What are the types of proteinuria?
upper limit is 60 mg/M2 or 100 mg/day
assuming 1.5 L of urine a day, the concentration should be around 7 mg/dL
50-60% plasma proteins - 40% albumin, 9% alpha1 globulins, 2% alpha2 globulins
hormones, enzymes, glycoproteins
40-50% protein of tissue origin - uromucoid, glycoproteins, etc.
incidence of 20% in screenings
rarely indicates significant renal pathology
normally increased by exercise, stress, norepinephrine, renin, and other stimuli
observed only when the subject assumes an upright or lordotic position
may be associated with mild glomerular histological abnormalities, but there is no evidence lnking this finding with significant renal disease
present when several urine collections obtained with the subject supine at rest contain detectable protein
What are the two components to filtration?
permissive - facilitating filtration of small molecules
restrictive - retarding or preventing hte passage of larger molecules and solid elements of the blood
Describe the structure of the glomerular tuft.
Describe the structure of the glomerular filtration barrier.
inner fenestrated endothelial layer
glomerular basement membrane
visceral epithelial cells
a transmembrane protein of the immunoglobulin gene family that interacts in a homotypic fashion with nephrin molecules from an adjacent podocyte
WHat is the size cutoff for glomerular filtration?
size-selective function is called steric hindrance
What are the roles of a podocyte?
post-mitotic cell with highly specialized structure and function specific to the glomerulus
structural support for capillary
remodeling of GBM
endocytosis of filtered proteins
What are the selectivity criteria for filtration?
size (steric hindrance)
shape and deformability
hemodynamics (convection and diffusion)
diffusion vs convection across the glomerular filter
diffusion - moving down a concentration gradient, more likely in a patient who is more dehydrated
convection - being dragged across by increased filtration, more likely in a patient who has strong perfusion of fluid through the glomerular filter
a model of glomerular filtration where negatively charged molcules get into the space between the podocytes and concentrate there to a certain extent
this prevents excessive filtration of negatively charged molecules and also prevents filtration of positive molecules
How are filtered proteins reabsorbed into the plasma?
mostly reabsorbed in the proximal tubule
bindd to tubular transport proteins such as megalin, cubulin, and anmionless in clathrin-coated pits
some of this protein is pinocytosed into endocytic vesicles and degraded to constituent amino acids
other, particularly albumin, is reabsorbed intact through a poorly understood "salvage" pathway
What proteins are secreted into the urine?
uromucoid (Tamm-Horsfall protein) is added in the distal tubule
other proteins are added in the bladder and lower urinary tract, some from accessory sex glands such as the prostate in males
factors mediating autoregulation
vessel distension from tissue pressure
metabolic (buildup of vasoactive metabolites)
diversion of flow into shunt vessels
vascular remodeling (long-term)
What are some clinical modulators of glomerular macromolecule handling? What are their mechanisms?
hypertension - excessive filtration pressure, unless protected by autoregulation
fluid overload - filtration equilibrium no reached, convection "drags" protein across filtration barrier
fever, obesity - increases metabolic activity
dehydration - hemoconcentration, increased diffusion of protein
sepsis - podocyte dysfunction alters slit diaphragm structure and function
What tubular dysfunctions can lead to proteinuria?
proximal tubular dysfunction
Dent disease - proximal tubule x-linked condition, a cause of Fanconi syndrome
Fanconi syndrome (nephropathic cystinosis)
proximal renal tubular acidosis
classification sof conditions that cause proteinuria
causes of persistent proteinuria
increased glomerular permeability to plasma proteins due glomerulonephritis, primary nephrotic syndrome, and other factors such as hemodynamic factors, increased filtration fraction, and increased perfusion
decreased tubular reabsorption of filtered protein from Fanconi syndrome, Dent disease, tubulointerstitial nephritis, drugs, and toxins
overflow proteinuria from repeated albumin infusions or blood transfusions, myeloma, or leukemia as well as chronic kidney disease with decreased neprhon mass
secretory proteinuria from Tamm-Horsfall proteinuria, pyelonephritis, heavy metal poisoning, or prostate disease
histuria from urothelial carcinoma or diseases causing damage to the basement membranes
causes of intermittent proteinuria
non-renal abnormalities such as fever, stress, exercise, exposure to cold
contamination of urine - vaginal secretions
false positive test
What is the underlying pathophysiology of nephrotic syndrome?
significant loss of plasma protein in the urine leads to decreased levels of plasma proteins, peripheral edema and multiple metabolic abnormalities
these manifestations of nephrosis may represent an appropriate physiological response by the kidney to the initial changes in plasma proteins
What are the four main findings in nephrotic syndrome?
proteinuria - usually considered to be at least 3 gm/day, children 50mg/kg/day, urine protein:creatinine > 2
hypoproteinemia (hypoalbuminemia) - with a serum albumin of less than 2 gm/dL
What is the difference between nephrosis and nephritis?
nephritis has a pathologic diagnosis denoting renal inflammation - low serum albumin, peripheral edema, decreased intravascular volume, significant edema, sometimes comes with hypertension, and CXR showing normal heart with pleural fluid
nephrosis characterizes the symptom complex without any particular disease process - renal inflammation, decreased GFR, increased intravascular volume, mild edema, hypertension usually, and CXR showing cardiomegaly and pulmonary edema
What is the initiating event in the establishment of nephrosis?
urinary loss of albumin
some have decreased fractional excretion of many macromolecules
others have increased macromolecular clearance
What are the two classes of nephrotic patients?
those with mainly albuminuria
those with so much generalized proteinuria that they become hypoalbuminemic
What is the characteristic of nephrotic syndrome caused by chronic glomerulonephritis?
hyprid clearance curve - decreased clearance of smaller macromolecules and enhaced clearance of larger ones
What are the causes decreased clearance of some molecules in nephrotic syndrome?
foot process effacement - less space between the podocyte foot processes
What are the different theories why albumin levels are decreased when glomerular filtration is decreased?
effacement and loss of negative charge in the basement membrane allows albumin to be filtered
also believe that albumin being filtered can lead to loss of charge in the basement membrane
could be due to the fact that the glomerular filter is "heteroporous" where there are large pores that are more open due to disease and hemodynamics
How does renal handling of beta2-microglobulin differ between glomerular and tubular dysfunction?
protein is freely filtered by glomerulus
normally low in the plasma
glomerular dysfunction - high serum levels, low urine levels
tubular dysfunction - low serum levels, high urine levels