R11 Proteinuria

• Glomerulus
• -restricts filtration of proteins
• -150-180L per day of free filtration
• -high selectivity of membrane (capillary wall, slit diaphragm, negative membrane charges)

*filtered proteins are often cleared by mesangial cells --> one of the reasons a lot of cases of proteinuria result in mesangial proliferation

• Tubule
• -reabsorbs most of the proteins that are filtered

*Can have proteinuria from tubular or glomerular dysfunction

• Fenestrated epithelium
• -keeps cells from filtering but not protein

• Basement Membrane
• -negative charge: glycosaminoglycans produced by foot processes
• -disease of podocytes leads to decrease in negative charge of BM

• Podocytes
• -if foot processes fuse --> areas of the capillary that are uncovered
• -also decreases the negative charge of the BM

Large proteins like immunoglobulins won't evern make it across, but albumin can

-Pima indians: develop DM2 at a very young age

-even at very early stages in disease there is a significant decrease in epithelial cell density

-there is a further reduction in the number of epithelial cells as the patients develop clinical nephropathy

• -associated with proteinuria
• -these patients have a decreased number of podocytes and an increase in foot process width (stretching to cover more area)

• -500-1000mg albumin filtered daily by the glomerulus, only 20-30mg appear in the urine
• --> reabsorbed by tubular epithelial cells

-low molecular weight proteins and peptides are freely filtered at the glomerulus and reabsorbed by the proximal tubule

-enzymes, immunoglobulins, peptide hormones (insulin, PTH) are also filtered and reabsorbed

• Mechanism of Reabsorption:
• -proteins are absorbed into tubule cells
• -they are degraded in lysosomes into amino acids
• -amino acids are absorbed back into the systemic circulation

**insulin is normally metabolized and then excreted in the proximal tubule. Patients with diabetes who get kidney disease stop filtering and metabolizing their insulin so their exogenous insulin requirement can decrease!

<150 mg/24 hrs

20-30 mg albumin

glycoproteins and immunoproteins

proteins synthesized by distal tubules cells (ie: one that is lost in the urine but also used to make the matrix of casts)

Can be due to problems with the glomerulus or with the tubules

• Glomerulus
• -altered glomerular permeability
• -increased albumin passage
• -filtration of high levels of circulating abnormal low molecular weight proteins (ie: BJ proteins in MM/amyloidosis)
• -overwhelm tubular filtration

• Tubules
• -failure to reabsorb

• 1. Interstitial Inflammation
• -proteinuria allows filtration of cytokines and chemokines
• -tubular damage also secretes molecules that cause interstitial inflammation

• 2. Tubular effects
• -cytokines and C' filtered also cause tubules to secrete activators
• -these lead to interstitial inflammation and fiborsis

Both interstitial inflammation and tubular effects lead to FIBROSIS

Fibrosis is the real indicator of renal function (vs. glomerular changes)

• 1. Qualitative
• -dipstick (only detects albumin)
• *BJ proteinuria will be negative

• 2. Quantitative
• -24 urine collection: gold standard but difficult for patient
• -protein:Cr ratio: random urine sample, reasonable ratio

If a patient has two positive dipsticks --> 24 hour urine collection

• Nephrotic Range Proteinuria (>3.5g)
• -Glomerulonephritis (Diabetic Nephropathy, MGN, FSGS, MCD, Amyloidosis, MPGN)

• Low Grade Proteinuria (150mg -3.5g)
• -R/O transient or orothostatic
• -Transient: fever, decompensated CHF, strenuous exercise (benign)
• -Orthostatic: only have proteinuria when standing (not unusual in young ppl)

• -early treatment can significantly change disease course
• -but microalbuminuria is not detectable by urine dip (need to do spot test or 24h collection)

• Microalbuminuria
• -linked to increased risk of ischemic heart disease
• -greatest risk factor for CAD (greater than dyslipidemia!)

• Proteinuria
• -level of proteinuria associated with mortality
• -CV mortality, stroke, CHD events
• -even low amounts of proteinuria are associated with significant risk of events in african americans

-aggressive detection and treatment of microalbuminuria is important

• ARB tx:
• -reduction in time to develop overt proteinuria
• -delays progression of kidney disease
• -if stop tx, proteinuria increases

• ACEI tx:
• -also viable

**as you reduce proteinuria there is a decrease in change in renal outcomes (lower protein, lower progression)

• 1. Thromboembolism
• -lose ATIII in urine (hypercoagulable)
• -if have any events will need anticoagulation as long as they are proteinuric
• -not all patients with proteinuria need anticoagulation

• 2. Tubular Dysfunction
• -tubular injury and sclerosis (due to increased tubular reabsorption of filtered protein)

• 3. Hypoalbuminemia
• -tubular catabolism of albumin

• 4. Edema
• -due to hypoalbuminemia

• 5. Increased Infections
• -increased turnover of immunoglobulins (pneumococcal)
• -reduced cellular immunity (due to increased plasma protein filtration)
• -massive amounts of edema lead to skin breakdown and "weeping"
• -most common cause of death in children with nephrotic syndrome

• 6. Hyperlipidemia
• -increased hepatic synthesis of lipoproteins

• -Control BP-ACEI or ARB tx (don't combine --> can lead to hyperkalemia)
• -low protein intake
• -low sodium intake (enhances action of ACEIs and ARBs)
• -smoking cessation
• -aldosterone antagonist tx

• -decrease systemic pressure
• -decrease glomerular permeability
• -decrease fractional mesangial volume
• -decrease extracellular matrix components
• -decrease filtration of proteins across glomerular capillary wall
• -restore BM pore size distribution
• -normalize nephrin gene expression
• -decrease MCP-1 (monocyte chemoattractant)

• -disease specific tx based on bx findings
• -glucocorticoids
• -ACEIs/ARBs
• -manage hyperlipidemia
• -anticoagulation in specific cases

-aldo antagonists have been shown to be helpful

• -fibrosis
• -collagen formation
• -inflammatory response
• -etc

• ***why Aldo blockers have beneficial effects on the heart
• --> but can cause hyperkalemia when used in kidney disease (bad for CV system)

**also lead to significant reduction in proteinuria