Nephrotic syndrome is defined by nephrotic range proteinuria, edema, hyperlipidemia, and hypoalbuminemia. It results from increased glomerular permeability allowing protein loss in the urine. The most common causes are minimal change disease in children and membranous nephropathy in adults. Treatment involves diuretics, albumin, steroids, and steroid-sparing immunosuppressants depending on disease severity and steroid responsiveness. Prognosis is generally good but depends on underlying pathology.

1. NEPHROTIC SYNDROME
DR. MATE SHILULI

2. Definition
• Presence of nephrotic range proteinuria, edema,
hyperlipidemia and hypoalbuminemia.
• Results from a severe, prolonged increase in glomerular
permeability for protein
• Proteinuria
– Adults – more than 3.5g/day
– Children – more than 40mg/m2/hr
_Urinary protein:creatinine ratio >2

3. Classical features
• Heavy proteinuria
• Hypoalbuminemia(<2.5g/dL)
• Generalized edema
• Hyperlipidemia and lipiduria

4. Epidemiology
• 2-7/100,000 children ≤ 16 years
• 76.6% of children with NS had MCD on biopsy, with 7% associated with
FSGS
• In children ≤ 8 years at onset, the ratio of M:F vary from 2:1 to 3:2.
• In older children, adolescents, adults, the ratio is 1:1.
• Of patients with MCNS, 70% ≤ 5 years. Only 20-30% of adolescents have
MCNS on biopsy.
• In the first year of life, genetic forms & secondary NS due to congenital
infection predominate.

5. Basic Physiology

6. Basic Physiology cont.…

7. Histology

8. Pathophysiology
Proteinuria & hypoalbuminemia
– Pathogenesis is believed to be immune-related
– Various cytokines have been implicated – IL-2, IL-4,
IL-12, IL-15
– The nephron is characteristically found to have fused
podocytes - alteration of GBM plays a role

9. Cont.…
– The glomerular capillary permeability to albumin is
selectively increased, this overcomes the modest
ability of the tubules to reabsorb proteins causing
proteinuria (protein leak)
– There is urinary loss of albumin, immunoglobulins,
metal binding proteins, erythropoietin, transferrin,
complement & coagulation components.

10. Cont...
• The largest proportion of protein lost in the urine is
albumin, but globulins are also excreted in some diseases.
• Normally the GBM is –vely charged due to presence of
polyanions e.g. Heparan sulfate, chondroitin sulfate and
sialic acid.
• This negative charge deters filtration of –vely charged
proteins e.g. albumin

11. Cont…
• A highly selective proteinuria consists mostly
of low molecular weight proteins (albumin,
transferrin)
• A poorly selective proteinuria consists of
higher molecular weight globulins as well as
albumin

12. Pathophysiology cont…
• Edema
– Proteinuria causes a decrease in plasma oncotic
pressure(due to low albumin), causing extravasation of
plasma water into the interstitial space.
– Reduced plasma volume causes activation of the renin-
angiotensin aldosterone axis and ADH.
– This causes a retention of sodium and water respectively by
renal tubules and extension of edema.

13. Cont…
– Another theory of edema states that massive
proteinuria leads to tubulointerstitial inflammation
and release of local vasoconstrictors and inhibition
of vasodilation.
– This leads to a reduction in GFR and thus sodium
and water retention.

14. Cont.…
– Is characteristically soft & pitting.
– Most marked in the periorbital regions &
dependent portions of the body.
– It may be massive, with pleural effusions &
ascites.

15. Pathophysiology cont…
• Hyperlipidemia
– NS is accompanied by disordered lipid metabolism.
– Apolipoprotein (apo)-B containing lipoproteins are elevated,
including VLDL, IDL, LDL & lipoprotein (a), with resultant
increases in total cholesterol & LDL-cholesterol.
– HDL-cholesterol is normal or low.
– Mechanism – increased hepatic synthesis of LDL, VLDL &
lipoprotein (a) in response to hypoalbuminemia.

16. Hyperlipidemia Cont…
– Decreased plasma oncotic pressure may play a role
– reduction in hyperlipidemia in patients receiving
either albumin or dextran infusions.
– Also contributing are abnormalities in regulatory
enzymes, such as lecithin-cholesterol
acyltransferase, lipoprotein lipase and cholesterol
ester transfer protein.

17. Pathophysiology cont…
• Lipiduria
– Due to leakage of lipoproteins across the GBM.
– The lipid appears in the urine as free or as oval fat
bodies(represent lipoprotein resorbed by tubular
epithelial cells and then shed along with the
degenerated cells).

18. Pathophysiology cont…
• Thrombosis
– Patients have increased risk of thrombosis.
– Could be due to loss of anticoagulant factors (eg
antithrombin III) and antiplasmin activity through
the leaky glomerulus.

19. Pathophysiology cont…
• Thrombosis
– There are abnormalities such as increased platelet activation and
aggregation: elevation in factors V, VII, VIII and XIII and
fibrionogen, and decreased antithrombin III, proteins C and S,
and factors XI and XIII; and increased activities of tissue
plasminogen activator and plasminogen activator inhibitor-1.
– These factors combined with potential hypovolemia, immobility
and increased incidence of infection lead to a hypercoagulable
state.

20. Pathophysiology cont…
• Infection
– Patients are at risk of infection, especially Streptococcus
pneumoniae.
– May be due to low IgG levels.
– Increased urinary losses of factor B, a cofactor of C3b in
the alternative complement pathway.
– Medications used to treat NS, such as corticosteroids and
alkylating agents also suppress the immune system.

21. Classification
i. Based on steroid sensitivity
• Steroid –sensitive
• Steroid –resistant
• Relapsing
• Steroid dependent

22. Classification cont…
ii. Based on etiology
– Secondary causes – etiology extrinsic to the kidney
• Infections – HIV, malaria, syphillis, Hep B, Hep C
• Systemic diseases – DM, SLE
• Drugs and toxins – NSAIDs, penicillin derivatives (penicillamine),
ACE-I (captopril), street heroin
• Mechanical factors – Renal vein thrombosis
• Tumors – Hodgkin disease, lymphoproliferative disorders
• Miscellaneous – bee-sting allergy, hereditary nephritis

23. Classification cont…
– Primary causes (Idiopathic NS) – glomerular
diseases intrinsic to the kidney
• Minimal change disease
• Proliferative changes
• Focal Segmental Glomerulosclerosis
• Membranous nephropathy

24. Minimal Change NS
• Most common cause in childhood (65%).
• Usually idiopathic, but may occur in association with
malignancies (Hodgkin lymphoma & other T-cell
malignancies), exposure to nonsteroidal anti-inflammatory
drugs, or in association with IgA nephropathy or immune-
mediated diseases (SLE, Kimura disease).
• MCNS is characterized by response to corticosteroids (>90%),
a chronic relapsing course (60-80%), and an excellent long-
term prognosis.

25. MCD Cont…
• Macroscopic hematuria is rare.
• Characterized by: oval fat bodies and hyaline
casts in urine.
• Pathogenesis – A soluble factor released by T
cells causes damage to the GBM (hypothesis)

26. Membranoproliferative
Glomerulonephritis
• In some patients with NS, mild non-sclerotic
widening of the mesangial matrix occurs, and
may include deposits (mesangial proliferative
glomerulonephritis)

27. Focal Segmental Glomerulosclerosis
• Characterised by complete collapse of a segment of the
glomerulus with mesangial sclerosis.
• Affects the deep juxtamedullary glomeruli first.
• Typically occurs between age 2 and 7.
• Macroscopic hematuria is rare.
• Poor response to immunosuppressive therapy and a
high rate of recurrence in renal allografts.

28. Membranous Nephropathy
• Most common cause of NS in adults.
• Is a noninflammatory glomerular disease characterized by the presence of
immune deposits (usually containing IgG and C3) within the basement
membrane.
• Leads to diffuse thickening of the glomerular capillary wall.
• Characterized by proteinuria.
• Insidious in onset and progression.
• Appears to be antibody-mediated.
• Immune complexes form in situ with antigens of exogenous or endogenous
origin.

29. Membranous Nephropathy
• It may occur in association with other systemic diseases, where it is
referred to as secondary membranous glomerulopathy
• Most commonly associated with:
– Drugs – penicillamine, captopril, NSAIDs
– Underlying malignant tumors – esp carcinoma of the lung and colon and
melanoma
– SLE
– Infections – chronic Hep B, Hep C, syphilis, schistosomiasis, malaria
– Other autoimmune disorders such as thyroiditis

30. Management
History
• Age of onset
• Infections e.g. Malaria, schistosomiasis, filariasis, Hepatitis B,
C; HIV, Leprosy
• Malignancy e.g. Solid tumours, Lymphomas
• Drugs e.g. NSAIDs, penincillamine, captopril, gold, mercury,
lithium, probenecid
• History of URTI
• History of recent hypersensitivity reaction or allergy.

31. – Abdominal swelling and/or pain
– Weight gain, general body swelling-dependent areas
– Oliguria
– Urine that is foamy
– Hematuria-more common in MPGN
– Hypertension
– Dyspnoea
– Facial puffiness–worse in the morning
– Signs of shock
– Symptoms of infection such as fever and irritability
– Anorexia,easy fatiguabilty,abdominal discomfort and diarrhea are common.

32. Physical Examination
• Oedema- Pitting, mostly found in the lower extremities, face
and periorbital regions, scrotum or labia and abdomen (ascites)
• There maybe palor
• Tachypnea (mechanical restriction to breathing due to marked
ascites)
• Pulmonary effusion and edema can also respiratory distress.
• Nonspecific- headache, irritability, malaise, fatigue

33. • Hepatomegaly
• Tender abdomen may indicate peritonitis
• Hypotension and signs of shock

34. Differential Diagnosis
• Congestive cardiac failure
• Liver failure
• Protein-losing enteropathy
• Protein energy malnutrition (Kwashiorkor)
• Hereditary angioedema
• Allergic reaction
• Acute Poststreptococcal Glomerulonephritis
• Acute Renal Failure

35. Investigations
Urinalysis
– Spot
– Dipstick : Proteinuria 3+ or >300mg/dl
– Protein/ creatinine ratio >2
– Microscopy
– 24-hour collection: quantitative proteinuria (50mg/kg/d or
40mg/m2/hr)

36. Cont…
Blood tests.
-serum proteins-hypoalbuminemia <2.5g/dl.
-lipid profiles-increased cholesterol,LDL.Elevated triglycerides with severe
hypoalbuminemia.Low or Normal HDL
- U/E/Cs- hyponatremia ~ dilutional.
-others:, LFTs, Ca2+,RBS & HbA1c
-CBC-HB, hct increased ~ plasma volume contraction
-Serologic studies( if necessary):
ANA, C3 C4, Hep B/C SAgs, ASOT, Anti-GBM
-Genetic screening

37. Cont…
Imaging
Renal Ultrasound
• normal or large kidneys in acute disease
• Small kidneys in chronic disease
• Parenchymal architecture
Surgical
Renal biopsy.
– Define the pattern of glomerular involvement
– Hence make definitive diagnosis
– Make management decisions

38. Indications For Renal Biopsy
-family history suggestive of disease other than MCD.
-1st yr of life or >8 yrs.
-frequently relapsing NS.
-steroid dependent.
-steroid resistant.
-change in clinical course.
-failure to respond to adequate Steroid therapy in 28 days.

39. Contraindications To Biopsy
• Bleeding diathesis (uncorrectable)
• Small kidneys- may indicate chronic irreversible d’se
• Severe HPTN- can’t be controlled
• Multiple bilateral cysts
• Renal tumor
• Hydronephrosis
• Active renal/ perirenal infection
• One kidney.

40. Treatment
a.)Initial Therapy/First Episode
1.Supportive management
– In-patient management
– Sodium restriction
– Fluid restriction( if pt hyponatremic)
– Elevation of limbs/genital area (pillow)
– Input/output charting, daily weighing
– Oral penicillin may be given to children with gross edema
2. Diuretics
• Chlorothiazide 10mg/kg/dose bd OR
• Furosemide 1-2mg/kg/does bd

41. Cont…
3. I.V albumin
• 25% human albumin 0.5g/kg bd
• Complication includes pulmonary edema.
4. Oral prednisone, starting as a single daily dose of
60mg/m2/day or 2mg/kg/d(max 60mg/d) for 4 to 6 weeks.
Switch to 40 mg/m2/d or 1.5mg/kg/d (max 40mg) on alternate
days for 2-5 months with tapering.
Minimum total duration of treatment of 12 weeks.

42. b.) Infrequent Relapses
For infrequent relapses (one relapse within 6 months of initial
response, or 1-3 relapses in any 12-month period):Administer
initial treatment dose.
Prednisone, 2 mg/kg/d or 60 mg/m2/d as a single dose until
remission for at least 3 days; then 1.5 mg/kg/d or 40 mg/m2/d as a
single dose on alternate days for 4 weeks. Steroids may then be
stopped or gradually tapered.

43. c.) Frequent Relapses/Steroid
Dependent
• Frequently relapsing nephrotic syndrome (FRNS) is
defined as steroid-sensitive nephrotic syndrome (SSNS) with 2
or more relapses within 6 months, or 4 or more relapses within
a 12-month period.
• Steroid-dependent nephrotic syndrome (SDNS) is defined
as SSNS with 2 or more consecutive relapses during tapering
or within 14 days of stopping steroids

44. cont…
Frequent relapser/dependent
change therapy to a steroid-sparing agent once remission of
proteinuria has been achieved.
• Prednisone 2 mg/kg/d or 60 mg/m2/d as a single morning
dose until remission then 1.5 mg/kg or 40 mg/m2/d single
dose on alternate days and tapered over 3 or more months.
• A steroid-sparing agent can be considered on remission.
Alkylating agent.

45. • Cyclophosphamide 2-3mg/kg/day OD for 8-12 wks. Continue
alt. day prednisone
• Cyclophosphamide should not be started until child is in
remission
• Chlorambucil 0.1- 0.2mg/ kg/day for 8wks 3-6mg/kg/day
• Methylprednisolone
– 30mg/kg bolus (max 1gm)
– Alternate days x 6 doses
– Taper regimen up to 18 months
• Other drugs include tacrolimus and levamisole

46. d.) Steroid Resistant
• A minimum of 8 wks treatment with corticosteroids
• The following are required to evaluate a child with SRNS, Diagnostic
kidney biopsy, Evaluation of kidney functions by GFR and quantitative
urine protein analysis
• Calcineurin inhibitor as the initial Rx and should be continued for a
minimum of 6 months until full or partial remission is achieved should
be combined with low dose steroids
• In children who fail to achieve remission with CNI, give
Mycophenolate mofetil, high dose steroids or a combination of these.

47. Cont..
Adjuncts
1. ACE inhibitors and ARBs reduce proteinuria in resistant patients
2. Antibiotics and vaccination
3. Anticoagulation
E. 20 NEPHROTIC SYNDROME
Treat the cause!!!
F. Congenital- Give albumin as you await transplant

48. References
• Wang, C. S., & Greenbaum, L. A. (2019). Nephrotic
syndrome. Pediatric Clinics, 66(1), 73-85.
• Tullus, K., Webb, H., & Bagga, A. (2018). Management of
steroid-resistant nephrotic syndrome in children and
adolescents. The Lancet Child & Adolescent Health, 2(12),
880-890.
• Parthasarathy, A., Menon, P. S. N., & Nair, M. K. C.
(2019). IAP Textbook of pediatrics. JP Medical Ltd.