Transcript Proteinuria and nephrotic syndrome

Proteinuria and nephrotic
syndrome
Hamid Moradi M.D.
Division of Nephrology and Hypertension
Case- Isolated Proteinuria
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22 yo white male without past medical history was noted to
have 1+ protein on dipstick on routine UA (health screening
for a job)
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Denies any history of HTN or DM
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No family history of kidney disease
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No new medications or over the counter meds
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No edema on exam
Assessing Proteinuria
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Urinary protein excretion in the normal adult should be less than 150
mg/day. Can increase up to 300 mg with exercise.
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Higher rates of protein excretion that persist beyond a single measurement
should be evaluated?increase in glomerular permeability that allows the
filtration of normally nonfiltered macromolecules such as albumin.
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Isolated proteinuria is defined as proteinuria without hematuria or an
elevated serum creatinine concentration.
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Isolated proteinuria, the patient is asymptomatic and the presence of
proteinuria is discovered incidentally by use of a dipstick during routine
urinalysis in which the urine sediment is unremarkable.
Assessing Proteinuria

This is different from renal disease : heavy proteinuria (>3 g/day), edema,
active urine sediment with dysmorphic red cells/red cell casts.
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Annual screening for proteinuria is not cost-effective in the general
population of healthy individuals under age 60
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routine urinalysis is recommended for high risk patients, including those with
diabetes or hypertension.
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Early detection of proteinuria in high risk patients is important because the
administration of an ACEI or ARB has been shown to slow the progression
of proteinuric chronic kidney disease.
Assessing Proteinuria
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Types of proteinuria —
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Glomerular proteinuria — Glomerular proteinuria is due to increased
filtration of macromolecules (such as albumin) across the glomerular
capillary wall.
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Only glomerular proteinuria (albuminuria) is identified on dipstick. Most
cases of persistent proteinuria are due to glomerular proteinuria.
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The proteinuria associated with diabetic nephropathy and other glomerular
diseases, as well as more benign causes such as orthostatic or exerciseinduced proteinuria fall into this category.
Assessing Proteinuria
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Tubular proteinuria —
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Low molecular weight proteins — such as ß2-microglobulin,
immunoglobulin light chains, retinol-binding protein, and amino acids —
have a molecular weight that is generally under 25,000 D in comparison
to the 69,000 molecular weight of albumin.

These smaller proteins can be filtered across the glomerulus and are then
almost completely reabsorbed in the proximal tubule.

Interference with proximal tubular reabsorption, due to a variety of
tubulointerstitial diseases or even some primary glomerular diseases, can
lead to increased excretion of these smaller proteins
Assessing Proteinuria

Tubular proteinuria is often not diagnosed clinically since the dipstick for
protein does not detect proteins other than albumin and the quantity
excreted is relatively small.
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The increased excretion of immunoglobulin light chains (MGUS) in
tubular proteinuria is mild, polyclonal (both kappa and lambda), and not
injurious to the kidney.
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This is in contrast to the monoclonal and potentially nephrotoxic nature of
the light chains in the overflow proteinuria seen in multiple myeloma.
Assessing Proteinuria
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Overflow proteinuria — Increased excretion of LMW proteins due to
marked overproduction of a particular protein, leading to increased
glomerular filtration and excretion.
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Almost always due to immunoglobulin light chains MM, but may also be
due to lysozyme (in acute myelomonocytic leukemia), myoglobin (in
rhabdomyolysis), or hemoglobin (in intravascular hemolysis)

In these settings, the filtered load exceeds the normal proximal
reabsorptive capacity.
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Patients with myeloma kidney also may develop a component of tubular
proteinuria, since the excreted light chains may be toxic to the tubules,
leading to diminished reabsorption.
Assessing Proteinuria

Some patients have mixed forms of proteinuria. As an example,
glomerular diseases such as focal segmental glomerulosclerosis can be
associated with proximal tubular injury, leading to tubular proteinuria.
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In addition, patients with multiple myeloma and Bence Jones proteinuria
can also develop nephrotic syndrome due to AL (primary) amyloidosis.
Case
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Repeat UA on the 22 yo man revealed 1+ proteinuria on dipstick,
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How should we quantify the proteinuria?
Assessing Proteinuria
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The standard urine dipstick primarily detects albumin via a colorimetric
reaction between albumin and tetrabromophenol blue producing different
shades of green
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The dipstick is insensitive to the presence of non-albumin proteins. Thus a
positive dipstick usually reflects glomerular proteinuria.
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Pure tubular or overflow proteinuria will not be diagnosed unless a 24hour urine is collected for some other reason, or the urine is tested with
sulfosalicylic acid which detects all proteins.
Assessing Proteinuria
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Proteinuria on the urine dipstick is graded from 1+ to 4+, which reflects
the urine albumin concentration:
Negative
Trace — between 15 and 30 mg/dL
1+ — between 30 and 100 mg/dL
2+ — between 100 and 300 mg/dL
3+ — between 300 and 1000 mg/dL
4+ — >1000 mg/dL
Assessing Proteinuria
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Dipstick is semiquantitative and is strongly influenced by the urine
volume
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A high urine flow rate will lower the urine protein concentration by
dilution but will not affect total protein excretion.
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The urine dipstick is highly specific, but not very sensitive for mild
proteinuriapositive only when protein excretion exceeds 300- 500
mg/day.
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Thus, the standard urine dipstick is an insensitive method to detect initial
increases > 150 mg/day as occurs in patients with microalbuminuria
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False-positive urine dipstick results are common with many iodinated
radiocontrast agents  the urine should not be tested for protein with the
standard dipstick for at least 24 hours after a contrast study.
Assessing Proteinuria
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Sulfosalicylic acid test — In contrast to the urine dipstick, which
primarily detects albumin, sulfosalicylic acid (SSA) detects all proteins in
the urine
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Use of sulfosalicylic acid is primarily indicated in patients who present
with acute renal failure, a benign urinalysis, and a negative or trace
dipstick, a setting in which myeloma kidney should be excluded.
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A significantly positive sulfosalicylic acid test (SSA) in conjunction with
a negative dipstick usually indicates the presence of nonalbumin proteins
in the urine, most often immunoglobulin light chains.
Assessing Proteinuria
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The sulfosalicylic acid (SSA) test is performed by mixing one part urine
supernatant (eg, 2.5 mL) with three parts 3% sulfosalicylic acid, and
grading the resultant turbidity
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0 = no turbidity (0 mg/dL)
trace = slight turbidity (1 to 10 mg/dL)
1+ = turbidity through which print can be read (15 to 30 mg/dL)
2+ = white cloud without precipitate through which heavy black lines on a
white background can be seen (40 to 100 mg/dL)
3+ = white cloud with fine precipitate through which heavy black lines
cannot be seen (150 to 350 mg/dL)
4+ = flocculent precipitate (>500 mg/dL
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Assessing Proteinuria
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Similar to the standard urine dipstick, the SSA test will also record false
positive results in the presence of many of the commonly used iodinated
radiocontrast agents.
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Protein excretion may be overestimated by as much as 1.5 to 2 g/L
the urine should not be tested for protein for at least 24 hours
aftercontrast
Both the dipstick and sulfosalicylic acid test will detect urinary lysozyme,
the production and excretion of which may be increased in patients with
acute leukemia.
Assessing Proteinuria
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Thus, lysozyme excretion should be measured in this setting, particularly
if other signs of the nephrotic syndrome (such as edema and
hyperlipidemia) are absent.
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The results with the dipstick and SSA serve as only a rough guide of the
degree of protein excretion since urine concentration will affect the
measurement. A dilute urine, for example, will underestimate the degree
of proteinuria.
Assessing Proteinuria
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Measurement of quantitative protein excretion —
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The quantity of protein excretion is important clinically for several
reasons:
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Most patients with benign forms of isolated proteinuria excrete <1-2
g/day.
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The degree of proteinuria is prognostically important in patients with a
primary glomerular dz, ie membranous nephropathy or FSGS
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Progression to renal failure most often occurs in patients with nephrotic
range proteinuria,
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The degree of proteinuria is used to monitor the response to therapy, as
with immunosuppressive drugs for primary glomerular diseases
Assessing Proteinuria
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Most patients with persistent proteinuria should undergo a 24-hour urine
measurement
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This can be cumbersome in ambulatory care settings specially if serial
monitoring of protein excretion is used as a guide to the efficacy of
therapy.
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An alternative method requires only a random urine specimen to estimate
the degree of proteinuria
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This test calculates the total protein-to-creatinine ratio (mg/mg). This
ratio correlates with daily protein excretion expressed in g per 1.73m2 of
BSA
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Thus, a ratio of 4.9 represents a daily protein excretion of approximately
4.9 g per 1.73 m2
Assessing Proteinuria
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Calculating the spot urine protein-to-creatinine ratio is much easier for the
patient and closely correlates with a wide range of levels of proteinuria
It is particularly valuable for serial monitoring of protein excretion.
Assessing Proteinuria
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Microalbuminuria —
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The urine dipstick is highly specific, becomes positive only when protein
excretion exceeds 300 to 500 mg/day but not very sensitive for the
detection of initial increases in protein excretion above the upper limit of
normal of 150 mg/day.
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Thus, the standard urine dipstick is an insensitive method to detect
microalbuminuria, which is the earliest clinical manifestation of diabetic
nephropathy and, in patients without diabetes, is a marker of increased
cardiovascular risk.
Assessing Proteinuria
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The normal rate of albumin excretion is less than 30 mg/day;
microalbuminuria = persistent albumin excretion between 30-300 mg/day
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Dipsticks are available that detect the urine albumin concentration in this
range, but the preferred test for diagnosis and monitoring is the urine
albumin-to-creatinine ratio, which is the similar in concept to the urine
protein-to-creatinine ratio
Case
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22 yo with 1+ proteinuria on dipstick twice
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Protein to creatinine ratio showed 1 gm of proteinuria/1.73 m2 BSA
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24 hour urine protein to creatinine ratio was the same
Assessing Proteinuria
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Approach to proteinuria —
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History and exam looking for a systemic or renal disease, such as diabetes
mellitus or autoimmune disease, that could account for the proteinuria
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In these cases, management of the proteinuria is part of the management
of the underlying condition.
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A careful medical history may reveal a cause for proteinuria, such as
diabetes mellitus or a prior history of renal disease. Poststreptococcal
glomerulonephritis, for example, may be associated with persistent
proteinuria years after recovery from the acute episode, a possible
reflection of some irreversible glomerular damage
Assessing Proteinuria
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Examination of the urine —
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The urine sediment should be examined for other signs of glomerular
disease such as hematuria, red cell casts,
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Red cell casts, are virtually pathognomonic for glomerulonephritis.
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If the sediment is unremarkable, the differential diagnosis includes
transient proteinuria, orthostatic proteinuria, and persistent proteinuria.
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The urine dipstick should be repeated on at least one other visit. If these
subsequent tests are negative for protein, the likely diagnosis is transient
proteinuria.
Assessing Proteinuria
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Rule out transient proteinuria —
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Transient proteinuria is common, occurring in 4% of men and 7% of
women on a single examination, with resolution on subsequent
examinations in almost all patients
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A transient increase in protein excretion may be seen with fever and
exercise, as well as with symptomatic urinary tract infection.
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With marked exercise, protein excretion can exceed 2 g/day and excretion
of both albumin and LMW proteins is increased, suggesting both an
increase in glomerular permeability and a reduction in proximal
reabsorption
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These patients need no further evaluation and should be reassured that
they do not have kidney disease.
Assessing Proteinuria
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Rule out orthostatic proteinuria —
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A split urine collection should be obtained if the patient is younger than
age 30 and has documented proteinuria on more than one occasion.
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This test detects orthostatic proteinuria, a relatively common finding in
adolescents (occurring in 2- 5%), but uncommon in those over the age of
30
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Orthostatic proteinuria is characterized by increased protein excretion in
the upright position, but normal protein excretion when the patient is
supine.
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? neurohumoral activation and altered glomerular hemodynamics
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Total protein excretion is generally less than 1 g/day in orthostatic
proteinuria, but may exceed 3 g/day in selected patients
Assessing Proteinuria
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Orthostatic proteinuria is a benign condition requiring no further
evaluation or specific therapy
In many patients, the condition resolves over time.
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Split urines are collected :
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The first morning void is discarded.
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A 16-hour upright collection is obtained between 7 AM and 11 PM, with
the patient performing normal activities and finishing the collection by
voiding just before 11 PM.
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A separate overnight 8 hour collection is obtained between 11 PM and 7
AM.
Assessing Proteinuria
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You can also do the protein-to-creatinine (Pr/Cr) ratio on a first morning
spot urine specimen and on a specimen collected while upright.
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For this, the patient is instructed to void before going to bed and to remain
recumbent until the first morning sample is obtained.
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A normal Pr/Cr ratio on the first morning void and dipstick-positive
proteinuria with an elevated Pr/Cr ratio on a second specimen collected
while the patient is upright indicates orthostatic proteinuria.
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The diagnosis of orthostatic proteinuria requires that protein excretion be
normal when supine (less than 50 mg per 8 hours), not merely less than
when in the upright position.
Case- Follow up
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22 yo patient with 1+ proteinuria on dipstick
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Urinary sediment negative
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Patient admitted to heavy exercise, intermittent use of steroids and
significant intake of protein supplements
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Proteinuria persisted on several other exams
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Split urine samples revealed normal urine protein while supine
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Orthostatic proteinuria suspected although heavy exercise can also be
contributing
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Patient warned regarding hyperfiltration proteinuria and advised
against use of anabolic steroids
Case
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50 year old Asian gentleman with history of persistent proteinuria for past
7 years referred to UCI Renal Clinic.
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Creatinine stable, no hematuria, no change in degree of proteinuria
(600mg/day)
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U/S normal, serologies all negative
Assessing Proteinuria
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Persistent isolated proteinuria — thorough evaluation is warranted when
isolated proteinuria persists.
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Usually reflects an underlying renal or systemic disorder.
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Underlying glomerular disease that may be primary (focal segmental
glomerulosclerosis or membranous nephropathy) or secondary (diabetic
nephropathy or hypertensive nephrosclerosis due to systemic
hypertension).
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Renal function tests including BUN and creatinine should be obtained, as
well as a quantitative measurement of urine protein excretion.
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In addition, the patients should undergo an ultrasound examination to rule
out structural causes, such as reflux nephropathy or PCKD
Assessing Proteinuria
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All patients with persistent proteinuria should be referred to a nephrologist
for decisions regarding further management (eg, renal biopsy).
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A renal biopsy is performed if there is some sign of severe or progressive
disease, such as nephrotic syndrome, increasing protein excretion, or an
elevation in the plasma creatinine concentration.
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By contrast, biopsies are often not performed among patients with stable
non-nephrotic proteinuria, providing renal function is stable and
hematuria is not present, since knowledge of histology obtained by the
biopsy is unlikely to alter therapy.
Assessing Proteinuria
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The level of non-nephrotic proteinuria that should be evaluated by biopsy
is not clear.
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? perform a biopsy in patients with non-nephrotic proteinuria of 2 to 3
g/day but not for proteinuria that is less than one g/day
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If a patient with proteinuria greater than one g/day is reluctant to undergo
biopsy, absolute indications include increasing proteinuria or plasma
creatinine concentration, or a significant elevation in blood pressure over
baseline values.
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PROGNOSIS — The prognosis of patients with glomerular proteinuria is
related to the quantity of protein excreted. Non-nephrotic proteinuria (less
than 3 g/day) is associated with a much lower risk of progressive chronic
kidney disease than nephrotic range proteinuria.
Assessing Proteinuria
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Most patients with persistent isolated proteinuria in the absence of
decreased renal function or a systemic disease will have an indolent
course.
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In one study, only 10% of such patients developed an elevation in plasma
creatinine during a mean follow-up of six years.
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These observations indicate the need for persistent monitoring of patients
with apparently benign, nonorthostatic, and persistent isolated proteinuria.
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Those with evidence of progressive disease (either increasing proteinuria
or rising plasma creatinine concentration) may benefit from therapy with
an angiotensin converting enzyme inhibitor or angiotensin II receptor
blocker.
Case
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Patient insisted on a biopsy
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Biopsy showed some foot processes effacement on EM otherwise
negative
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Clinical and histopathology not consistent with MCD
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Biopsy nondiagnostic
Glomerular disease
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Three different urinary and clinical patterns: Nephritic and
nephroticfocal nephritic, diffuse nephritic (RPGN)
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Focal nephritic — Disorders resulting in a focal nephritic sediment are
generally associated with inflammatory lesions in less than one-half of
glomeruli on light microscopy.
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The urinalysis reveals red cells (which often have a dysmorphic
appearance), occasionally red cell casts, and mild proteinuria (usually less
than 1.5 g/day).
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The findings of more advanced disease are usually absent, such as heavy
proteinuria, edema, hypertension, and renal insufficiency.
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Often present with asymptomatic hematuria and proteinuria discovered on
routine examination or, occasionally, with episodes of gross hematuria.
Glomerular disease
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Diffuse nephritic —
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The urinalysis in diffuse glomerulonephritis is similar to focal disease, but
heavy proteinuria (which may be in the nephrotic range), edema,
hypertension, and/or renal insufficiency may be observed.
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Diffuse glomerulonephritis affects most or all of the glomeruli.
Glomerular disease
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Nephrotic —
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The nephrotic sediment is associated with heavy proteinuria and lipiduria,
but few cells or casts.
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The term nephrotic syndrome refers to a distinct constellation of clinical
and laboratory features of renal disease.
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It is specifically defined by the presence of heavy proteinuria (protein
excretion greater than 3.5 g/24 hours), hypoalbuminemia (less than 3.0
g/dL), and peripheral edema. Hyperlipidemia, hypertension and
thrombotic disease are also frequently observed.
Glomerular disease
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Isolated heavy proteinuria without edema is an important clinical
distinction heavy proteinuria in patients without edema or
hypoalbuminemia is more likely to be due to secondary FSGS
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Edema secondary to decreased oncotic pressure as well as albumin in
tubular lumen increasing activity of Na/H+ exchanger
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Therefore need salt restriction and diuretic for treatment
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Hypercholestrolemia correlates with hypoalbuminemia
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Factor V, VIII and fibrinogen increased while X, XI and ATIII are
decreased, platelete aggregation increased
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Risk of infection with encapsulated bacteria increased due to loss of
complement factor B and gamma globulin pneumococcal vaccine
Nephrotic syndrome
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Heavy proteinuria and the nephrotic syndrome associated with variety of
primary and systemic diseases.
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Minimal change disease is the predominant cause in children.
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In adults, approximately 30% have a systemic disease such as diabetes
mellitus, amyloidosis, or systemic lupus erythematosus; the remaining
cases are usually due to primary renal disorders such as minimal change
disease, focal segmental glomerulosclerosis, and membranous
nephropathy
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European study patients 15-65 years of age, membranous nephropathy
(24%), minimal change disease (16%), lupus (14%), FSGS (12%), MPGN
(7%), amyloidosis (6%), and IgA nephropathy (6%).
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Age greater than 65 years an increased incidence of amyloidosis (17%)
and a decreased incidence of lupus (1%).
Nephrotic syndrome
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A study of 233 renal biopsies performed 1995-1997 at the University of
Chicago in adults (in the absence of an obvious underlying disease such as
diabetes mellitus or lupus) found the major causes to be membranous
nephropathy and FSGS (33% each), minimal change disease (15%), and
amyloidosis (4% overall, but 10% in patients over age 44)
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The main change over time (compared to 1976-1979) was a marked
increase in frequency of FSGS (35 versus 15%), particularly in black
patients in whom it accounted for more than 50% of cases.
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Similar findings were noted in a report from Springfield, Massachusetts
Over time, the relative frequency of membranous nephropathy fell from
38 to 15%, while the frequency of FSGS increased from 14 to 25%
overall; this increase was primarily seen in black and Hispanic patients.
Nephrotic syndrome
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Nephrotic syndrome can also develop in patients with postinfectious
glomerulonephritis, MPGN, and IgA nephropathy. However, these
individuals typically have a "nephritic" type of urinalysis with hematuria
and cellular (including red cell) casts as a prominent feature.
Nephrotic syndrone
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Case
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9 yo boy presenting with edema and significant proteinuria (around 9 gms
per day)
No family history of kidney disease
Biopsy is completely normal on light microscopy and IF is not very
specific
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Nephrotic Syndrome
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Minimal change disease — Minimal change disease (also called nil
disease or lipoid nephrosis) accounts for 90% of cases of the nephrotic
syndrome in children under the age of 10 (peak age 2-3), and more than
50% of cases in older children, 10-15% in adults.
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It also may occur in adults as an idiopathic condition, in association with
the use of NSAIDS, or as a paraneoplastic effect of malignancy, most
often Hodgkin lymphoma. Also seen after treatment of melanoma with
IFN beta
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? Related to defect in cell mediated immunity
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Tcells from MCD patients release a vascular permeability factor
Lymphokine that reduces negative charge of BM and is toxic to the
podocytes
Nephrotic syndrome

The terms minimal change and nil disease reflect the observation that light
microscopy in this disorder is either normal or reveals only mild
mesangial cell proliferation.

Immunofluorescence and light microscopy typically show no evidence of
immune complex deposition.

The characteristic histologic finding in minimal change disease is diffuse
effacement of the epithelial cell foot processes on electron microscopy.

IF with some IgM and C3 deposit, heavy IgM deposit associated with
mesangial hypercellularity has a worse prognosis.
Nephrotic syndrome

Hematuria may be seen although it is not common

Trearment usually involves steroids, relapses are common may be
provoked by a URI

Steroid resistant disease or frequent relapsers can be treated with cytoxan
or CNI.
Nephrotic syndrome
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45 yo female with history of morbid obesity, hypertension admitted for
CHF and diastolic dysfunction.
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On cardiac echo had infiltrative pattern.
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Urine with 2.5 grams of proteinuria, creatinine normal.
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Renal bx to rule out amyloidosis
Nephrotic syndrome
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Focal segmental glomerulosclerosis —
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Focal segmental glomerulosclerosis (FSGS) accounts for 35% of all cases
of nephrotic syndrome in the U.S. and over 50% of cases among blacks

FSGS is characterized on light microscopy by the presence in some but
not all glomeruli (hence the name focal) of segmental areas of mesangial
collapse and sclerosis

FSGS can present as an idiopathic syndrome (primary FSGS) or may be
associated with HIV infection, reflux nephropathy, healed previous
glomerular injury, an idiosyncratic reaction to NSAIDs, or morbid
obesity, chronic transplant rejection, Heroin nephropathy.

50-60% of patients reach ESRD withing ten years although depending on
type this is variable (HIVAN withing 2 years)
Nephrotic syndrome
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There are three important diagnostic concerns in FSGS:
Sampling error
Distinguishing primary and secondary FSGS
Identifying FSGS associated with collapsing glomerulopathy.

Sampling error can easily lead to misclassification of a patient with FSGS
as having minimal change disease.
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Clinical features that are seen in FSGS are hematuria, hypertension, and
decreased renal function. There is, however, substantial overlap in these
features. 30% only have proteinuria.

In addition to careful review of the renal biopsy, steroid-resistance in a
patient considered to have minimal change disease should raise suspicion
about FSGS.
Nephrotic syndrome
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Primary FSGS is an epithelial cell disorder that may be related
etiologically to minimal change disease.

Mutation in genes encoding podocyte proteins nephrin, podocin
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In addition, as noted above, FSGS can occur as a secondary response to
nephron loss (as in reflux nephropathy) or previous glomerular injury.

Differentiating primary and secondary FSGS has important therapeutic
implications.

The former may respond to immunosuppressive agents such as
corticosteroids, while secondary disease is best treated with modalities
aimed at lowering the intraglomerular pressure, such as angiotensin
converting enzyme inhibitors.
Nephrotic syndrome

The distinction between primary and secondary FSGS can usually be
made from the history (such as one of the disorders associated with
secondary disease) and the rate of onset and degree of proteinuria.

Patients with primary FSGS typically present with the acute onset of the
nephrotic syndrome, whereas slowly increasing proteinuria and renal
insufficiency over time are characteristic of the secondary disorders.

The proteinuria in secondary FSGS is often nonnephrotic; even when
protein excretion exceeds 3 to 4 g/day, both hypoalbuminemia and edema
are unusual
Nephrotic syndrome

Collapsing FSGS is a histologic variant that is usually but not always
associated with HIV infection.

Two major features distinguish it : a tendency to collapse and sclerosis of
the entire glomerular tuft, rather than segmental injury; and often severe
tubular injury with proliferative microcyst formation and tubular
degeneration

These patients often have rapidly progressive renal failure and optimal
therapy is uncertain.
Nephrotic Syndrome
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Primary FSGS will need to be treated with 6-9 mos of steroids

Steroid resistant cases are treated with MMF, CSA or cytoxan

Factors associated with poor prognosis are persistent high grade
proteinuria, extent of TIN, degree of glomerulosclerosis, higher creatinine,
AA race, lack of response to steroids

30% recurrence rate in transplanted kidney rapid progression and
higher degree proteinuria
Nephrotic Syndrome
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Mesangial proliferative GN

Microscopic hematuria or proteinuria, occasional nephrotic syndrome

ACEI/ARB

Steroids then CSA if no response

IgM deposition and lack of response to steroid are a bad sign
Nephrotic Syndrome
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57 yo Caucasian male with history of hypertension and COPD presented
with elevated creatinine 4-5 mg/dL for the past year or so
Significant proteinuria at 6 gms/day
Serologies are all negative
Renal biopsy performed
Membranous nephropathy
Nephrotic syndrome

Membranous nephropathy —

Membranous nephropathy most common cause of primary nephrotic
syndrome in Caucasians.

It is characterized by basement membrane thickening with little or no
cellular proliferation or infiltration, and the presence of electron dense
deposits across the glomerular basement membrane

Membranous nephropathy is most often idiopathic in adults and secondary
in children, although it can be associated with hepatitis B antigenemia,
autoimmune diseases, thyroiditis, carcinoma, and the use of certain drugs
such as gold, penicillamine, captopril, and NSAIDs.

In patients over age of 50 there is 20% association with malignancy
therefore colon CA, lung CA, breast CA etc need to be ruled out
Nephrotic Syndrome

Patient with primary membranous 1/3 spontaneously go into remission
(so follow for 6 months before treating), 1/3 remain stable (creat and
proteinuria) and 1/3 progress

Treat the 1/3 that progress with Ponticelli protocol (6 months of
steroid/cytoxan alternating)

Relapsers are treated with Rituxan and CNI
Nephrotic Syndrome





46 yo hispanic male referred to
LBVA for proteinruia, has
significant edema and pleural
effusions
Albumin 2.2, urine with 10 gms
protein per day
Serologies negative
Patient progressed to
hemodialysis, also found to have
CHF with EF 15% (nonischemic)
Renal biopsy showed congo red
positive stain
Nephrotic syndrome

Amyloidosis —

amyloidosis accounts for 4 to 17% of cases of seemingly idiopathic
nephrotic syndrome, with the increased infrequency observed among
older individuals

There are two major types of renal amyloidosis: AL or primary amyloid,
which is a light chain dyscrasia in which fragments of monoclonal light
chains form the amyloid fibrils; and AA or secondary amyloidosis, in
which the acute phase reactant serum amyloid A forms the amyloid fibrils.

AA amyloid is associated with a chronic inflammatory disease such as
rheumatoid arthritis or osteomyelitis.

The diagnosis is suspected by a history of a chronic inflammatory disease
or, with primary disease, detection of a monoclonal paraprotein in the
serum or urine.
Nephrotic syndrome

AL amyloid- cardiac disease, renal dysfunction and interstitial fibrosis are
associated with a poor outcome

Treatment consists of chemotherpay to reduce light chain production

Melphelan and prednisone are the commonly used combination

Best results in patients treated with melphelan and bone marrow
transplantation

AA amyloid- treat the underlying cause of inflammation. Colchicine in
patients with FMF.
Nephrotic syndrome

AA amyloid- treat the underlying cause of inflammation. Colchicine in
patients with FMF.

Eprodisate is a member of a new class of compounds designed to interfere
with interactions between amyloidogenic proteins and
glycosaminoglycans and thereby inhibit polymerization of amyloid fibrils
and deposition of the fibrils in tissues.
Nephrotic syndrome

randomized, double-blind, placebo-controlled trial AA amyloidosis and kidney
involvement.

Assigned 183 patients to receive eprodisate or placebo for 24 months.
At 24 months, disease was worsened in 24 of 89 patients on eprodisate (27%) and
38 of 94 patients on placebo (40%, P=0.06); the hazard ratio for worsening
disease with eprodisate was 0.58 (P=0.02).
The mean rates of decline in creatinine clearance were 10.9 and 15.6 ml per
minute per 1.73 m(2) of body-surface area per year in the eprodisate and the
placebo groups, respectively (P=0.02).
The drug had no significant effect on progression to end-stage renal disease
(hazard ratio, 0.54; P=0.20) or risk of death (hazard ratio, 0.95; P=0.94).
Eprodisate slows the decline of renal function in AA amyloidosis. N Engl J
Med. 2007 Jun 7;356(23):2349-60




Nephrotic syndrome

Monoclonal immunoglobulin deposition disease

Deposition of light chain, heavy chains or both in a variety of organs
including the kidney

LCDD- immunoglobulin light chains deposit in the glomerulus and do not
form fibrils

Most deposits are derived from the constant region of kappa light chains

Paraprotein detected in plasma and urine by immunofixation in 85% cases
Nephrotic syndrome



Most common presentation is nephrotic syndrome, HTN and decreased
GFR
Light microscopy with mesangial nodules, may have dense deposits
IF positive for light chains in the glomerulus and basement membrane

Subset of patients have cast nephropathy
Overall prognosis is poor if renal failure present

Some patients respond to melphalan and prednisone

Heavy chain deposition disease has a similar presentation except has
heavy chain deposition in glomerulus and basement membrane

Nephrotic syndrome

Lupus nephritis- six WHO classes

Class V is membranous nephropathy and is associated with nephrotic
syndrome

Very similar to other forms of membranous with similar treatment and
prognosis

There is a class IV + class V variety which has the worst prognosis and
poorly responds to treatment
Nephrotic syndrome




45yo hispanic female with history of hypertension and diabetes for 10
years, both poorly controlled, ? history of DR, proteinuria and elevated
creatinine
Protein to creatinine ratio is 10 gms per day, also has significant edema,
low albumin at 2 gm/L and severe hypertension
Serologies are all negative
Renal biopsy done
Nephrotic syndrome






Diabetic nephropathy
Most common cause of nephrotic syndrome and ESRD in the U.S.
Patients with type I diabetes and nephropathy have 50X increased risk of
mortality
Risk of nephropathy peaks after 20years of living with disease and then
decreases
Nodular glomeruosclerosis known as kimmelstiel-Wilson’s disease
Time of initial diagnosis first decade marked by glomerular
hyepertrophy and hyperfiltration glomerulopathy in the absence of
clinical disease (microalbuminuria clinically evident disease with
dipstick + proteinuria, HTN and decreased GFR ESRD
Nephrotic syndrome

Five stages of DN are well characterized in typeI

They are similar in patients with type II except with one difficulty time
of onset of type II is usually not as distinct

In type I diabetes, presence of retinopathy correlates with nephropathy
almost 100% of patients of the time

In type II diabetes 2/3 of patients with retinopathy have nephropathy,
therefore absence of retinopathy does not rule out nephropathy

Presents with proteinuria, occasional hematuria will need full work up.
However most common cause of microscopic hematuria is DN.
Nephrotic syndrome





Treatment is mainly aimed at controlling blood sugar and HgA1c less than
7
Controlling BP with goal BP <130/80
ACEI or ARB to decrease intraglomerular pressure
Decreasing cardiovascular risk factors
Aggressive BP and BS management is aimed at decreasing proteinuria
and hence slowing down/cessation of progression of disease