Protein-Losing Nephropathy (PLN)

Protein-losing nephropathy (PLN)

Renal disorder involving abnormal urinary protein loss due to glomerular, tubular, or interstitial injury

Primary renal structure emphasized in PLN

Glomerulus

What is the major protein lost in PLN?

Albumin

Six consequences of PLN

1.) Hypoalbuminemia

2.) Effusions

3.) Hypertension

4.) Hypercoagulability

5.) Muscle loss

6.) Progressive renal injury

Three broad etiologies of PLN

1.) Hereditary

2.) Immune-mediated

3.) Idiopathic

Proteinuria

Presence of an abnormal amount of protein in urine

Proteinuria is frequently identified _______ during routine wellness testing

incidentally

Proteinuria is both a ______ and a ______ of progressive kidney injury

Marker; contributor

Animals with PLN may remain ______ for years despite significant kidney disease

Nonazotemic

Why might animals reappear completely healthy for years before developing azotemia or other obvious signs of kidney disease?

glomerular damage and nephron loss can develop gradually, while remaining functional nephrons initially maintain an adequate GFR

Three categories of proteinuria

1.) Prerenal

2.) Renal

3.) Postrenal

Prerenal proteinuria

Proteinuria resulting from abnormalities originating outside the kidneys that increase urinary protein or alter filtration

Four major causes of prerenal proteinuria

1.) Hemoglobin or myoglobin

2.) Immunoglobulin light chains

3.) Systemic hypertension

4.) Steroids

Two pigments associated with prerenal proteinuria

1.) Hemoglobin

2.) Myoglobin

Hemoglobinuria

Presence of hemoglobin in urine, commonly associated with intravascular hemolysis

Myoglobinuria

Presence of myoglobin in urine, commonly associated with severe muscle injury

Bence-Jones proteins

Immunoglobulin light chains associated with plasma cell disorders

Systemic hypertension may increase proteinuria by increasing...

Glomerular capillary pressure

Renal proteinuria

originates from abnormalities within the kidneys themselves

Three categories of renal proteinuria

1.) Glomerular

2.) Tubular

3.) Interstitial

Glomerular proteinuria

occurs when the glomerular filtration barrier becomes damaged, allowing proteins that would normally remain in the bloodstream to enter the filtrate

Tubular proteinuria

occurs when damaged renal tubules cannot adequately reabsorb filtered proteins

Interstitial proteinuria

Proteinuria associated with injury or inflammation of the renal interstitium

Examples of potential causes of interstitial proteinuria

-Infection

-Inflammation

-Neoplasia

Postrenal proteinuria

Proteinuria caused by addition of protein to urine after it passes through the renal filtering structures

Two mechanisms producing postrenal proteinuria

1.) Hemorrhage

2.) Inflammatory exudate

Four common causes of postrenal proteinuria (cause hemorrhage or inflammatory exudate)

1.) UTI

2.) FIC

3.) Urolithiasis

4.) Neoplasia

What can falsely cause proteinuria? Why?

Traumatic cystocentesis; blood is introduced into the collected sample

Proteinuria does not automatically indicate...

Primary kidney disease

Prerenal and postrenal causes must be considered before concluding that protein loss is renal in origin

glomerulus

A ball of capillaries surrounded by Bowman's capsule; responsible for filtering blood into Bowman's space

Three layers of the normal glomerular filtration barrier

1.) Fenestrated endothelium

2.) Glomerular basement membrane

3.) Podocyte epithelium

Fenestrated endothelium

Capillary lining containing pores that allow passage of water and small solutes

Glomerular basement membrane

Specialized filtration barrier between the capillary endothelium and podocytes

Podocytes

Specialized epithelial cells with foot processes that form filtration slits

The layers of the glomerulus allow _____ and ______ to pass through while restricting _________

water; small solutes

large proteins

Mesangium

Supportive glomerular structure that helps hold glomerular capillaries together and regulates glomerular function

Permselectivity

Selective permeability of the glomerular filtration barrier based on molecular size and electrical charge

Two mechanisms of glomerular permselectivity

1.) Size selectivity

2.) Charge selectivity

Approximate molecular size restricted by the glomerular filtration barrier

Greater than 60 kDa

Electrical charge repelled by the normal glomerular filtration barrier

Negative

Based on mechanisms of glomerular permselectivity, does albumin pass the filtration barrier? Why?

No! It is too large and negatively charged

Small amounts of albumin may pass through the normal glomerular barrier, however...

The proximal tubules can reabsorb and process these small quantities

However, excessive albumin filtration can overwhelm...

Proximal tubular reabsorptive capacity

PLN develops when the normal _______ barrier is damaged or its ________ is disrupted

filtration; permselectivity

Primary glomerular abnormality in PLN

Loss of normal filtration barrier permselectivity

Damage to the glomerular filtration barrier causes increased ______ filtration

Albumin

Three major consequences of excessive protein filtration in the proximal tubules

1.) Apoptosis

2.) Inflammation

3.) Fibrosis

Apoptosis, inflammation, and fibrosis all progessively impair...

proximal tubule function, so less and less protein will be reabsorbed and more will end up in the urine

Two types of substances albumin may carry into the tubular lumen

1.) Drugs

2.) Free fatty acids

Albumin-bound substances may contribute to further renal injury through ______ damage

Oxidative

Continued protein-induced inflammation and fibrosis can eventually render individual __________ nonfunctional

nephrons

Eventually, enough functional nephrons are lost that...

GFR decreases and azotemia develops

Progression of protein-induced renal injury

Glomerular injury → proteinuria → tubular inflammation → fibrosis → nephron loss → decreased GFR

Progressive nephron loss eventually causes ______ when sufficient renal function is lost

Azotemia

PLN can be present without azotemia because...

Remaining functional nephrons initially maintain adequate GFR

Three major types of glomerular nephropathy

1.) Immune-complex glomerulonephritis

2.) Non-immune-mediated hereditary disease

3.) Amyloidosis

Immune-complex glomerulonephritis (ICGN)

Glomerular inflammation caused by deposition of antigen-antibody complexes

Pathogenesis of immune-complex glomerulonephritis

1.) Immune complexes deposit in glomerular structures

2.) Once deposited, they activate inflammatory pathways and recruit immune cells

3.) The resulting inflammation damages the filtration barrier and increases protein leakage

4.) This lead to proteinuria

Examples of underlying causes of immune-complex glomerulonephritis

1.) Heartworm disease

2.) Tick-borne diseases

3.) Neoplasia

4.) Chronic inflammation

5.) Persistent infections

Immune complexes damage glomeruli by recruiting...

Inflammatory cells

Underlying cause of immune-complex glomerulonephritis is often...

Not identified!

Treatment that may benefit selected patients with immune-complex glomerular disease

Immunosuppression

Non-immune-mediated hereditary glomerular disease

Inherited structural abnormalities of the glomerular filtration barrier

Two structures that may be abnormal in hereditary glomerular disease

1.) Basement membrane collagen

2.) Podocytes

Hereditary glomerular disease causes proteinuria because...

Abnormal filtration barrier structure impairs permselectivity

Amyloidosis

Abnormal deposition of insoluble amyloid proteins within tissues

Protein structure characteristic of amyloid

Beta-pleated sheets

Renal amyloidosis causes proteinuria by...

Disrupting normal glomerular structure and filtration barrier function, promoting proteinuria

Two breeds predisposed to amyloidosis

1.) Shar-Pei dogs

2.) Abyssinian cats

Most common early clinical presentation of PLN

Asymptomatic proteinuria detected during routine testing

Four common findings in early PLN

Initially asymptomatic!!

1.) Normal appetite

2.) Normal activity

3.) Normal physical examination

4.) Normal serum creatinine

5.) Persistent proteinuria

Seven possible findings in advanced PLN

1.) Hypoalbuminemia

2.) Effusions

3.) Subcutaneous edema

4.) Muscle loss

5.) Hypertension

6.) Azotemia

7.) Hypercoagulability

Lyme nephritis

Acute, severe immune-complex-associated glomerular injury associated with Borrelia infection

Four possible clinical findings of Lyme nephritis

1.) Fever

2.) Rapidly progressive azotemia

3.) Marked proteinuria

4.) Severe reduction in GFR

Approximate time course of severe Lyme nephritis

24-48 hours

Lyme nephritis differs from typical PLN because it progresses...

Rapidly rather than gradually

Initial screening test for proteinuria

Urinalysis

Urine dipstick

Semiquantitative screening method used to estimate urinary protein

Five dipstick protein results

1.) Negative

2.) Trace

3.) 1+

4.) 2+

5.) 3+

important limitations of urine dipsticks

originally developed for human urine and are not perfectly accurate in dogs and cats. Therefore, both false positives and false negatives can occur

Dipstick protein results should be interpreted alongside two findings

1.) Urine specific gravity

2.) Urine sediment

A small amount of protein in dilute urine may be more concerning than the same result in ______ urine

Concentrated

Ex:

USG of approximately 1.030 or lower: A 1+ protein result may justify further evaluation with a UPC

USG greater than approximately 1.040: Trace or 1+ protein may be less concerning, while 2+ protein is more likely to prompt UPC testing

Proteinuria with active urine sediment may indicate prerenal, renal, or postrenal proteinuria?

Postrenal

Urine protein-to-creatinine ratio (UPC)

Measurement of urinary protein relative to urinary creatinine used to quantify proteinuria

The Urine protein-to-creatinine ratio (UPC) helps account for differences in urine ________

concentration; performed when urinalysis suggests clinically important proteinuria

UPC formula

Urine protein concentration ÷ urine creatinine concentration

Three proteinuria classifications

1.) Nonproteinuric

2.) Borderline proteinuric

3.) Proteinuric

Nonproteinuric

UPC below 0.2 in dogs and cats

Borderline proteinuric

UPC 0.2-0.5 in dogs

UPC 0.2-0.4 in cats

Proteinuric

UPC greater than 0.5 in dogs

UPC greater than 0.4 in cats

The degree of proteinuria can provide clues about the _______ disease.

underlying

Tubular disease produces what degree of proteinuria?

relatively low-grade

Glomerular disease produces what degree of proteinuria?

high grade

Amyloidosis may produce UPC values greater than ______

8

Immune-complex glomerular disease may produce UPC values approximately between ______

2 and 14

UPC alone cannot definitively distinguish ______ from ______ proteinuria

Glomerular; tubular

Two findings that can falsely increase UPC

1.) Gross hematuria

2.) Active inflammatory urine sediment

Persistent proteinuria

Proteinuria confirmed on repeated urine testing rather than a single transient abnormal result

Recommended interval for repeating an initial abnormal urine protein result

Approximately 1-2 weeks

Three potential causes of transient proteinuria

1.) Stress

2.) Exercise

3.) Fever