Nephrotic Syndrome

Nephrotic Syndrome Charles Cho

Proteinuria
Increase in glomerular permeability that allows the filtration of nonfiltered maromolecules (albumin)
Heavy proteinura: >3 g/day

Basic Questions
How much protein is being excreted?
Under what conditions is protein excreted?
What kind of protein is being excreted?

Amount of protein excreted
Used to be measured within a 24hour urine collection
Total protein-to-creatinine ratio (mg/mg) on randome urine
Benign forms of isolated proteinurea < 1-2g/day
Amount also indicates prognosis

Under what conditions is protein excreted?
Transient Proteinuria – m/c – Stress (fever/exercise)


Orthostatic Proteinuria – Primarily in adolescents – Increase protein excretion on upright position – No further workup necessary


Persistent Proteinuria – Underlying renal or systemic disorder

Definition of Nephrotic Syndrome
Proteinuria: Nephrotic range proteinuria – Protein >3.5 g/day


Hypoalbuminemia (< 3.0 g/dL)
Edema
Hypercholesterolemia – Fasting level >200 mg/dL – d/t increased production from liver

Clinical manifestation (1)
Protein loss – – – – –

Albumin Thyroxine-binding protein Cholecalciferol-binding protein Transferrin Metal biding protein

Clinical manifestation (2)
Hypercoagulable state
Occur when serum albumin <2g/dL
Due to – urinary loss of antithrombin III • Factor IX, X, XI, thrombin activity increase

– – – –

Protein C, S activity or level decrease Hyperfibrinogenemia Platelet activation increase hyperlipidemia


Venous thromboembolism – Esp MGN

Clinical manifestation (3)
Increased risk of infection
d/t loss of IgG and complement
S. pneumoniae, E. Coli

Clinical manifestation (4)
Change of phamacokinetics due to loss of albumins and other drugbinding proteins

Etiology of Primary nephrotic Syndrome
Minimal Change Disease – = Nil Disease, Lipoid Nephrosis








FSGS (Focal & Segmental Glomerulosclerosis) MGN (Membranous glomerulonephritis) MPGN (Membranoproliferative GN) Mesangial proliferative glomerulonephritis Others – Crescentic glomerulonephritis – Focal and segmental proliferative glomerulonephritis – Fibrillary-immunotactoid glomerulopathy

Etiology of Secondary Nephrotic Syndrome
Infections: – PSGN, endocarditis, “shunt nephritis”, secondary syphilis, leprosy, Hep B, AIDS, Infectious mononucleosis, malaria, schistosomiasis, filariasis


Drugs – Gold, mercury, penicillamine, heroid, NSAID, captopril …


Neoplasia – Hodgkin’s Dz, lymphoma, leukemia, Wilm’s tumor


Multisystem – SLE, HS purpura, vasculitis, Goodpasture’s Dz, dermatomyositis, sarcoidosis, Sjogren’s, RA, MCTD


Heredofamilial – DM, Alport’s Syndrome, Sickle cell dz, Fabry’s disease


Others – Thyroiditis, myxedema, RVH, chronic allograft rejection

Complications of NS
ARF – – – – – –

Drug-iduced interstitial nephritis Acute renal vein thrombosis Superimposed crescentric GN Acute volume depletion UTI, Obstruciton Uncontrolled HTN


Thromboembolic complications – Renal vein thrombosis


Infection – S. Pneumoniae, E. Coli

Principle of therapy (1)
Salt and free water restriction
Diuretics – Thiazide or loop diuretics. – Caution for dehydration that can cause ARF


Modest protein restriction – 0.5-0.6 g/kg/day


Hyperlipidemia treatment
Vitamin D suppliment

Principle of therapy (2)
Modest protein restriciton
High protein diet increases urinary protein excretion rate => worsen glomerular lesion
If proteinuria >10g/day – (-) nitrogen balance & protein malnutrition • Need supplimental dietary protein

Primary Nephrotic Syndrome
MGN > FSGS > MCD
Renal Bx: – often required in adjust for Dx and treatment plan









Membranous Glomerulonephritis (MGN) Focal & Segmental Glomerulosclerosis (FSGS) Minimal Change Disease (MCD) Membranoproliferative GN (MPGN) Mesangial Proliferative Glomerulonephritis Fibrillary-immunotactoid glomerulopathy

Membranous glomerulonephritis (MGN)
m/c non-DM adult nephrotic syndrome (30-40%)
Rare in children
Age of 30’s-50’s, Male:Female = 2:1
30-50% => DVT.
Increased risk of RVT
4-11% association to cancer if >60yo
Complement level = normal

Membranous glomerulonephritis
glomerular basement membrane thickening with little or no cellular proliferation or infiltration
Most often idiopathy (85%)
Secondary (15%) – Hepatitis B, autoimmune disease, throiditis – Malignancies: breast, lung, colon, gastric, melanoma, RCC, neuroblastoma – Drugs: gold penicillamine, captopril, NSAID – Others: DM, sarcoidosis, sickle cell, GuillainBarre, Fnaconi’s, etc.

MGN


Stage IV: thickening of the glomerular basement membrane together with segmental or global glomerulosclerosis are detectable by light microscopy

Membranous glomerulonephritis Treatment and Prognosis
Steroid: Not effective as MCD
ACEi
Anticoagulation d/t increased risk of DVT
Prognosis – 20-30%: complete recovery without Tx – 25%: persistent proteinuria, normal kidney finction – 20-30%: progress to CRF – Poor Prognosis indicator: • male, old age, HTN, severe proteinuria >10g/d • hyperlipidemia, worsening renal function, • interstitial fibrosis on renal Bx => req. immunosupp. Tx

Focal & Segmental Glomerulosclerosis (FSGS)
15% of Nephrotic syndrome in adult
7-10% of nephrotic syndrome in children
Characterized for nonselective proteinuria
The most common primary glomerular disease underlying end-stage renal disease
Microscopic hematuria (80%)
HTN, poor renal function (BUN, Cr ↑) Differ from MCD


Severe tubulointerstitial damage

FSGS: Etiology
Mostly primary
Secondary – AIDS, DM, Fabry’s disease, Charcot-MarieTooth Dz – d/t persistent glomerular capillary HTN • Congenital oligonephropathy: solitary kidney • Acquired nephron loss: surgery, GN or tubulointerstitial nephritis • Others: sickle cell nephropathy, obesity, heroin abuse

FSGS: Pathology
LS: focal segmental sclerosis
EM: diffuse fusion of the epithelial cell foot processes, similar to that seen in minimal change disease
IF: deposition of IgM and C3 around sclerotic segment

FSGS


collagenous sclerosis runs across the middle of the glomerulus.

FSGS: Treatment and Prognosis
Rare spontaneous recover, poor prognosis
Steroid responsive in 40%
Cyclophosphamide, cyclosporine – 50-60% partial/complete remission in steroid responsive patients – No effect on steroid-resistent patient


ACEi: – decrease proteinuria, – delay progression of renal failure


Most progress to ESRD in 5-10 years
No transplantation: recur in 50%

Membranoproliferative GN (MPGN)
5-10% of idiopathic NS in children
Rare in adult (<5%)
Proteinuria, hematuria, azothemia, edema, HTN
Mostly type I: 1/3 has recent URI Hx
70% has decreased complement (C3)
C3 nephritic factor: decrease C3

MPGN: Pathology
Type I: immune-complex GN – LM: subepithelial deposits & mesangial hypertrophy – EM: subendothelial & mesangial deposit – IF: • C3 in mesangium, • IgG, IgM deposits in capillary loop


Type II: double deposit Dz – LM: similar to type I – EM: electron dense deposit in GBM lamina densa


Type III: mesangial & subendothelial & subepithelial deposits

MPGN: Type I


The "classic" form is characterized by massive mesangial proliferation, mesangial matrix expansion and diffuse thickening of the glomerular basement membrane ‘ ’

MPGN: Type II


Type II MPGN is characterized by a dense homogenous deposition along the glomerular basement membrane and in the mesangium. Deposits can be different, in dimension and diffusion, even among the glomeruli of a given biopsy. When deposition is mild, ultrastructural examination is fundamental for diagnosis.

MPGN: Etiology
Primary
Secondary: – SLE, mixed cryoglobulinemia, Sjogren’s SD – Hep B and C, HIV, subacute bacterial endocarditis, sepsis. P. falciparum, Schistosomiasis – Cnacer: leukemia, lymphoma – Others: heroin abuse, sarcoidosis, inherited C2 deficiency, rhtombotic microangiopathies

MPGN: Tx and Prognosis
No effective therapy
Very rare spontaneous recovery
Type I: benign, 70-85% survive
Type II: variable course, – may lead to ESRD in 5-10 years

Minimal Change Disease (MCD)
m/c idiopathy NS in children (>90%)
m/c in 6-8 years old
15-20% in adult
Male > female
Highly selective proteinuria – Mostly albumin


Microscopic hematuria (20%)
Complement level: normal
No HTN, azothemia (normal BP, BUN, Cr)

MCD: Etiology
Mostly primary
Secondary – Drug induced: NSAID, rifampin, interferon – Lymphoproliferative malignancy (Hodgkin’s) – AIDS, Fabry’s Disease, Sialidosis – DM, IgA nephropathy, Heroin use – Iron dextran administration

MCD: Pathology
LM: normal
EM: foot process effacement (fusion)
IF: mostly normal – Rarely IgM and C3 deposition

MCD: Tx and Prognosis (1)
Children: 30-40% recover spontaneously
High-dose steroid: 8weeks – 90% response in children – No need to do Bx in children – Adult: 50% respond • 90% remission if used for 20-24 weeks

– Recur 50% if steroid is stopped


If no response to steroid => suspect FSGS

MCD: Tx and Prognosis (2)
Cytotoxic agent – Cyclophosphamide, chlorambucil – Cyclosporine => nephrotoxic, high recurrence rate – Ix: No response to steroid, steroid dependent, requiring high dose steroid, frequent relapse


10 year survival: >90% – Rarely progress to CRF