Proteinuria and nephrotic syndrome

1
Proteinuria and nephrotic syndrome

• Hamid Moradi M.D.
• Division of Nephrology and Hypertension

2
Case- Isolated Proteinuria

• 22 yo white male without past medical history was
  noted to have 1 protein on dipstick on routine
  UA (health screening for a job)
• Denies any history of HTN or DM
• No family history of kidney disease
• No new medications or over the counter meds
• No edema on exam

3
Assessing Proteinuria

• Urinary protein excretion in the normal adult
  should be less than 150 mg/day. Can increase up
  to 300 mg with exercise.
• 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.
• Isolated proteinuria is defined as proteinuria
  without hematuria or an elevated serum creatinine
  concentration.
• 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.

4
Assessing Proteinuria

• This is different from renal disease heavy
  proteinuria (gt3 g/day), edema, active urine
  sediment with dysmorphic red cells/red cell
  casts.
• Annual screening for proteinuria is not
  cost-effective in the general population of
  healthy individuals under age 60
• routine urinalysis is recommended for high risk
  patients, including those with diabetes or
  hypertension.
• 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.

5
Assessing Proteinuria

• Types of proteinuria  
• Glomerular proteinuria  Glomerular proteinuria
  is due to increased filtration of macromolecules
  (such as albumin) across the glomerular capillary
  wall.
• Only glomerular proteinuria (albuminuria) is
  identified on dipstick. Most cases of
  persistent proteinuria are due to glomerular
  proteinuria.
• The proteinuria associated with diabetic
  nephropathy and other glomerular diseases, as
  well as more benign causes such as orthostatic or
  exercise-induced proteinuria fall into this
  category.

6
Assessing Proteinuria

• Tubular proteinuria  
• 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

7
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.
• The increased excretion of immunoglobulin light
  chains (MGUS) in tubular proteinuria is mild,
  polyclonal (both kappa and lambda), and not
  injurious to the kidney.
• This is in contrast to the monoclonal and
  potentially nephrotoxic nature of the light
  chains in the overflow proteinuria seen in
  multiple myeloma.

8
Assessing Proteinuria

• Overflow proteinuria  Increased excretion of LMW
  proteins due to marked overproduction of a
  particular protein, leading to increased
  glomerular filtration and excretion.
• 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.
• 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.

9
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.
• In addition, patients with multiple myeloma and
  Bence Jones proteinuria can also develop
  nephrotic syndrome due to AL (primary)
  amyloidosis.

10
Case

• Repeat UA on the 22 yo man revealed 1
  proteinuria on dipstick,
• How should we quantify the proteinuria?

11
Assessing Proteinuria

• The standard urine dipstick primarily detects
  albumin via a colorimetric reaction between
  albumin and tetrabromophenol blue producing
  different shades of green
• The dipstick is insensitive to the presence of
  non-albumin proteins. Thus a positive dipstick
  usually reflects glomerular proteinuria.
• Pure tubular or overflow proteinuria will not be
  diagnosed unless a 24-hour urine is collected for
  some other reason, or the urine is tested with
  sulfosalicylic acid which detects all proteins.

12
Assessing Proteinuria

• 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 gt1000 mg/dL

13
Assessing Proteinuria

• Dipstick is semiquantitative and is strongly
  influenced by the urine volume
• A high urine flow rate will lower the urine
  protein concentration by dilution but will not
  affect total protein excretion.
• The urine dipstick is highly specific, but not
  very sensitive for mild proteinuria?positive only
  when protein excretion exceeds 300- 500 mg/day.
• Thus, the standard urine dipstick is an
  insensitive method to detect initial increases gt
  150 mg/day as occurs in patients with
  microalbuminuria
• 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.

14
Assessing Proteinuria

• Sulfosalicylic acid test  In contrast to the
  urine dipstick, which primarily detects albumin,
  sulfosalicylic acid (SSA) detects all proteins in
  the urine
• 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.
• 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.

15
Assessing Proteinuria

• 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
• 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 (gt500 mg/dL

16
Assessing Proteinuria

• 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.
• 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.

17
Assessing Proteinuria

• Thus, lysozyme excretion should be measured in
  this setting, particularly if other signs of the
  nephrotic syndrome (such as edema and
  hyperlipidemia) are absent.
• 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.

18
Assessing Proteinuria

• Measurement of quantitative protein excretion  
• The quantity of protein excretion is important
  clinically for several reasons
• Most patients with benign forms of isolated
  proteinuria excrete lt1-2 g/day.
• The degree of proteinuria is prognostically
  important in patients with a primary glomerular
  dz, ie membranous nephropathy or FSGS
• Progression to renal failure most often occurs in
  patients with nephrotic range proteinuria,
• The degree of proteinuria is used to monitor the
  response to therapy, as with immunosuppressive
  drugs for primary glomerular diseases

19
Assessing Proteinuria

• Most patients with persistent proteinuria should
  undergo a 24-hour urine measurement
• 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.
• An alternative method requires only a random
  urine specimen to estimate the degree of
  proteinuria
• 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
• Thus, a ratio of 4.9 represents a daily protein
  excretion of approximately 4.9 g per 1.73 m2

20
Assessing Proteinuria

• 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.

21
Assessing Proteinuria

• Microalbuminuria  
• 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.
• 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.

22
Assessing Proteinuria

• The normal rate of albumin excretion is less than
  30 mg/day microalbuminuria persistent albumin
  excretion between 30-300 mg/day
• 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

23
Case

• 22 yo with 1 proteinuria on dipstick twice
• Protein to creatinine ratio showed 1 gm of
  proteinuria/1.73 m2 BSA
• 24 hour urine protein to creatinine ratio was the
  same

24
Assessing Proteinuria

• Approach to proteinuria  
• History and exam looking for a systemic or renal
  disease, such as diabetes mellitus or autoimmune
  disease, that could account for the proteinuria
• In these cases, management of the proteinuria is
  part of the management of the underlying
  condition.
• 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
  

25
Assessing Proteinuria

• Examination of the urine  
• The urine sediment should be examined for other
  signs of glomerular disease such as hematuria,
  red cell casts,
• Red cell casts, are virtually pathognomonic for
  glomerulonephritis.
• If the sediment is unremarkable, the differential
  diagnosis includes transient proteinuria,
  orthostatic proteinuria, and persistent
  proteinuria.
• 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.

26
Assessing Proteinuria

• Rule out transient proteinuria 
•  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
• A transient increase in protein excretion may be
  seen with fever and exercise, as well as with
  symptomatic urinary tract infection.
• 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
• These patients need no further evaluation and
  should be reassured that they do not have kidney
  disease.

27
Assessing Proteinuria

• Rule out orthostatic proteinuria  
• A split urine collection should be obtained if
  the patient is younger than age 30 and has
  documented proteinuria on more than one occasion.
  
• This test detects orthostatic proteinuria, a
  relatively common finding in adolescents
  (occurring in 2- 5), but uncommon in those over
  the age of 30
• Orthostatic proteinuria is characterized by
  increased protein excretion in the upright
  position, but normal protein excretion when the
  patient is supine.
• ? neurohumoral activation and altered glomerular
  hemodynamics
• Total protein excretion is generally less than 1
  g/day in orthostatic proteinuria, but may exceed
  3 g/day in selected patients

28
Assessing Proteinuria

• Orthostatic proteinuria is a benign condition
  requiring no further evaluation or specific
  therapy
• In many patients, the condition resolves over
  time.
• Split urines are collected
• The first morning void is discarded.
• 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.
• A separate overnight 8 hour collection is
  obtained between 11 PM and 7 AM.

29
Assessing Proteinuria

• 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.
• For this, the patient is instructed to void
  before going to bed and to remain recumbent until
  the first morning sample is obtained.
• 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.
• 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.

30
Case- Follow up

• 22 yo patient with 1 proteinuria on dipstick
• Urinary sediment negative
• Patient admitted to heavy exercise, intermittent
  use of steroids and significant intake of protein
  supplements
• Proteinuria persisted on several other exams
• Split urine samples revealed normal urine protein
  while supine
• Orthostatic proteinuria suspected although heavy
  exercise can also be contributing
• Patient warned regarding hyperfiltration
  proteinuria and advised against use of anabolic
  steroids

31
Case

• 50 year old Asian gentleman with history of
  persistent proteinuria for past 7 years referred
  to UCI Renal Clinic.
• Creatinine stable, no hematuria, no change in
  degree of proteinuria (600mg/day)
• U/S normal, serologies all negative

32
Assessing Proteinuria

• Persistent isolated proteinuria   thorough
  evaluation is warranted when isolated proteinuria
  persists.
• Usually reflects an underlying renal or systemic
  disorder.
• Underlying glomerular disease that may be primary
  (focal segmental glomerulosclerosis or membranous
  nephropathy) or secondary (diabetic nephropathy
  or hypertensive nephrosclerosis due to systemic
  hypertension).
• Renal function tests including BUN and creatinine
  should be obtained, as well as a quantitative
  measurement of urine protein excretion.
• In addition, the patients should undergo an
  ultrasound examination to rule out structural
  causes, such as reflux nephropathy or PCKD

33
Assessing Proteinuria

• All patients with persistent proteinuria should
  be referred to a nephrologist for decisions
  regarding further management (eg, renal biopsy).
• 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.
• 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.

34
Assessing Proteinuria

• The level of non-nephrotic proteinuria that
  should be evaluated by biopsy is not clear.
• ? 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
• 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.
• 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.

35
Assessing Proteinuria

• Most patients with persistent isolated
  proteinuria in the absence of decreased renal
  function or a systemic disease will have an
  indolent course.
• In one study, only 10 of such patients developed
  an elevation in plasma creatinine during a mean
  follow-up of six years.
• These observations indicate the need for
  persistent monitoring of patients with apparently
  benign, nonorthostatic, and persistent isolated
  proteinuria.
• 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.

36
Case

• Patient insisted on a biopsy
• Biopsy showed some foot processes effacement on
  EM otherwise negative
• Clinical and histopathology not consistent with
  MCD
• Biopsy nondiagnostic

37
Glomerular disease

• Three different urinary and clinical patterns
  Nephritic and nephrotic?focal nephritic, diffuse
  nephritic (RPGN)
• 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.
• 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).
• The findings of more advanced disease are usually
  absent, such as heavy proteinuria, edema,
  hypertension, and renal insufficiency.
• Often present with asymptomatic hematuria and
  proteinuria discovered on routine examination or,
  occasionally, with episodes of gross hematuria.

38
Glomerular disease

• Diffuse nephritic
• 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.
• Diffuse glomerulonephritis affects most or all of
  the glomeruli.

39
Glomerular disease

• Nephrotic
• The nephrotic sediment is associated with heavy
  proteinuria and lipiduria, but few cells or
  casts.
• The term nephrotic syndrome refers to a distinct
  constellation of clinical and laboratory features
  of renal disease.
• 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.

40
Glomerular disease

• 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
• Edema secondary to decreased oncotic pressure as
  well as albumin in tubular lumen increasing
  activity of Na/H exchanger
• Therefore need salt restriction and diuretic for
  treatment
• Hypercholestrolemia correlates with
  hypoalbuminemia
• Factor V, VIII and fibrinogen increased while X,
  XI and ATIII are decreased, platelete aggregation
  increased
• Risk of infection with encapsulated bacteria
  increased due to loss of complement factor B and
  gamma globulin? pneumococcal vaccine

41
Nephrotic syndrome

• Heavy proteinuria and the nephrotic syndrome
  associated with variety of primary and systemic
  diseases.
• Minimal change disease is the predominant cause
  in children.
• 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
• 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).
  
• Age greater than 65 years? an increased incidence
  of amyloidosis (17) and a decreased incidence of
  lupus (1).

42
Nephrotic syndrome

• 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)
• 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.
• 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.

43
Nephrotic syndrome

• 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.

44
Nephrotic syndrone

• Case
• 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

45
Nephrotic Syndrome

• 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.
• 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
• ? Related to defect in cell mediated immunity
• Tcells from MCD patients release a vascular
  permeability factor
• Lymphokine that reduces negative charge of BM and
  is toxic to the podocytes

46
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.

47
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.

48
Nephrotic syndrome

• 45 yo female with history of morbid obesity,
  hypertension admitted for CHF and diastolic
  dysfunction.
• On cardiac echo had infiltrative pattern.
• Urine with 2.5 grams of proteinuria, creatinine
  normal.
• Renal bx to rule out amyloidosis

49
Nephrotic syndrome

• Focal segmental glomerulosclerosis  
• 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)

50
Nephrotic syndrome

• 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.
• 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.

51
Nephrotic syndrome

• Primary FSGS is an epithelial cell disorder that
  may be related etiologically to minimal change
  disease.
• Mutation in genes encoding podocyte proteins
  nephrin, podocin
• 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.

52
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

53
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.

54
Nephrotic Syndrome

• 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

55
Nephrotic Syndrome

• 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

56
Nephrotic Syndrome

• 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

57
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

58
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

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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

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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.

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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.

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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.

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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, P0.06) the hazard
  ratio for worsening disease with eprodisate was
  0.58 (P0.02).
• 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 (P0.02).
• The drug had no significant effect on progression
  to end-stage renal disease (hazard ratio, 0.54
  P0.20) or risk of death (hazard ratio, 0.95
  P0.94).
• Eprodisate slows the decline of renal function in
  AA amyloidosis. N Engl J Med.   2007 Jun
  7356(23)2349-60

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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

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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

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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

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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?

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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-Wilsons 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

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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.

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Nephrotic syndrome

• Treatment is mainly aimed at controlling blood
  sugar and HgA1c less than 7
• Controlling BP with goal BP lt130/80
• 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

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