Naresuan University

Nephrotic syndrome
Suri Tangchitthavorngul , M.D., MS.c.
Nephrology Division, Department of Medicine
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Outlines
•Glomerular structure and function
•Definition of Nephrotic syndrome
•Signs and symptoms of Nephrotic syndrome
•Diseases of nephrotic syndrome
•Management of nephrotic syndrome
•Conclusion
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Glomerular pathology

Schwesinger CM. and Huber TB. In Brenner and Rector’s the kidney. 11st ed. Philadelphia: Saunders Elsevier; 2020. p. 115-31.
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Glomerular structure
• The glomerulus -spherical
mass of specialized capillaries
• The urinary space (Bowman’s
space) - surrounded by
Bowman’s capsule
• Mesangial cells and
mesangial matrix form the
central, tuft-like structure
• GFB – 3 layers: glomerular
endothelial cells (with
glycocalyx), the glomerular
basement membrane (GBM),
and podocytes
A. Richard Kitching and Holly L. Hutton. Clin J Am Soc Nephrol 11: 1664–1674, 2016. doi: 10.2215/CJN.13791215
Schwesinger CM. and Huber TB. In Brenner and Rector’s the kidney. 11st ed. Philadelphia: Saunders Elsevier; 2020. p. 115-31.
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Glomerular filtration barriers

GFB – 3 layers Functions

Fenestrations and glycocalyx

facilitate selective permeability
and filtration

Collagen type 4 with laminin

Visceral glomerular epithelial

layer with slit diaphragm

A. Richard Kitching and Holly L. Hutton. Clin J Am Soc Nephrol 11: 1664–1674, 2016. doi: 10.2215/CJN.13791215
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Key function and responses of cells

A. Richard Kitching and Holly L. Hutton. Clin J Am Soc Nephrol 11: 1664–1674, 2016. doi: 10.2215/CJN.13791215
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Pathophysiology of nephrotic syndrome

Extensive effacement of the
podocytes and loss of this
barrier to protein, allowing
excessive serum albumin to
leak into the urine

Pathogenesis
• Primary: systemic
podocyte-derived
circulating factor
• Secondary: genetic,
infection, neoplasm

Damien G Noone, Kazumoto Iijima, Rulan Parekh, Lancet 2018; 392: 61–74
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Sign and symptoms of glomerular diseases

•Edema
• Underflow hypothesis – hypoalbuminemia
• Overfill hypothesis – salt and water retention

Eric C. Siddal lJai Radhakrishnan, kidney International(2012)82, 635–642635

BERNARDO RODRI Ǵ UEZ-ITURBE et al. Kidney International, Vol. 62 (2002), pp. 1379–1384
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Foamy urine/ Proteinuria

• Normal total protein excretion does not usually exceed 150
mg/24 hours or 10 mg/100 mL in any single specimen
• More than 150 mg/day is defined as proteinuria
• Glomerular proteinuria > 2 gm/24 hr
• Proteinuria > 3.5 gm/24 hours is severe and known as nephrotic
syndrome.
Urinalysis mg/dL
1+ 30
2+ 100
3+ 300
4+ 1,000

[Link]
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Hypercholesterolemia/Hypertriglyceridemia in Nephrotic
syndrome
Lipid metabolism in
Nephrotic syndrome

Agrawal, S., Zaritsky, J., Fornoni, A. et al. Nat Rev Nephrol 14, 57–70 (2018)
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Lipiduria
Oval fat body
Maltese cross
(Sloughed tubular cells with lipids)

Under polarized light, oval fat bodies

Filtration of HDL particles
demonstrate the "Maltese cross"
(relatively small size)
appearance.
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Glomerular syndrome

Asympto Acute Nephrotic

Nephrotic
RPGN CGN
matic nephritis syndrome
syndrome

RPGN, rapidly progressive glomerulonephritis

CGN, chronic glomerulonephritis
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Nephrotic syndrome definitions

• Edema
• Nephrotic proteinuria
• 24-hr urine protein ≥ 3.5 g/d
• Urine protein/creatinine ratio ≥ 3,000 mg/g
• >3+ proteinuria on dipstick
• Hypoalbuminemia ( Serum albumin < 2.5 g/dL)
• Hypercholesterolemia
• Lipiduria
M.K. Saha, et al. In Brenner and Rector’s the kidney. 11st ed. Philadelphia: Saunders Elsevier; 2020. p. 115-31.
Damien G Noone, Kazumoto Iijima, Rulan Parekh, Lancet 2018; 392: 61–74
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Nephrotic syndrome causes

• Primary (Idiopathic)
• Secondary
Conditions Causes
Medications Mercury, Gold, Penicillamine, Heroin, Probenecid, NSAIDs, Lithium,
Pamidronate, Interferon, Warfarin, Clonidine, Contrast media
Allergens, Venoms, Bee sing, pollens, poison ivy, antitoxin, snake venom, tetanus toxoid,
Immunizing agents diphtheria, vaccines
Infections Bacterial (post strep GN, IE, shunt nephritis, syphilis, mycoplasma, TB)
Virus (HBV, HCV, EBV, HZV, HIV)
Protozoal (malaria, toxoplasmosis)
Helminthic: schistosomiasis, filariasis
M.K. Saha, et al. In Brenner and Rector’s the kidney. 11st ed. Philadelphia: Saunders Elsevier; 2020. p. 115-31.
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Secondary nephrotic syndrome

Conditions Causes
Neoplasms Solid tumors (lung, colon, stomach, breast, cervix, kidney,
thyroid, ovary, prostate, adrenal, melanoma)
Leukemia/lymphoma
Multisystem disease SLE, MCTD, Dermatomyositis, Rheumatoid arthritis, IgA vasculitis,
Mixed cryoglobulinemia, amyloidosis
Familial/Metabolic disease DM, hypothyroid, Graves’ disease, Fabry disease, Alport
syndrome, Nail patella syndrome, Nephrin/podocin mutation
Miscellaneous Pregnancy, obesity, congenital heart

M.K. Saha, et al. In Brenner and Rector’s the kidney. 11st ed. Philadelphia: Saunders Elsevier; 2020. p. 115-31.
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Differential diagnosis
Diseases Associations Serologic tests
Minimal change disease (MCD) NSAIDs, Hodgkin disease, allergy -
Focal segmental African american, HIV infection, heroine, HIV antibody
glomerulosclerosis (FSGS) pamidronate, interferon, obesity, reflux
nephropathy
Membranous nephropathy Lupus nephritis class V, ANA, anti-dsDNA
(MN) rheumatoid arthritis, Rheumatoid factor
Solid maliganancy (Breast, lung, colon), Screening solid
Drugs (NSAIDs, gold, penicillamine, lithium), malignancy
Infection (HBV, HCV)
Diabetic Kidney Disease (DKD) Other diabetic microangiopathy HbA1C, FPG
Amyloidosis Myeloma Serum protein
Rheumatoid arthritis, Bronchiectasis, Crohn disease, electrophoresis, Urine
Famillial Mediterranean syndrome protein electrophoresis
B Satirapoj, Essentials of glomerular disease. 2018
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Differential disease by age

Age Diseases
< 15 years old Primary MCD, familial FSGS, primary MPGN
15 – 35 years old Familial FSGS, MPGN, focal and diffuse GN (LN, IgA
nepropathy, post infectious GN)
35 – 60 years old MN, DN, FSGS
> 60 years old Primary MCD, secondary FSGS, MN, DN, amyloidosis

T Kanjanabuch. Glomerular disease. CPG chula book 2015

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Characteristic of nephrotic syndrome

Features Characteristic Diseases
Abrupt MCD, FSGS (tip-variant)
Onset
Insidious Others
Heavy proteinuria MCD, primary MN, FSGS,
Severity of disease
Serum albumin < 2 g/dL amylodiosis
Sediment Hematuria FSGS > MN > MCD

Response to steroid Rapid response MCD > FSGS (tip) > FSGS > MN

P Puapatanakul. Approach to glomerular disease, 2017

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Differential disease by associated conditions

Pathologic patterns Common associated conditions

MCD Allergy, Hodgkin’s disease, CLL, NSAIDs, Rifampicin
FSGS HIV, parvovirus B19, Interferon alpha, heroin, genetics
MN HBV, SLE, Solid tumors (lungs, breast, colon)
MPGN HCV, SLE, chronic active infection
IgAN Celiac disease, chronic liver disease, Rheumatoid arthritis, HIV,
HBV

T Kanjanabuch. Glomerular disease. CPG chula book 2015

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Minimal change disease

•Pathogenesis • Cell mediated immune
response
• Increased activated T cells
• Th2 cytokine (IL-13)
• Decrease Treg
• Aggravate factor
• Infection, allergy, cancer
• Soluble mediators

R. Mehrotra, et al. Glomerular disease update for clinician. Clin J Am Soc Nephrol 12: 332–345, 2017.
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Clinical & causes

• Nephrotic syndrome
• Heavy proteinuria
• Hypoalubmin (< 2 g/dL)
• Abrupt-onset
• No microscopic hematuria
(<20%)
• AKI – intra-renal hemodynamic
change, proteinaceous cast, foot
process effacement (EM)
• Anasarca
• Acute RVT (rare)

R. Mehrotra, et al. Clin J Am Soc Nephrol 12: 332–345, 2017.

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Pathology
Diffuse podocyte foot process effacement
Normal glomerulus from and microvillous transformation from
light microscopy electron microscopy

M.K. Saha, et al. In Brenner and Rector’s the kidney. 11st ed. Philadelphia: Saunders Elsevier; 2020. p. 115-31.
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Treatment of MCD
Contraindications
- Hyperglycemia
- Osteoporosis
- Steroid psychosis
- Unwilling

Remission rates
Medication Regimen
(CR or PR)
Prednisolone Dosage: 1 MKD (max 80 mg/day) or 2 mg/kg AD 80 – 90%
(max 120 mg)
Durations: 4 weeks to 4 months
Others: PO. cyclophosphamide, cyclosporin, tacrolimus, rituximab, mycophenolic acid

KDIGO 2021 Clinical practice guideline for the management of glomerular disease. Kidney Int. 2021 Oct;100(4S):S1-S276
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Definition after treatment

Definition Details
Complete remission Proteinuria < 0.3 g/d (UPCR < 0.3 g/gCr) AND
(CR) Stable serum creatinine AND
Serum albumin > 3.5 g/dL
Partial remission Proteinuria 0.3 – 3.5 g/d (UPCR 0.3 – 3.5 g/gCr) AND decrease > 50%
from baseline
Relapse Proteinuria > 3.5 g/d or UPCR > 3.5 g/gCr after CR

Steroid-resistant Persitence of proteinuria > 3.5 g/d or UPCR > 3.5 g/gCr with
MCD decrease > 50% from baseline with primary regimen for > 4 months
Steroid-dependent Relapse occuring during or within 2 wks of completing steroid
MCD therapy
KDIGO 2021 Clinical practice guideline for the management of glomerular disease. Kidney Int. 2021 Oct;100(4S):S1-S276
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Focal segmental glomerulsclerosis

MCD FSGS

R. Mehrotra, et al. Glomerular disease update for clinician. Clin J Am Soc Nephrol 12: 332–345, 2017.
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Types of FSGS
Glom epithelial cells
• Diffuse foot process - Viral: HIV, CMV, B19
effacement - Drug: mTOR, CNIs,
• Sudden onset Heroin, Li, INF, NSAIDs,
• Amenable to therapy DAA
Glom hypertension
Primary Secondary
- Reduce nephron N:
FSGS FSGS
reflux, dysplasia, sickle
cell, age
- Normal nephron N:
obesity, primary glom,
FSGS of
Genetic undetermined DN, HT
FSGS causes
• Segmental foot process
• Familial
effacement
• Sporadic
• Proteinuria, No 2o
• Syndromic
causes

KDIGO 2021 Clinical practice guideline for the management of glomerular disease. Kidney Int. 2021 Oct;100(4S):S1-S276
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FSGS – clinical manifestration

Characters Primary Secondary FSGS Genetic
FSGS Adaptive APOL1 Infection Drugs FSGS

Mechanism Circulating Alters of APOL1 Cytokine Direct High

factors glom/glom variant (possible) injury penetrance
(SuPRA) HT genetic
History Acute onset Low birth Maybe no HIV, CMV, Bisphospho Family
edema wt., family Hx B19 nate, Li history
obesity,
reflux
Labs Heavy Any Any Any Any Any
proteinuria, proteinuria, proteinuria proteinuria proteinuria proteinuria
nephrotic normal Alb
syndrome,
AKI, HT
Treatment Response RAAS ± response Treat virus Stop Not
steroid blockage steroid medication response
R. Mehrotra, et al. Glomerular disease update for clinician. Clin J Am Soc Nephrol 12: 332–345, 2017.
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Treatments of FSGS

KDIGO 2021 Clinical practice guideline for the management of glomerular disease. Kidney Int. 2021 Oct;100(4S):S1-S276
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Definition after treatment

Definition Details
Complete remission Proteinuria < 0.3 g/d (UPCR < 0.3 g/gCr) AND
(CR) Stable serum creatinine AND
Serum albumin > 3.5 g/dL
Partial remission Proteinuria 0.3 – 3.5 g/d (UPCR 0.3 – 3.5 g/gCr) AND decrease > 50%
from baseline
Relapse Proteinuria > 3.5 g/d or UPCR > 3.5 g/gCr after CR

Steroid-resistant Persisitence of proteinuria > 3.5 g/d or UPCR > 3.5 g/gCr with
FSGS decrease > 50% from baseline with primary regimen for > 4 months
Steroid-dependent Relapse occuring during or within 2 wks of completing steroid
FSGS therapy
KDIGO 2021 Clinical practice guideline for the management of glomerular disease. Kidney Int. 2021 Oct;100(4S):S1-S276
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Membranous nephropathy

MCD (H&E) Spike and Hole formation (PAS)

GBM thickening (H&E) Subepithelial electron dense deposition (EM)

R. Mehrotra, et al. Glomerular disease update for clinician. Clin J Am Soc Nephrol 12: 332–345, 2017.
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Pathogenesis of MN

HBV infection
PLA2R1 Ab (85 %) Autoimmune
Malignancy
THSD7A Ab (3-5 %) disease (LN)
Drug/toxin
Couser WG. Glin J Am Soc Nephrol 2017. 12:983-97
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Clinical features and natral history

• Nephrotic syndrome with hypoalbuminemia,
hyperlipidemia, peripheral edema, and lipiduria.
• 70 – 80% of cases
• Proteinuria (> 3.5 gm/day, 80%), hypertension 13 – 55%,
microscopic hematuria 30 – 50%
• Complications: Renal vein thrombosis (RVT) (4 – 52%)
• Natural history
• 35% progress to ESKD at 10 yr
• 25% spontaneous remission at 5 yr
• OR 1/3 spontaneous remission, 1/3 stable clinical, 1/3
progress CKD
M.K. Saha, et al. In Brenner and Rector’s the kidney. 11st ed. Philadelphia: Saunders Elsevier; 2020. p. 115-31.
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Causes of MN
Primary MN anti-PLA2R Ab, anti-THSD7A Ab*

*PLA2Rab, antibodies against the M-type phospholipase A2 receptor, anti-THSD7A antibodies, thrombospondin type-1 domain-containing 7A

R. Mehrotra, et al. Glomerular disease update for clinician. Clin J Am Soc Nephrol 12: 332–345, 2017.
 Naresuan University

Risk stratification for treatment

Normal GFR GFR drop or massive

Normal GFR Nephrotic
Non-nephrotic proteinuria/
proteinuria
Nephrotic proteinuria
Fail conservative syndrome/AKI

KDIGO 2021 Clinical practice guideline for the management of glomerular disease. Kidney Int. 2021 Oct;100(4S):S1-S276
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Treatment of primary MN

Secondary MN
Mx. causes

KDIGO 2021 Clinical practice guideline for the management of glomerular disease. Kidney Int. 2021 Oct;100(4S):S1-S276
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Diabetic nephropathy
• Definitions: Kidney disease attributed to diabetes
• Risk factors:
• Susceptibility factors (e.g., age, sex, race/ethnicity, and
family history),
• Initiation factors (e.g., hyperglycemia and AKI)
• Progression factors (e.g., hypertension, dietary factors,
and obesity)
• “legacy effect,” or “metabolic memory,” suggests
that early intensive glycemic control can prevent
irreversible damage
M.K. Saha, et al. In Brenner and Rector’s the kidney. 11st ed. Philadelphia: Saunders Elsevier; 2020. p. 115-31.
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Pathophysiology

Radica Z. Alicic, et al. Diabetic Kidney Disease. Clin J Am Soc Nephrol 12: 2032–2045, 2017.
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Natural history of DKD

• Atypical features: Rapidly decreased eGFR, Nephritic syndrome,

Nephrotic syndrome, refractory hypertension, eGFR decline >
30% after RAASi initiation
Radica Z. Alicic, et al. Diabetic Kidney Disease. Clin J Am Soc Nephrol 12: 2032–2045, 2017.
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DKD stage and death

M.K. Saha, et al. In Brenner and Rector’s the kidney. 11st ed. Philadelphia: Saunders Elsevier; 2020. p. 115-31.
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Pathology

Radica Z. Alicic, et al. Diabetic Kidney Disease. Clin J Am Soc Nephrol 12: 2032–2045, 2017.
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Pathology

Radica Z. Alicic, et al. Diabetic Kidney Disease. Clin J Am Soc Nephrol 12: 2032–2045, 2017.
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Management of DKD

Comprehensive
management of DKD

Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group. KDIGO 2022 Clinical Practice Guideline for Diabetes
Management in Chronic Kidney Disease. Kidney Int. 2022;102(5S):S1-S127.
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Glycemic control

Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group. KDIGO 2022 Clinical Practice Guideline for Diabetes
Management in Chronic Kidney Disease. Kidney Int. 2022;102(5S):S1-S127.
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Metformin initiation and follow-up

Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group. KDIGO 2022 Clinical Practice Guideline for Diabetes
Management in Chronic Kidney Disease. Kidney Int. 2022;102(5S):S1-S127.
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Proteinuria reduction and follow-up

KDIGO 2022 CLINICAL PRACTICE GUIDELINE FOR DIABETES MANGEMENT IN CHRONIC KIDNEY DISEASE
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SGLT2i and kidney

Restore TGF
Decrease glomerular pressure
Decrease proteinuria

Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group. KDIGO 2022 Clinical Practice Guideline for Diabetes
Management in Chronic Kidney Disease. Kidney Int. 2022;102(5S):S1-S127.
Katherine R. Tuttle, et al. Am J Kidney Dis. 77(1):94- 109. Published online October 26, 2020.
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Amyloidosis
AL amyloid
• Symptoms: weight loss, fatigue, light-headedness, shortness of
breath, peripheral edema, pain due to peripheral neuropathy
(often carpal tunnel syndrome), and orthostatic hypotension
• Organ: kidney (50%), heart (40%), Nerve (25%)
• Investigation: Affected organ
• Kidney/Liver (90%)
• Fat pad aspirate (60%–90%), rectal biopsy (50%–80%), bone marrow
aspirate (30%–50%), gingival biopsy (60%), or dermal biopsy (50%)

R. Mehrotra, et al. Glomerular disease update for clinician. Clin J Am Soc Nephrol 12: 332–345, 2017.
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Clinical features
Periorbital purpura Macroglossia

Shoulder pad sign Septal granular sparking pattern

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Renal amyloidosis
• Immunoglobulin-related (AIg) amyloidosis
• AL > AH > AHL amylodosis
• 40% plasma cells in BM > 10%
• <20% MM
• Age ~ 60 years, Male
• Median cr 1.2 mg/dL, Nephrotic syndrome 2/3
• Proteinuria 6 g/day
• Urine sediment, HT (uncommon)
• ESRD at 14 mo (without treatment)
• Serum FLC K:L ratio (0.26 – 1.65, 0.37 – 3.1 if impaired GFR)
R. Mehrotra, et al. Glomerular disease update for clinician. Clin J Am Soc Nephrol 12: 332–345, 2017.
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Renal pathology

normal Marked nodular mesangial expansion

Congo red positive Under polarized light, apple green birefringence

R. Mehrotra, et al. Glomerular disease update for clinician. Clin J Am Soc Nephrol 12: 332–345, 2017.
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Treatment
•Treatment of AL amyloid
• Primary AL amyloid à autologous HST (if
eligible)
• Low-dose melphalan + Dexamethasone
• Bortezomib-base therapy
• Thalidomide/lenalidomide

R. Mehrotra, et al. Glomerular disease update for clinician. Clin J Am Soc Nephrol 12: 332–345, 2017.
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General management
Supportive GN treat Management
1. Edema Loop diuretics (first-line)
Restrict dietary sodium < 2 g/d (90 mmol/d)
2. HT and proteinuria ACEi or ARB (first-line), stopped if SCr risng > 30%
reduction Target office SBP < 120 mmHg
Goal proteinuria < 1 g/d
Treatment metabolic acidosis (if HCO3 < 22 mmol/l)
Restrict dietary sodium, exercise, stop smoking
3. Hyperlipidemia Statin (first-line) according to ASCVD risk
eGFR < 60 and ACR > 30 mg/gCr
4. Dietary management Dietary sodium < 2 g/d, Planted based diets
Protein 0.8 – 1 g//kg/day, add 1 g/g of protein losses (>
5g)Calory intake 35 kcal/kg/d, if eGFR < 60 use 30 – 35
Restrict dietary fat < 30% of calories, mono, polysat 7-10%
5. Infection screening, malignancy screeining, Immunization, contraception,
management of CV risk factors
KDIGO 2021 Clinical practice guideline for the management of glomerular disease. Kidney Int. 2021 Oct;100(4S):S1-S276
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Thrombophilic stage in Nephrotic syndrome

Joseph Loscalzo. N Engl J Med 2013; 368:956-958

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Anticoagulant of nephrotic syndrome

KDIGO 2021 Clinical practice guideline for the management of glomerular disease. Kidney Int. 2021 Oct;100(4S):S1-S276
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Conclusions
• Nephrotic syndrome
• Sudden onset: MCD, FSGS
• Insidious onset: MN, DN, amyloidosis
• MCD/some types of FSGS are steroid response
• Some antibodies to defined primary MN without
kidney biopsy needed.
• Supportive GN management is included edema
treatment, salt restriction, HT and DLP management,
dietary intakes
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Thank you for your attention