delay adverse outcomes), a reduction in the magnitude of proteinuria is also observed during treatment
Methods of measuring proteinuria
Dipstick - 80% sensitivity but POOR SPECIFCITY (high false positive). Correlate with USG and pH
Urine Sulfosalicylic acid - more accurate for proteins that may not be measured by DS (ie Bence Jones). Mix supernatant with SSA and assess turbidity. Does not add much information for cats if DS negative
UPCR - wide daily variation best to use pooled samples
Urine protein electrophoresis - to detect BJ bodies (interpret with serum PE)
sulfate polyacrylamide gel electrophoresis (SDS-PAGE)
pattern of protein banding can help determine if glomerular damage, tubular damage, or both are contributing to the proteinuria
(most often mixed in dogs).
Urinary IgM and IgG are significantly associated with immune complex mediated glomerulonephritis (ICGN) compared with other glomerular and tubular disease categories
Recommended test for detection of albuminuria in cats
urine albumin detection in the feline patient should always be performed with a higher quality assay such as the species-specific albuminuria ELISA
feline urine samples, both routine-screening tests (dipstick and SSA) performed poorly and appear to be of minimal diagnostic value
In 239 urine samples from 37 cats with CKD the sensitivity and specificity for a > trace reaction on the dipstick and for a > 5 mg/dl reaction on the SSA were 81%/68% and 63%/96%
How and why is microalbuminuria detected
quantitative immunoassays at reference laboratories
Testing indicated where screening for proteinuria produces equivocal or conflicting results
Young dogs and cats that have a familial risk for developing proteinuric renal disease and a more sensitive screening test is desired.
Screening dogs or cats with illness that have negative UPCR though illness is associated with proteinuria
Steps in proteinuria investigation (7) from ACVIM consensus
Assessment of proteinuria involves investigation of: localisation (site/mechanism of proteinuria); documentation of persistence; determination of magnitude
1) Exclude extraurinary post-renal dz (use cysto sample)
2) Exclude pre-renal disease (dysproteinemia, fever, exercise)
3) Identify urinary post-renal by identification of inflammation in urine
4) determine if interstitial renal (inflammation and signs of nephritis, renal pain, fever)
5) Identify if pathologic glomerular (UPC >2)
6) Functional renal - mild UPC increase and resolves with subsequent evaluatin
7) If persistent low grade then consider pathologic glomerular (low grade) or tubular disease
When is UPCR indicated
patient with 2+ results without pyuria, or 1+ results in urine with USG <1.012
Do not use this test if preglomerular or overload proteinuria is suspected or if there is interstitial proteinuria, or post-renal proteinuria from haemorrhage or inflammation (interstitial proteinuria).
Recommendations for evaluating change in UPCR trends
probably need to differ by as much as 40%, especially in the lower ranges of abnormality, to conclude with a high level of confidence that the prevailing magnitude of proteinuria actually has changed
Variation of UPCR observed in cats with values within the reference range suggests that serial UPCRs need to differ by as much as 90% (ie, nearly double) to conclude with a high level of confidence that a cat’s magnitude of proteinuria has increased
When to investigate proteinuria and when to intervene
Monitor if:
Nonazotemic and persistent microalbuminuria
Nonazotemic and UPCR >0.5 (+/- treatment for underlying condition if found
Diagnostic investigation if:
Nonazotemic with rising microalbuminuria
Nonazotemic with persistent renal proteinuria UPCR >1
Treat if:
After appropriate treatment of any underlying disease. Treatment indicated in dogs with azotemic CKD and UPC >0.5; cats with CKD and UPC >0.4; nonazotemic dogs/cats with UPC >2.0
Change in diet - reduced by high quality protein; omega-3 FA supplementation
ACE inhibitor
Typical findings of tubular vs glomerular proteinuria
UP:UC > 0.4 and <2 in azotemic dogs: Proteinuria is thought to be mostly tubular with less of a glomerular component.
UP:UC ≥2 in non-azotemic or azotemic dogs: This is considered compatible with glomerular proteinuria
Tier classification of proteinuria
Tier I - Persistent renal proteinuria without hypoalbuminemia or azotemia
A - Persistent subclinical renal proteinuria that is not accompanied by any discernible renal-related signs or sequelae
B - Persistent renal proteinuria with hypertension as the only discernible renal-related sign or sequelae, with or without evidence of target organ damage
Tier II - Renal proteinuria associated with hypoalbuminemia, with or without any of its associated complications or sequelae (mainly oedema and thromboembolic events), but not azotemia
A - Persistent renal proteinuria with hypoalbuminemia, but without hypertension or azotemia
B - Persistent renal proteinuria with hypoalbuminemia, plus hypertension (with or without evidence of target organ damage)
Tier III - Renal proteinuria associated with renal azotemia
A - Renal proteinuria with renal azotemia, but not hypertension or hypoalbuminemia
B - Renal proteinuria with renal azotemia and hypertension (with or without evidence of target organ damage), but without hypoalbuminemia
C - Renal proteinuria with renal azotemia and hypoalbuminemia (with or without any of its associated complications), which often (but not always) are accompanied by hypertension (with or without evidence of TOD)
Additional diagnostics in progressive proteinuria or UPC >3.5 +/- low albumin or azotaemia
Aim is to identify the underlying cause of disease as well as determine severity of sequelae.
CBC, Biochem, UA
2 UPCRs from at home samples - get an estimate of ongoing proteinuria
Urine culture
Blood pressure measurement - if increased look for extrarenal causes (adrenal, heart, drugs, fluid/salt overload)
If low Albumin: look for neoplasia, look for GI disease, assess liver function
Characterise progression of azotaemia if present
Ultrasound abdomen - look for renal/adrenal changes and presence of ascites
Thoracic rads - look for infiltration and effusion
Infectious disease testing: Borrelia (lyme), Leishmaniasis, HWD; Ehrlichia, Leptospirosis (IDEXX snap 4dx)as appropriate depending on geographical location
Examine oral cavity and skin for infections.
Immune mediated disease testing
When to investigate for immune mediated disease in proteinuria
1) also exhibits concurrent extrarenal clinical signs or laboratory test findings that might be explained by an immune-mediated disease (PUO; joint swelling; anaemia; thrombocytopenia; dermatological changes)
Test for auto-antibodies such as ANA; Coomb’s test; RF.
possibility that the glomerular disease actually is part of a multisystemic immune-mediated disorder (eg, systemic lupus erythematosus) becomes highly relevant, both diagnostically and therapeutically
2) patient with renal proteinuria but does not exhibit any other signs or test abnormalities that might be explained by an immune-mediated disease
no evidence available that indicates that the results of any test for the presence of autoantibodies (eg, ANA, Coombs’) that reliably differentiates those that have an immune-complex glomerulonephritis from those that do not (in dogs with proteinuria)
Considerations for renal biopsy
- provides a definitive diagnosis but is not required if an underlying cause of proteinuria is detected and treatable
-Dogs with suspected glomerular disease benefit the most from a renal biopsy before the disease has progressed to an advanced stage. Secondary fibrosis and interstitial tubulonephritis mask original glomerular disease
- Cortical tissue only and preserve samples in different fixatives
Tests run on renal biopsies
Transmission electron microscopy
–> Detects electron dense deposits and their locations in the glomerulus
–> if no EDD, focus on evaluatin of the glomerular filtration barrier
Immunostaining
–> looks for immune complex desposits (IgG, IgM, IgA, C3)
Light Microscopy
–> overall structure but unlikely to determine cause of glomerular disease
Disturbance of any of the components of the glomerular filtration barrier – loss of the endothelial glycocalyx, abnormalities/ remodelling of the GBM, electron dense deposits along the GBM, podocyte foot process fusion or podocyte loss – can result in proteinuria.
