The document outlines a seminar on nephrotic syndrome, presented by Dr. Getasew G., covering definitions, clinical presentations, complications, investigations, and management of the syndrome with specific focus on types like minimal change disease, focal segmental glomerulosclerosis, and secondary causes. It details mechanisms behind proteinuria, metabolic consequences, potential complications such as infections and kidney injury, and approaches for treatment and management of the condition. The outline includes a comprehensive examination of diagnostic tests, management strategies for proteinuria and hyperlipidemia, and specific treatment protocols including steroid therapy for minimal change disease.

1. SEMINAR ON
NEPHROTIC SYNDROME
Presenter: Dr Getasew G. ( IMR 1)
Moderator: Dr Workagegnehu Hailu.
(Consultant Internist, Nephrologist)
October 2024

2. Out line
Definations
General clinical presentation and pathogenesis
Complications of NS
General investigations
General managment of NS
Spacific deases of NS
MCD
FSGS
MN
secondary types of NS

3. Definations
 Nephrotic syndrome is pathognomonic of glomerular diseaes with a
characteristic pentad .
 Proteinuria: adult >3.5 g/day; child >40mg/h/m2
 Hypoalbuminemia <3.5g/dL
 Edema
 Hypercholesterolemia
 Lipiduria
 Not all patients will have full pentad; some have
 a normal serum albumin and no edema.; increase in albumin
synthesis in response to heavy proteinuria
 has preserved renal function, but if left untreated,in many
progressive kidney failure will become superimposed

4. Mechanisms of proteinuria
 Normally, negatively charged proteins
repelled by the negatively charged proteins in
the
 sialoglycoproteins and
 heparan sulfate proteoglycans
 size barrier in the glomerular basement
membrane (GBM) and at the slit diaphragm
so that only small amounts of albumin pass
into the urinary space.
 In most proteinuric states, the podocytes are
injured,

5. Result from:
Podocyte damage
Slit diaphragm defects
Changes in the glomerular
endothelium
Changes in the GBM and
altered
electrical forces across the GBM.
Severe albuminuria reflects a
glomerular defect.

6.  Normal urine protein excretion is
 < 150 mg/24 h,
 20 to 30 mg of albumin,
 10 to 20 mg of LMWP that undergo glomerular filtration.
 40 to 60 mg of secreted proteins (e.g.Tamm-Horsfall, IgA).
 Protien to Creatinine ratio less than 200mg/g( 0.2mg/mg)
 microal buminuria( mederatly increased protien uria)
 excretion rate of 30 to 300 mg per day
 albumin-to-creatinine (gram/gram) ratio of 0.03 to 0.3.
 Proteinuria is identified and quantified by
 dipstick testing.
 by assay in timed urine collections.

7. types of protien uria
 Overflow Proteinuria
 Tubular Proteinuria
 Glomerular Proteinuria
 Functional proteinuria
 Orthostatic proteinuria.
 Fixed nonnephrotic proteinuria.

8. Etiology

9. causes of nephrotic syndrome

10. clinical manifestation
Hypoalbuminemia
consequence of urinary losses
blunted liver response
The increase in protein synthesis
in response to proteinuria;
large molecules are not lost in
urine and will increase in plasma,
whereas smaller proteins will enter
urine and will decrease in plasma.

11. Edema
A. low serum albumin
 stimulation of the RAS system
B. activation of the (ENaC) by proteolytic
enzymes
 hypertension
 transudation of fluid into the
extracellular space and edema
 bilateral periorbital on the morning, often
dependent may be mild or severe,
presenting as anasarca with pleural effusions
and ascites.
 signs of hypovolumia
hypotension
cold extrimity
oliguria
urine color change

13. Hypercoagulability
 venous thromboembolism common at
any site, but spontaneous arterial
thrombosis may rarely occur
high risk
 membranous nephropathy
 serum albumin < 2 g/dL.
 Risk of TE event increases by 2x
for every 1gm/dl drop of albumin
from 2.8gm/dl

14. con”d
DVT:
 Most common TE event in nephrotic patients (lowe extremities)
Renal vein thrombosis
 an important complication presents clinically in up to 8% of nephrotic
patients; .
 Symptoms fank pain and hematuria; rarely, AKI can occur if the
thrombosis is bilateral.
PE:
 Seen with/out evidence of DVT or RVT
 Prevalence of asymptomatic PE: 20-30% of NS patients
 Symptomatic PE: higher than general population

15. Metabolic Consequences of Nephrotic Syndrome
Negative Nitrogen Balance
 Nephrotic syndrome is a wasting illness,with Loss of 10% to 20% of lean
body mass
 increased in response to the tubular catabolism of filtered protein.
 Increasing protein intake increases urine protein losse and A low-protein
diet will reduces the albumin synthesis so both will not improve Negative
Nitrogen Balance.

16. Hyperlipidemia
 associated with heavy proteinuria that it is
regarded as an integral feature of nephrotic
syndrome
 Serum cholesterol > 500 mg/dL,
 The lipid profile is known to be highly
atherogenic in other populations
 have about a fivefold increased risk for
coronary death, except for those with MCD
for lipid-lowering drugs are primarily
indicated.

17. Lipiduria,
 the fifth component of the nephrotic
syndrome,
 presence of refractile accumulations of
lipid in cellular debris and casts (oval fat
bodies and fatty casts;
 However, the lipiduria appears to be a
result of the proteinuria and not the
plasma lipid abnormalities.

18. Cont…

19.  loss of binding proteins in the urine.
 low plasma 25-hydroxyvitamin D levels
 total circulating thyroxine reduced
 copper,
 iron
 zinc deficiency
 Drug binding may be altered
 clofibrate,
 warfarin (Coumadin),
 furosemide
Other Metabolic Effects of Nephrotic Syndrome

20. Infection
 Nephrotic patients are prone to bacterial infection
 sepsis was the most common cause of death Before corticosteroids were
shown to be effective in childhood nephrotic syndrome
 Primary peritonitis , pneumococci,
 . Cellulitis,over severe edema , β-hemolytic streptococci
 explanationsfor increased risk of infection
 Large fluid collections
 fragile skin
 edema may dilute local humoral immune factors.
 Loss of immunoglobulin G (IgG) and complement
 .Zinc and transferrin are lost in the urine,
 impaired Neutrophil phagocytic function

21. Acute Kidney Injury
mechanisms
 volume depletion or sepsis,
resulting in prerenal AKI or acute
tubular necrosis
 bilateral renal vein thrombosis;
 NSAIDs and ACE inhibitors or
ARBs;
 increased risk for allergic
interstitial nephritis secondary to
drugs, including diuretics.

22. Chronic Kidney Disease
 With the exception of MCD, most causes of nephrotic syndrome are
associated with progressive kidney failure
 major risk factor for progression
 protein excretion is more than 5 g/day
 but uncommon if proteinuria of less than 2 g/day
 proteinuria itself may be toxic, especially to the
tubulointerstitium
 reduction of proteinuria (e.g., ACE inhibitors) also prevent
tubulointerstitial disease and progressive kidney failure

23. investigations
 CBC
 Blood cultures
 hepatitis B,
 VDRL
 Stool
 hepatitis C,
 HIV test
 PLA2R
 serum electrolyte
 RFT
 LFT(albumin,coagulation profile)
 urine analyisis
 lipid profile
 24-Hour Protein Excretion
 Protein/Creatinine Ratio and
Albumin/Creatinine
 kidney ultrasound
 Kidney Biopsy

24. GENERAL MANAGMENT OF NS
 Supportive treatment
 hypertension,
 proteinuria,
 edema
 other metabolic consequences of nephrotic
syndrome
 life style modifications

25. Hypertension
 reduces cardiovascular risk and also delays progressive kidney
function loss
 ACE inhibitors and ARBs as the first-choice
 Nondihydropyridine calcium channel blockers
 salt restriction<2gm/day
 weight normalization,
 regular exercise, and smoking cessation)
 (KDIGO) guideline recommends a BP target of 130/80 mm Hg in
proteinuric patients.

26. Treatment of Nephrotic Edema
the mainstay of current treatment of nephrotic edema is
diuretic therapy with moderate dietary sodium restriction
 Nephrotic patients are diuretic resistant even if GFR is normal
 hypoalbuminemia
 bounded to protein present in the urine
 decreased absorvation with intestinal wall edema
 Oral diuretics with twice-daily administration are usually preferred,
 a loop diuretic with a thiazide diuretic
 third alternative is adding amiloride to loop diuretic
 Daily weight should decrease by no more than 1 to 2 kg/day.

28. Treatment of Proteinuria
 second key modifiable factor to preserve GFR
 loss of kidney function can be minimized
 if proteinuria <0.5 g/d .
 proteinuric urine may be toxic to the tubulointerstitium
 induce serum proteins to rise.
 ACEI and ARB reduce proteinuria by( 40% to 50%),
 reduction in GFR;but, the decrease in GFR is of a lower
magnitude than the decrease in protein excretion.
if proteinuria persists low dose of an aldosterone antagonist

29. side effects
 hyperkalemia
 cough
 10% to 30% increase in serum creatinine
 aviod
 NSAID and radio-contrast agents
 aminoglycosides),
 proton pump inhibitors... acute interstitial nephritis and
CKD,
 A low-protein diet will lessen proteinuria but must be advised
with great care because of the risk of malnutrition.

30. Treatment of Hyperlipidemia
 Treatment of hyperlipidemia should usually follow the guidelines that
applay to the general population to prevent cardiovascular disease
 A statin or statin/ezetimibe is recommended in adults older than 50 years
with CKD stage 3 to 5.
 Statins alone FOR adults over 50 years with earlier-stage CKD
 younger adults significant comorbidity (coronary disease, diabetes
mellitus, stroke;)
 Statins may protect from a decrease in GFR not firmly established.

31. Correction of Hypoproteinemia
 Adequate dietary protein should be ensured
(0.8–1 g/kg/day with a high carbohydrate
intake
 in a very rare setting of proteinuria is so severe
that need to resort to medical nephrectomy
with
 deliberate use of NSAIDs with ACE
inhibitors and diuretic to lessen
proteinuria by provoking AKI
 bilateral renal artery embolization
 final alternative is bilateral
nephrectomy

32. Treatment of Hypercoagulability
high risk, .
 Prophylactic low-dose anticoagulation (e.g., heparin 5000 U subcutaneously
twice daily) is indicated
 at times of Full-dose anticoagulation with low-molecular-weight heparin or
warfarin should be considered if serum albumin decreases to less than 2
g/dLor if a thrombosis or pulmonary embolism
 Heparin is used for initial anticoagulation with increased dose
 Warfarin may require dose reductions.

33. Management of Infection
 Bacteremia is common even if clinical signs are localized
 A high degree of clinical suspicion ,
 ascitic flluid analysis
 elevated C-reactive protein level
 Parenteral antibiotics should include coverage for pneumococci.
 If repeated infections occur, serum immunoglobulins should be measured.
If serum IgG is less than 600 mg/dL,
 monthly administration of intravenous immune globulin (10–15 g) to keep
the IgG levels above 600 mg/dL.

34. Clasification of NS
Etiology
1. primary
2. secondary

35. Minimal Change Disease
 the most common in children ( 80%) and 10% to 20%of
cases in adults.
 kidney biopsy, glomeruli are normal or near normal on light
microscopy
 is a steroid-sensitive
 accounted for 94% of cases younger than 6 years reaching
about 50% of all cases between ages 8 and 16 years, with a
rising proportion with to (FSGS)
 In adults, MCD is generally rarer than in children, although
incidence is less well defined

36. ETIOLOGY
Most patients have idiopathic MCD
reported triggers of MCD relapses.
 upper respiratory infection,
 atopic reactions, such as to pollen, bee stings, and food
familial MCD. mutation in genes encoding for slit diaphragm
proteins
PATHOGENESIS
 pathogenesis remains poorly understood
 alter capillary charge and podocyte integrity
 IL-4 and IL-13.
 (TNF-α), CD80 or CD40/40L
 Hemopexin
 Microbial Products
 Loss of Anionic Charges in the Glomerular Filtration Barrier
 Podocyte Dysfunction

37. MCD-secondary causes

39. CLINICAL MANIFESTATIONS
 bilateral periorbital edema, mimics as an allergic process.
 Bowel edema may manifest as diarrhea
 20% of adult hypertensive
 Macroscopic hematuria is concerning for renal vein
thrombosis
 Infections are a common complication(19%)

40. Kidney Biopsy
not routinely done in
children younger than 10 years
 hypertension,
 red cell casts
gross hematuria,
kidney dysfunction, or no
response to steroids (4- to 6-
week course
Electron microscopy
demonstrates diffuse podocyte
foot process effacement or
fusion.with no change or Mild
changes on light microscopy

41. NATURAL HISTORY OF MINIMAL CHANGE DISEASE
 Steroid treatment is usually effective in inducing remission, and time to
remit 50% with ( 2 vs 8 months)
 Among children with MCD
 25% never relapse,
 25% relapse infrequently,
 and 50% have numerous relapses
 frequent relapsers at least four relapses per year
 steroid dependent if relapse occurs during the steroid taper or soon
after it is stopped.
 In contrast to FSGS, long-term kidney function in MCD is usually
good.

42. Primary MCD treatment
 supportive managment discused above
Steroids
 first-line therapy to induce remission in children with idiopathic NS
and biopsy-proven MCD, because 95% of MCD patients respond to
this therapy
the 2021 (KDIGO) guidelines in children
induction phase
 prednisolone at 60 mg/m2/day or 2 mg/kg/day (maximum 60
mg/day) as therapy for 4 to 6 weeks
the tapering phase
 40 mg/m2 or 1.5 mg/kg on alternate days and continued for another
4 to 6 weeks.

43. Teartment

45. MCD treatment algorithm

46. Focal and Segmental Glomerulosclerosis
 represents as many as 35% of cases of primaryNS in adults
 a common final pathway of podocyte injury and depletion thought to be
mediated by circulating permeability factors.
 Presence of sclerosis in parts (segmental) of at least one glomerulus (focal)
in addition to diffuse podocyte foot process effacement
 Progressive renal failure—common
 Response to immunosuppressive—only 50% except tip variant
 Primary (idiopathic), secondary, genetic form or unknown

47. primary FSGS:
 referred to as primary podocytopathies
 human FSGS permeability factor
 suPAR, B7-1 (also known as CD-80), or
 cardiotrophin-like cytokine 1 (CLC1),
 interleukin (IL)-6 family,
 mediates altered cell signaling and reorganization of the actin cytoskeleton
 resulting in foot process effacement eventually podocyte depletion though
detachment and apoptosis
 local propagation of damagey
 reduction in supportive factors such as nephrin signaling,
 increased toxic factors (Ang II), or
 mechanical strain on remnant podocytes.

48. Pathogenesis of secondary FSGS
 Adaptive response to glomerular hypertrophy & hyperfiltration
 Direct toxic injury to podocytes (drugs, viruses)
 Adaptive response to hyperfiltration because of intraglomerular HTN, eg due to:
 reduced renal mass
 DN, obesity
 sicklle cell anemia, G6PD deficiency
 cyanotic heart disease
familial dysautonomia
Virus-Associated
 podocytopathies, particularly collapsing FSGS .HIV,EBV, CMV, COVID-19
 The heightened cytokine release APOL1 genotype at risk of interferon mediated
podocyte injury,

49. Genetic form FSGS pathogenesis
 mutation of gene that code for protein expression in podocytes,
GBM & slit diaphragm
 polymorphisms in podocyte genes susceptibility to second hits
APOL1 gene
 increased podocyte membrane pores promoting intracellular
potassium depletion and induction of stress-activated protein
kinases
Genetic form FSGS prevalence:
varies depending on population being studied
 sporadic—5-30% of genetic form FSGS
 familial—30-50% of genetic form FSGS

50. FSGS-clinical presentation
 Primary FSGS:
70-100% present with NS
 Hematuria (50%) & HTN (20%)
Elevated serum Cr (25-50%)
 Secondary FSGS:
 associated with hyperfiltration
 lower levels of proteinuria,
 Typically present with slowly increasing proteinuria (mostly non
nephrotic)
 Drug associated FSGS (eg, pamidronate)
 Collapsing HIV associated nephropathy
 Over time, kidney function impairment
 Serum albumin—usually normal
 Usually, no peripheral edema even when proteinuria >3.3gmm/day

51. con”d
 Genetic form FSGS:
 Difficult to differentiate from primary FSGS
without genomic analysis
Findings suggestive of genetic FSGS:
 Family Hx of documented FSGS
 Disease onset at infancy/childhood

52. FSGS-clinical presentation

53. PATHOLOGY

54. FSGS-Diagnosis
 General investigations
 No histologic feature is pathognomonic for primary FSGS to
differentiate it from 2ry FSGS.
 Diffuse foot process effacement usually occur in primary FSGS
 not specific & can occur in 2ry or genetic form FSGS
 Abrupt onset marked proteinuria is typical for primary FSGS
-NS in 54-100% of primary FSGS

55. FSGS-Diagnosis

56. FSGS-Diagnosis

57. Utility of genetic testing in patients with FSGS

58. FSGS-Treatment

59. FSGS-Treatment
 Goal of Rx:
Remission of proteinuria preferably complete remission
 Primary FSGS:
Supportive measures
Immunosuppressants
 Secondary FSGS:
Eliminate offending drug & treat underlying cause
Supportive mesures
Immunosuppressants don’t help
 Genetic form FSGS
supportive measures (immunosuppressants don’t help)

60. Therapeutic Options in FSGS

61. Primary FSGS treatment-dosing, duration &
tapering of GC therapy
 Dosing—same as used for MCD
 Duration & tapering—varies based on:
 Degree & rapidity of response
 Complete or partial remission achievement
 Degree of GC toxicity
 Complete remission with in 8-12wks—start tapering after 1-
2wks post complete remission over 2-3mon
 Partial remission with in 8-12wks—taper over 3-9mon
 If CNI are used for initial therapy—continue for 6mon
following complete remission or 12mon following partial
remission…then taper over 6-12mon

62. Con…
 Treatment of GC dependent & resistant FSGS:
 CNI—preferred 2nd
therapy than continuing GC or no therapy
 Options if CNI are contra indicated—MMF, rituximab,
cyclophosohamide, ACTH, plasmapheresis, LDL apheresis
 Prognosis of FSGS:
 Spontaneous remission of primary FSGS <10%
 Response to longer treatment >70%
 Factors affecting prognosis:
 Response to initial Rx, degree of proteinuria, severity
of kidney impairment, histologic variant

63. Membranous Nephropathy (MN)
Definition:
Immune complex deposits of IgG & complements develop
predominantly or Exclusively beneath podocytes on the subepithelial
surface of glomerular capillary wall
 Epidemiology:
 Accounts 1/3rd
of biopsied cases of NS
 Peak age—30-50yrs
 M:F—2:1
 Classification
 Primary or idiopathic (75%) Vs
 Secondary (20-30%)

64. MN-classification

65. Pathogenesis of primary MN
 Circulating autoantibody IgG(subclass IgG4) targets antigens expressed
on/near podocyte foot processes
 Target antigens/receptors are
 phospholipase A2 receptor(m-type) (PLA2R)—70%
 Thrombospondin type1 7A (THSD7A)—5-10%)
 Semaphorin 3B
 Neural epidermal growth factor like 1 (NELL 1)
Circulating antibodies target receptor on podocytes , the complexes bind to
the underlying glomerular basement membrane (GBM), resist degradation,
and persist for weeks or months as immune deposits characteristic of MN

66. Pathogenesis of primary MN
 Sublethal podocyte injury induced by the complement membrane
attack complex C5b9 .triggers a cascade of changes,
 including oxidative injury,
 calcium influx,
 activation of cytosolic phospholipase A2, production of
arachidonic acid metabolites and
 This complement mediated podocyte injury :
 Proteinuria from loss of slit diaphragm integrity
 GBM expansion from over production of collagen type lV by
injured podocytes

67. Pathogenesis of primary MN

68. Possible antigens in secondary MN
 dsDNA—SLE
 Exostosin 1 & 2—subset of class V lupus nephritis
 Protocadherin FAT2—hematopoitic cell transplant recipients
 Thyroglobulin—thyroditis
 HBV, Treponemal, H.pylori antigens
 CEA & PSA for malignancy

69. MN-Clinical features
 80% present with NS
 20% diagnosed following asymptomatic proteinuria
 Marked proteinuria in the absence of hypoalbuminemia is rare
(unlike FSGS)
 Weight gain & edema develop more slowly than seen in MCD &
FSGS(gradual accumulation of subepithelial deposit)
 AKI—rare
 Spontaneous remission—20-33%
 Renal failure—1/3rd

70. MN-Clinical features

71. MN-Pathologic Diagnosis
 Light microscopy (LM):
 Diffuse thickening of GBM through out all glomeruli in the absent
of significant hypercellularity
 May be normal in early case of MN
 Immunofluorescence microscopy (IFM):
Diffuse granular pattern of IgG & C3 staining along GBM
 Electron microscopy (EM):
 Subepithelial electron dense deposit on outer aspect of GBM
 Overlying podocyte foot process effacement
 GBM expansion from deposition of new extracellular matrix

72. MN-Pathologic Diagnosis

73. Pathologic difference of primary VS
secondary MN

74. anti-PLA2R antibody assay
 All pts with suspected MN should be tested for PLA2R autoantibody
 70-80% of primary MN are positive for PLA2R
 Some primary MN may be negative & some 2ry MN may be positive
for PLA2R
 hepatitis virus, malignancies
 If PLA2R antibody titer is positive, normal RFT & no identified 2ry
disease,…diagnosis of PLA2R associated MN is established (no
renal biopsy)

75. Evaluating for secondary causes

76. Treatment of primary MN
 Depends on risk of progressive loss of kidney function
1) Very high risk of progression
-start immunosuppressive therapy without delay
2) High risk of progression
-start immunosuppressive therapy without delay
3) Moderate risk of progression
-may/may not require immunosuppressive (based on
proteinuria)
4) Low risk of progression
-no immunosuppressive Rx, supportive measures

77. Clinical criteria for assessing risk of progressive loss
of kidney function

78. Risk-based treatment of MN

79. Immunologic monitoring in MN after start
of therapy

80. Treatment response
 Complete remission (30-40%)—proteinuria
<300mg/24hrs
 Partial remission (30-50)—proteinuria of 0.3-
3.5gm/day & reduction in proteinuria >50% from
baseline
 No remission (10%)—proteinuria >3.5gm/day or
<50% reduction from baseline
 Immunologic remission —anti PLA2R antibody <14
by ELISA

81. Prognostic indicators of MN

82. Management of initial relapse after
therapy in MN

83. Management of resistant disease in MN

84. References
Comprehensive clinical nephrology, 7th
e
Harrisons principle of Internal medicine,
21st
e
KDIGO 2021
Uptodate online 2022

85. THANK
YOU!!!
Thank you
ALL !!!