Nephrotic Syndrome

1. Nephrotic Syndrome

2. Learning Outcomes
Discuss the pathogenesis of Nephrotic Syndrome and correlate with the
clinical presentation
Identify the glomerular causes of nephrotic syndrome; Primary glomerular
diseases and systemic causes
Discuss pathogenesis of the primary glomerular diseases presenting with
nephrotic syndrome
Compare the morphologic changes of these glomerular disorders

3. Structure of Glomerulus

4. Normal Glomerulus
W.B. Saunders Company items and derived items Copyright (c)
1999 by W.B. Saunders Company

5. Nephrotic Syndrome (NS)
A clinical complex that includes:
Massive proteinuria
(3.5 gm/24hrs or more in adults)
Hypoalbuminemia
(decreased plasma albumen)
Generalized edema
(anasarca)
Hyperlipidemia and lipiduria

6. Types of Proteinuria
Selective glomerular proteinuria:
Increased excretion of more than 300 mg
medium-sized negatively charged proteins
such as albumin in a 24-h urine collection,
it indicates moderate glomerular damage
e.g
• Minimal-change GN
• Membranous GN
• Membranoproliferative GN
• IgA-nephropathy
• EPH-gestosis
• Lupus nephritis with low activity
Non-Selective Glomerular Proteinuria:
Increased excretion of more than 3000 mg
proteins of any size in a 24-h urine
collection, it indicates severe glomerular
damage e.g
• Focal segmental glomerulosclerosis
• Lupus nephritis
• EPH-gestosis
• Amyloidosis
Microalbuminuria: Microalbuminuria is the
presence of more than 30 mg and up 300
mg albumin in a 24-h urine collection.
• diabetes mellitus
• hypertension
• post-streptococcal glomerulonephritis

8. Nephrotic Syndrome
Primary (most common)causes of NS
- Focal segmental glomerulosclerosis
(in adults)
- Minimal change disease in children
(common in children)
- Membranous nephropathy
(common in adults)
- Membranoproliferative GN
- IgA nephropathy
Systemic (most frequent) causes of NS
(seen in adults)
- Diabetes mellitus
- Amyloidosis
- Systemic Lupus Erythematosus (SLE)
Others causes
- Hypersensitivity reactions; drugs, bee
stings, snake bite
- Malignancy; carcinoma, myeloma
- Pregnancy; toxemia of pregnancy

10. Incidence Most frequent cause of NS in children (1-7yrs)
Etiology and
pathogenesis
Idiopathic majority of the cases
Nephrin gene mutation
T-cell derived factor, podocyte damage, effaced foot processes
Clinical Slow onset of NS
Some individuals present only with hematuria or proteinuria in the non-
nephrotic range; others combined nephrotic-nephritic picture.
Lab Selective proteinuria, normal blood complement levels
Pathology LM: Glomeruli normal, epithelial cells of PCT show protein droplets and
lipids, secondary to tubular reabsorption of the lipoproteins (Lipoid
Nephrosis)
EM: Diffuse effacement of foot processes, microvilli, GBM appears normal
IFM: No findings
Prognosis More than 90% respond to corticosteroid therapy, may recur, 5% progress
to chronic kidney disease
Minimal Change Disease

11. Minimal Change Disease
The three hallmarks of MCD

13. Incidence Common cause of NS in adults (30-50 years)
Etiology and
pathogenesis
Primary (85%) Idiopathic
Secondary (15%); Infections (HBV, malaria), Carcinoma (Lung, colon), SLE,
heavy metals (Gold), Drugs (penicillamine, NSAID’s)
Immune deposits and direct action of MAC activate mesangial cells and
podocytes to liberate proteases and oxidants, damages capillary walls which
become leaky
Clinical Nephrotic syndrome
Lab Non-selective proteinuria
Pathology LM: Subepithelial IgG-containing deposits along GBM, diffuse thickening of
capillary wall
EM: Subepithelial deposits separated by small spike of GBM matrix "spike and
dome” pattern, later spikes close over the deposits to form thick GBM and
effacement of foot processes
IFM: Granular deposits of IgG and C3 along GBM
Prognosis Less response to corticosteroids, 40% progress to glomerular sclerosis and
CRF
Membranous Glomerulonephritis

14. Membranous GN

16. Incidence Children and young adults (5-25 years)
Etiology and
pathogenesis
Type I; immune complexes deposit and is associated with classical complement
pathway.
Type II; mostly associated with dysregulation of alternative complement pathway.
Other associations with; chronic infections, SLE, Cancer, cirrhosis, heroin abuse
Clinical Nephrotic Syndrome in 50%, acute Nephritic Syndrome in 20%
Resent history of URI in 50%, hypertension or renal insufficiency
Lab Hypocomplementemia of classic and alternative pathways, C3 nephritic factor
(C3NEF), Circulating immune complexes, Non-selective proteinuria
Pathology LM: Diffuse proliferative GN, Large Glomeruli with lobular appearance, Thick
capillary wall and GBM splitting (Tram-Track), Mesangial proliferation, leucocyte
infiltrate
EM: Type I: sub-endothelial deposits, Type II: dense-deposit disease (within GBM)
IF: Type I: Granular IgG and C3 deposits along GBM and C1q &C4 often present,
Type II: C3 only present in irregular chunky and segmental linear foci in BM,
IgG usually absent
Prognosis Progressive loss of renal functions, , ESRD within 10 years in 50% of children and
80% of adults
Membranoproliferative Glomerulonephritis

17. Membranoproliferative GN
MPGN shows intramembranous
deposits which leads to "splitting"
of the GBM

18. Incidence NS in children and adolescents, leading cause of RF in adults
Etiology and
pathogenesis
Primary; 20-30% of all cases of NS. Idiopathic, may be transformation from
MCD, podocytes injury, entrapment of plasma proteins and lipids, form
hyaline masses followed by sclerosis
Secondary; HIV infection or heroin abuse, IgA nephropathy, mutations
affecting nephrin, and diabetic nephropathy
Clinical Nephrotic syndrome, RF may be present at the onset
Lab Foamy urine due to selective proteinuria, deranged RFTs
Pathology LM: Sclerosis affecting some glomeruli (focal) and involves only part of each
affected glomerulus (segmental), increased mesangial matrix, obliterated
capillary lumens, deposition of hyaline masses and lipid droplets, progress to
global sclerosis, tubular atrophy and interstitial fibrosis
EM: Effaced foot processes
IFM: IgM and C3 in hyalinized areas
Prognosis 50% progress to CRF, 20-40% recurrence in transplant,
Collapsing Variant; may be associated with HIV - worse prognosis
Focal Segmental Glomerulosclerosis (FSGS)

20. Focal Segmental Glomerulosclerosis
Focal and segmental deposits of
IgM and C3

21. Incidence Common, usually affects children and young adults
Etiology and
pathogenesis
Suggested that increased IgA synthesis in response to respiratory or exposure of
GIT to environmental agents (e.g., viruses, bacteria, food proteins) may lead to
deposition of IgA and IgA-containing immune complexes in the mesangium, where
they activate alternative complement pathway and initiate glomerular injury
Clinical Begins as an episode of gross hematuria that occurs within 1 or 2 days of a
nonspecific upper respiratory tract infection
Nephrotic syndrome may develop occasionally
Lab Blood in urine and mild proteinuria
Pathology LM: glomeruli may be normal or may show mesangial widening and segmental
inflammation
EM: electron-dense deposits in mesangium
IFM: mesangial deposition of IgA, often with C3
Prognosis Slow progression to CRF occurs in 25-50% of cases over a period of 20 years
IgA Nephropathy

22. IgA nephropathy

23. Self-Assignment
Q1. Name the commonest glomerular lesion which can cause nephrotic
syndrome in adult and in children.

24. References
• Basic Pathology, 10th Edition 2017; Kumar, Abbas, Aster
• www.webPath.com.