Nephrotic syndrome

Dr Akhator Joseph
Dept of Internal Medicine
University of Benin Teaching Hospital
NEPHROTIC SYNDROME

OUTLINE
 Definition
 Epidemiology
 Classification
 Presentation
 Complication
 Investigation
 Ateology
Minimal change disease
Focal segmental glomerulosclerosis
Mebranous nephropaty
DM nephropaty
Mebranoproliferative glomerulonephropaty
 Management of complications
 References

DEFINITION
Nephrotic syndrome is a clinical syndrome
characterized by: -
1. Heavy proteinuria (>3.5 g/day or
 urinary protein: creatinine ratio > 3 or
2. Hypoalbuminemia: Salb < 25g/L
3. Generalized oedema
4. ± Hyperlipidemia (Total Cholesterol >10mmol/L)

EPIDEMIOLOGY
The incidence of nephrotic syndrome worldwide
has been estimated to be about 3 new cases per
100,000 per year.
 In children, the annual incidence of nephrotic
syndrome ranges from 2-7 per 100,000 children,
and prevalence from 12-16 per 100,000.
Incidence /prevalence of adult nephrotic
syndrome in Nigeria is not so clear.
 However, nephrotic syndrome is not an
uncommon disease in Nigerian adult population.
1. Hull RP, Goldsmith DJ. Nephrotic syndrome in adults. BMJ. 2008 May 24;336(7654):1185-9.
2. Eddy AA, Symons JM. Nephrotic syndrome in childhood. Lancet 2003; 362 : 629-39.

Our local experience
Umezudike
et al
(Lagos)
N= 52
2009-2014
Chijioke et al
(Ilorin)
N= 52 (%)
1995-2001
Obiagwu et al
Kano n = 20
Paediatrics
2014
Oviasu et al
Benin 1992
Akinkugbe et
al
(Ibadan)
N = 81 (1965 -
67)
FSGS 25 (48) 10 (19) 8 (40) 26.3% 0
Membranous GN 1 (2) 13 (25) 3 (15) 14 (17)
MCD 6 (11) 3 (6) 4 (20) 33.3% 7 (9)
MPGN 1 (2) 15 (29) 3 (15) 2(3)
LN 16 (31) 0 0 0
IgA 2 (4) 0 0 0
Proliferative - - - 33.3% 35 (43)
Diffuse global
glomerulosclerosis
(Chr GN)
- - 1(5) 9 (11)
Diffuse mesengial
hpercellularity
- - 1(5) 0
Miscellaneous - - - 14 (17

CLASSIFICATION- etiological
• Primary Glomerular
– Minimal change disease
– Focal segmental glomerulosclerosis
– Membranous nephropathy
– Proliferative glomerulonephritis
– Mesangiocapillary
– IgA nephropathy

Secondary Glomerular
1. Infections- HBV, HCV, HIV,
Endocarditis, Post-infectious GN
2. Heredo-familial disorders- DM, SCA,
Alport’s syndrome, congenital
Nephrotic syndrome
3. Autoimmune- SLE, PAN,
4. Drugs- NSAIDS, Gold, Mercury, D-
Penicillamine, Captopril
5. Neoplastic- Hodgkin’s, Lymphoma,
Multiple myeloma, Solid tumors
6. Miscellaneous- Amyloidosis, BM
transplantation, Graft versus host ds,
Lithium, Baclizumab

PATHOPHYSIOLOGY
Hypoalbuminemia
mostly a consequence of
urinary losses
tubular catabolism of
filtered albumin
White bands in the nails
are characteristic signs
of hypoalbuminemia

Pathophysiology: proteinuria
Damage to glomerular filtration barrier leads to
passage of protein into the urine
The glomerular filter is made up of:
A charged endothelial cell glycocalyx layer
The endothelium and its fenestrations
The glomerular basement membrane (GBM)
The interdigitating podocytes with the slit diaphragm
Passage of albumin is limited by size-specific barrier
(slit diaphragm) and charge specific factors (the
anionic endothelial glycocalyx and GBM.
GBM exclude neutral molecules larger than 4 to 4.5 nm from filtration;
albumin molecules smaller than this are excluded because they are
anionic and are repelled by the negative charge on the GBM

Glomerular Barriers to Proteinuria
Glomerular basement
membrane (GBM)
Epithelial
cell foot
processes
Endothelial
cell with
fenestrations
Protein

Molecular anatomy of the podocyte foot process
The podocyte has many functions: 1) it acts as a size and charge barrier to proteins;
2) supports the glomerular capillary wall maintaining the capillary loop shape; 3)
opposes the high intraglomerular hydrostatic pressure; 4) provides synthesis and
maintenance of the GBM.
The impairment of any of these functions following podocyte injury results in proteinuria
and possibly renal failure.

Pathophysiology: proteinuria
Injury to the podocyte appears to be the major target in
diseases causing NS (podocytopathies)
Reduced levels of dystroglycans (adhesion molecules
believed to anchor podocytes to GBM) have also been
reported in MCD
 Podocyte overexpression of angiopoetinlike-4 (ANGPTL4)
has been shown to bind to the GBM, with loss of charge and
associated with nephrotic-range proteinuria.
The common ultrastructural phenotype seen in these diseases
is:
Podocyte foot process effacement
Slit diaphragm disruption
A relative or absolute depletion of podocytes

EDEMA
The underfill hypothesis holds that the loss of albumin
leading to lower plasma colloid pressure is the cause.
The overfill hypothesis states that the edema is due to
primary renal sodium retention.
Arguments against the underfill hypothesis
1. Plasma and blood volumes are normal or increased in nephrotic
syndrome.
2. The absolute decrease in plasma oncotic pressure does not affect the
volume of the intravascular space in nephrotic syndrome.
3. Bilateral adrenalectomy does not prevent sodium retention in
nephrotic syndrome in laboratory rats.

HYPERCOAGULABILITY
urinary loss of anticoagulant proteins, such as
antithrombin III and plasminogen, along with the
simultaneous increase in clotting factors, especially
factors I, VII, VIII, and X.
The net effect is a hypercoagulable state that is
enhanced further by immobility and coincidental
infection.
Individual levels of coagulation proteins are not helpful
in assessing the risk of thromboembolism, and serum
albumin is mostly used as a surrogate marker

HYPERLIPIDEMIA
The characteristic disorder is an increase in the low-
density lipoprotein (LDL), very-low-density lipoprotein
(VLDL), and/or intermediate-density lipoprotein (IDL)
fractions, but no change or decrease iHDL.
This results in an increase in the LDL/HDL cholesterol
ratio.
Hyperlipidaemia is the consequence of increased
synthesis of lipoproteins(such as apolipoprotein B, C-III
lipoprotein as a direct consequence of a low plasma
albumin.

PRESENTATION
 New-onset oedema (NS should be part of the
differential diagnosis)
 Initially periorbital or peripheral
 Later genitals, ascites, anasarca
 Frothy urine
 Generalised symptoms – lethargy, fatigue,
reduced appetite

Clinical signs/symptoms of
nephrotic syndrome
• Oedema
Periorbital oedema
Lower limb oedema
Oedema of the genitals
Ascites
• Diarrhea
Bowel wall oedema
• Low albumin
Tiredness
Leuconychia
• Breathlessness with chest pain
Thromboemboli
• Flank pain and Hematuria
Renal vein thrombosis.
• Breathlessness
Pleural effusion
Fluid overload (high
jugular venous pressure)
• Acute renal failure
Dyslipidaemia
Eruptive xanthomata
Xanthelasmata
• abdominal tenderness
peritonitis
• Other
• Frothy urine
• Infection.

Xanthelasmas in nephrotic
syndrome

Complications of Nephrotic
Syndrome
• Edema → cosmetic concerns
• Hypoalbuminemia, malnutrition
• Hyperlipidemia
• Infections- cellulitis, peritonitis,
• Thrombosis (loss of protein S & C, anti-
thrombin III)
• Poor wound healing

Other Metabolic Effects of
Nephrotic Syndrome
• Urinary loss of Vit D–binding protein low plasma 25-
hydroxyvitamin D levels.
• But plasma-free vitamin D is usually normal, and overt
osteomalacia .
• Thyroid-binding globulin lossreduced total thyroxine, but
again free thyroxine and thyroid-stimulating hormone are
normal, and there are no clinical alterations in thyroid status.
• copper, iron, or zinc deficiency caused by the loss of
binding proteins in the urine.
• Drug binding may be altered by the decrease in serum albumin.

INVESTIGATIONS
• Urinalysis 3-4+ of proteinuria; Urinary PCR >
3mg/mg or >3.5g/24 hrs
• Urine microscopy: RBC casts & dysmorphic
RBCs- proliferative GN
• Renal function: U/E/C
• Other Serum Biochemistry: Albumin, total protein,
lipid profile, Blood glucose,
• Typically, serum IgG levels are low and IgM is
increased.
• Serology
1. Infections: HBV, HCV, HIV, Syphilis
2. Immunologic: ANA, Anti-dsDNA, Complements,
Anti-PLA2R

Assessing Proteinuria
• Proteinuria on the urine dipstick is graded from 1+ to 4+, which reflects the
urine albumin concentration:
• Negative
• Trace — between 15 and 30 mg/dL
• 1+ — between 30 and 100 mg/dL
• 4+ — >1000 mg/dL
• Protein-creatinine ratio: This test calculates the total protein-to-creatinine
ratio (mg/mg). This ratio correlates with daily protein excretion expressed in
g per 1.73m2 of BSA
• Thus, a ratio of 4.9 represents a daily protein excretion of approximately 4.9 g
per 1.73 m2

Minimal Change Disease
Accounts for 10- 15% of NS in adults and 70-90% in
children.
Types:
Primary MCD
Secondary MCD
 Hodgkins dx,
 allergies,
 NSAIDs,lithium, antibiotics (cephalosporins, rifampicin, ampicillin), bisphosphonates and sulfasalazine
 infections, e.g. HCV, HIV and TB, are rarer causes.
Pathophysiology (not clear)
Circulating cytokine T-cell response altering capillary
charge and podocyte integrity.
Urine analysis
Acellular urine sediment
Microhematuria
24hr urine protine up to 10g with severe hypoalbuminemia

Normal glomerulus
Minimal change disease

Minimal Change Disease
Renal biopsy
No obvious glomerular lesion on light microscopy
No immune deposits on immunoflorecent microscopy
Effacement of the foot processes supporting the epithelial
podocyte with weakening of the slit pore membrane.
Treatment
Prednisone (1st line and ultimate drug)
Cyclophosphomide
Chlorambucil
Mycophenolate mefetil
Cyclosporine
Poor prognostic factors
AKI
Steroid resistant
1% ESRF

FOCAL SEGMENTAL GLOMERULOSCLEROSIS
• May be primary idiopathic or secondary(viruses,
e.g. HIV, erythrovirus B19, CMV,EBV). Drugs e.g
heroin, all interferons, anabolic steroids, lithium,
pamidronate and calcineurin inhibitors, e.g.
ciclosporin.)
High burden in African American
Pathophysiology
 T-cell mediated circulating permiability factor which is not well known but recent findings suggest
that cardiotrophin-like cytokine-1
 Increased soluble urokinase receptor are likely candidates in FSGS
 Podocyte abnormality associated with upregulation of CD80 in podocytes has a major role
Clinical features
NS
Impaired renal function

Biopsy
Segmental glomerulosclerosis is seen, which later progresses
to global sclerosis
The deep glomeruli at the corticomedullary junction are
affected first.
These may be missed on transcutaneous biopsy, leading to a
mistaken diagnosis of a MCD
Immunofluorescence shows deposits of C3 and IgM in
affected portions of the glomerulus
Light microscopy reveals mesangial hypercellularity, focal
tubular atrophy and interstitial fibrosis.
Electron microscopy shows capillary obliteration by hyaline
deposits (mesangial matrix and basement membrane
material) and lipids, with the other glomeruli exhibiting
ocassional primarily foot process effacement in a patchy
distribution.

Histological variants
Classic FSGS
Glomerular tip lesion
Collapsing FSGS
Perihilar variant
Cellular variant
Treatment
Prednisolone (0.5-2mg/kg/day * 6/12)
Cyclosporin(150-200ng/ml)
Cyclophosphamide,Chlorambucil, azathioprine
Poor prognostic factors
African american origin
Previous transplant
 Plasmaphoresis
 Immunoabsorption
About 50% of patients progress to ESKD within 10 years of
diagnosis..

FSGS
FSGS is diagnosed by the presence of sclerosis in parts (segmental) of some (focal)
glomeruli by light microscopy plus diffuse (>80 percent) effacement of the
foot processes by electron microscopy

MEBRANOUS GLOMERULOPATHY
Accounts for 20-30% of NS in adults and 2-5% in
children
Mainly primary idiopathic but can be secondary to
(Hepatitis B, Drugs e.g gold,penicilinamine and
NSAIDs, autoimmunitye.gthyroid and
SLE,malignancy
Pthophysiology
 IgG4 type autoantibodies against phospholipase receptor A2 (PLA2R),
a glycoprotein protein constituent of normal glomeruli.
 Specific IgG4 autoantibodies to anti-aldose reductase (AR) and anti-
manganese superoxide dismutase (SOD2) have also been found in the
sera and glomeruli of patients with membranous nephropathy but not
in other renal pathologies or normal kidney.

Treatment
Chlorambucil (0.2 mg/kg per day in months 2, 4 and 6
alternating with oral prednisolone 0.4 mg/kg per day in
months 1, 3 and 5) or
cyclophosphamide (1.5–2.5 mg/kg per day for 6–12 months
with 1 mg/kg per day of oral prednisolone on alternate days
for the first 2 months) are equally effective.
The alkylating agents, cyclophosphamide and chlorambucil,
Cyclosporine, mycophenolate and Anti-CD20 e.g rituximab
Poor prognosis
Males
Severe or prolonged nephrosclerosis(protinuria >6g/day >6/12),
hypertension and
High degree of renal impairment are
MEBRANOUS GLOMERULOPATHY

DIABETIC NEPHROPATHY
People with type 1 and type 2) have equivalent rates of
proteinuria, azotaemia, and ultimately ESKD.
Renal lesions are more common in African-American,
Native American, Polynesian, and Maori populations.
Risk factors for the development of diabetic nephropathy
include ( hyperglycemia, hypertension, dyslipidemia,
smoking, a family history of diabetic nephropathy, and
gene polymorphisms affecting the activity of the renin-
angiotensin-aldosterone axis.

Pathophysiology
Direct effects of hyperglycemia on the actin cytoskeleton of renal
mesangial and vascular smooth-muscle cells may account for
intra glomerular hypertension.
Sustained glomerular hypertension increases matrix production,
alterations in the GBM with disruption in the filtration barrier
(and hence proteinuria), and glomerulosclerosis.
Within 1–2 years after the onset of clinical diabetes, morphologic
changes appear in the kidney.
Microalbuminuria appears 5–10 years after the onset of diabetes.

Biopsy (usually diagnosed without a renal biopsy)
Light microscopy shows prominent vascular changes
Immunofluorescence microscopy often reveals the nonspecific
deposition of IgG
electron microscopy shows complement staining without immune
deposits.
Treatment
Life style modification
BP and glycemic control
ACE inhibitor and ARBs
Paricalcitol (pxs who respond poorly to ACE inhibitor and ARB
therapy).

MESANGIOCILLARY(MEMBRANOPROLIFERATIVE)
GLOMERULONEPHRITIS
It is an immune-mediated glomerulonephritis
characterized by thickening of the GBM wit
mesangioproliferative changes
70% of patients have hypocomplementemia.
rare in African Americans, and idiopathic disease
usually presents in childhood or young adulthood.
Subdivided pathologically into type I, type II, and
type III disease.
reclassified into
immunoglobulin-mediated disease (driven by the classical
complement pathway) and
non–immunoglobulin-mediated disease (driven by the alternative
complement pathway).

MESANGIOCILLARY(MEMBRANOPROLIFERATIVE) GLOMERULONEPHRITIS
Type 1 MCGN.
 Most proliferative of the three types,
 renal biopsy shows
 mesangial proliferation with lobular segmentation and
 mesangial interposition between the capillary basement membrane
and endothelial cells, producing a double contour sometimes called
tram-tracking
 Subendothelial deposits with low serum levels of C3 in classical
pathway are typical.
 often idiopathic but occurs with chronic infection (abscesses,
infective endocarditis, infected ventriculoperitoneal shunt) or
cryoglobulinaemia secondary to hepatitis C infections

MESANGIOCILLARY(MEMBRANOPROLIFERATIVE)
GLOMERULONEPHRITIS
Type 2 MCGN. (dense deposit disease)
 Low serum C3 and a dense thickening of the GBM containing ribbons
of dense deposits is typical
 Intramesangial deposits are rarely present and subendothelial deposits
are generally absent.
 This type may be idiopathic or be associated with partial lipodystrophy
(loss of subcutaneous fat on face and upper trunk).
 affects young adults who have low C3 levels as in type 1 but this is due
to the activation of the alternative pathway of the complement cascade.

MESANGIOCILLARY(MEMBRANOPROLIFERATIVE) GLOMERULONEPHRITIS
Type 3 MCGN
Proliferation is less common and often focal
mesangial interposition is rare, and subepithelial
deposits can occur along widened segments of the
GBM that appear laminated and disrupted..
Complement activation appears to be via the final
common pathway of the cascade.

MESANGIOPROLIFERATIVE GLOMERULONEPHRITIS
Features
Expansion of the mesangium,
mesangial hypercellularity;
thin, single contoured capillary walls;
mesangial immune deposits.
Clinically, it can present with varying degrees of
proteinuria and, commonly, hematuria.
may be seen in
IgA nephropathy,
Plasmodium falciparum malaria,
resolving postinfectious glomerulonephritis, and

MESANGIOPROLIFERATIVE GLOMERULONEPHRITIS
diagnosis of primary mesangioproliferative
glomerulonephritis is made in less than 15% of
renal biopsies. As an immune-mediated renal lesion
with deposits of IgM, C1q, and C3,
Clinical course:
Patients with isolated hematuria may have a very benign course,
and
those with heavy proteinuria occasionally progress to renal
failure.
Treatment
 BP control
 Steroids
 Aspirin (325mg dailyx 6-12/12)
 Dypyridamole (75-100mg daily x 6-12/12)
 Treat underlying cause

OTHER CAUSES OF NEPHROTIC SYNDROME
Glomerular deposition diseases
Light Chain Deposition Disease
Renal Amyloidosis
Fibrillary-Immunotactoid Glomerulopathy
Fabry’s disease
Systemic lupus erythematosus (lupus
glomerulonephritis)
Cryoglobulinaemic renal disease

MANAGEMENT OF NEPHROTIC SYNDROME
Treatment of Nephrotic Edema
• mainstays of treatment nowadays are diuretics
accompanied by
• moderate dietary sodium restriction (60 to 80
mmol/24 h).
• Oral diuretics with twicedaily administration are
usually preferred, given the longer therapeutic
effect compared with intravenous diuretics.
• However in severe nephrosis intravenous diuretic,
by bolus injection is used.
• Loop + thiazide or metolazone
• Daily weight is the best measurement of progress

Correction of Hypoproteinemia
• adequate dietary protein should be ensured (0.8 to 1
mg/kg per day) with a high carbohydrate intake to
maximize use of that protein.
• In heavy proteinuria amount of urinary protein loss
should be added to dietary protein intake.
• Nephrectomy in extreem proteinuria
– Medical nephrectomy
– Radiological
– Surgical

Treatment of Hypercoagulability
• High risk
– Serum albumin less than 2.5g/dL
– Immobility as a consequence of edema/hospitalisation
• Prophylactic low-dose anticoagulation (e.g.,
heparin 5000 units subcutaneously twice daily)
• Full dose if
– Serum albumin <2g/dL
– Hx of PE or DVT
• Warfarin for long term use.
• INR 2-3

Management of Infection
• Bacteremia is common even if clinical signs are
localized.
• ESR is unhelpful, but an elevated C-reactive protein
level may be more informative.
• Parenteral antibiotics should be started once culture
specimens are taken, and the
• regimen should include benzylpenicillin (to cover
pneumococci).
• administration of intravenous immune globulin (10
to 15 g).

Treatment of Proteinuria
• blocking efferent arteriolar constriction (ACE
inhibitors or ARBs)
• ACE inhibitors andARBs, which reduce proteinuria by an
average of 40% to 50%, particularly if the patient is on dietary
salt restriction.
• by reducing preglomerular pressure (most other
classes of antihypertensives)
• NSAIDs lessen proteinuria by reducing intrarenal
PG production and
• dipyridamole through adenosine-mediated afferent
arteriolar vasoconstriction

Treatment of Hyperlipidemia
• Dietary restriction alone has only modest effects on
hyperlipidemia
• Statin terapy

REFERENCES
Harrisons principle of internal medicine 20th
edition
WWW.Uptodate.com
http://www.kdigo.org/clinical_practice_guideli
nes/pdf/KDIGO-GN-Guideline.pd
Emedicine.medscape.com
NKF Primers on kidney diseases
Comprehensive Clinical Nephrology

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