Nephrotic Syndrome

Abdulrahman Mashi

Nephrotic Syndrome
Nephrotic-range proteinuria : urine protein
excretion of >3.5 g/24 h or a urine proteincreatinine ratio of >3500 mg/g in a 'spot'
morning urine sample
Hypoalbuminemia (serum albumin< 3 g/dL).
Edema
Hyperlipidemia

 Pathogenesis
Permeability of glom.cap.memb.
Intravascular vol

Hypoalbuminemia

Renal perfusion
pressure

ADH
Water
Reabsorptn
In
Collecting
ducts

Proteinuria

Hepatic protein synthesis

Hyperlipidemia

Actv. reinin
Ang. ald. sys
Tubular reabsorp.

Overfill Of Na
Model

Plasma oncotic
pressure

Underfill
Model

Transudation of fluid
from intravascular
comp. To interstial
space
Edema

 Elevated lipids occur from a combination

of
increased hepatic apolipoprotein
synthesis in response to a low plasma
oncotic pressure
decreased activity of key enzymes such
as lipoprotein lipase and lecithincholesterol acyltransferase.

Nephrotic Syndrome
Nephroti
c
Syndrom
e
Primary(Idiopat
hic)

Secondary

Nephrotic Syndrome
Primary (idiopathic)
Minimal change disease (MCD)
Membranous nephropathy (MN)
Focal segmental glomerulosclerosis (FSGS).
Mesangiocapillary (Membranoproliferative) GN
(MCGN / MPGN)
Fibrillary glomerulopathy : may be assocaited e
malignacy

Immunotactoid glomerulopathy :

May be
associated with chronic lymphocytic leukemia or B-cell
lymphomas

Nephrotic Syndrome
Secondary
Diabetes (the most common)
Infections
Drugs
Autoimmune diseases
Amyloidosis
Monoclonal immunoglobulin deposition
disease

Nephrotic Syndrome
Important points
Minimal change glomerulopathy is the most common cause of the
nephrotic syndrome in children
Membranous glomerulopathy and FSGS are the most common
causes of idiopathic nephrotic syndrome in adults.
Membranous glomerulopathy is the most common worldwide
FSGS is the most common in US and now increasing to be the most
common worldwide
FSGS is the most common cause in black persons
Membranous glomerulopathy is the most common cause in white
persons
Membranous glomerulopathy has the highest predilection for
renal vein thrombosis among all causes of the nephrotic syndrome

Evaluation

Treatment
General measures:
Elevated lipid levels are typically
treated with statin medications
Prophylactic anticoagulation :
In any type of Nephrotic if albumin level
2.0 g/dL (20 g/L) with low bleeding risk
regardless of cause.
In patients with membranous
glomerulopathy with low risk for bleeding
has been if albumin 2.8 g/dL (28 g/L).

Treatment
General measures:
Edema is treated with a low salt diet
and loop diuretics (alone or in
combination with a thiazide and
potassium-sparing diuretics).
ACE and ARB to reduce proteinurea
Maintain good nutrition
Treatment of underlying cause

 Complications

FSGS
Causes:
Idiopathic :

Some cases of idiopathic FSGS are thought to

be related to a circulating plasma factor because a significant
number of patients show recurrence after kidney
transplantation.

Genetic mutations to podocyte proteins

Secondary :
Hyperfiltration injury to the glomerulus (DM,
HTN &Morbid obesity )

Reduced kidney mass: progressive kidney disease,

obesity, sickle cell disease, reflux nephropathy,
congenital small kidneys

Direct podocyte injury: infections (HIV) and drugs

(pamidronate, interferon and NSAID). Lymphoma

FSGS
Five subtypes
not otherwise specified
perihilar variant
tip variant
cellular variant
collapsing variant (may be associated with
HIV infection, heroin use, parvovirus
infection, or pamidronate exposure)

FSGS
Clinical Manifestations :
Either asymptomatic proteinuria or edema.
More than two thirds of patients are fully
nephrotic at presentation
Subnephrotic proteinuria may occur,
especially with secondary FSGS from
hyperfiltration injury.
Hypertension, microscopic hematuria, and
varying degrees of kidney failure are
common.

FSGS
Diagnosis
The hallmark of FSGS is the presence of
segmental scars in some glomeruli.
Electron microscopy shows visceral
epithelial cell foot process effacement
no immune deposits.

Treatment and Prognosis

In idiopathic FSGS, only a minority of patients
experience a spontaneous remission.
Therefore, treatment is indicated in most
patients.
Therapy is usually with glucocorticoids or calcineurin
inhibitors, both at the time of initial presentation and
for relapsing disease.
A complete or partial remission may be seen in up to
40% to 60% of patients using these treatments.
FSGS recurs in the transplanted kidney in 30% or more
of cases.

 In secondary FSGS caused by infection or

drugs, treatment of the infection or removal
of the offending agent may halt progression
of the disease and improve symptoms.
In obese patients with likely secondary
FSGS, weight loss is sometimes associated
with a drop in proteinuria, as is the use of
ACE inhibitors or angiotensin receptor
blockers (ARBs), and is the preferred initial
therapy.

Membranous Glomerulopathy
Primary or secondary
Primary form (most common
worldwide): antiphospholipase
A2receptor autoantibodies can be
found in 75% of cases lead to
activation of complement and
damage the GBM.

Membranous Glomerulopathy
May be associated with or secondary to:
SLE
Infections: hepatitis B and C virus infections; syphilis;
malaria
Medication exposure: penicillamine; NSAIDs; TNF-
inhibitors; tiopronin
Mercury or gold exposure
Malignancies: Solid organ Malignancy (bladder,
breast, colon, lung, pancreas, prostate, stomach
carcinoma); carcinoid; sarcomas; lymphomas;
leukemias
Thyroid disease

Clinical Manifestations
Like other causes of the nephrotic
syndrome (edema, hypertension,
microhematuria), but the propensity to
thromboembolic events (particularly
renal vein thrombosis) is much higher.
Secondary causes should be sought,
particularly occult malignancy in older
patients.

Membranous
Glomerulopathy
Diagnosis
Light microscopy shows glomerular capillary
loops that often appear thickened without
any proliferative lesions.
Immunofluorescence and electron
microscopy show subepithelial immune
dense deposits.
Where available, PLA2R antibodies
should be measured.

Treatment
Up to one third of patients with idiopathic MG remit
spontaneously in 6 to 12 months.
Conservative management is appropriate during
this period.
In patients with idiopathic MG who have
persistent disease after 6 to 12 months or
who have worsening kidney function or a
thromboembolic event, regimens containing
alternating glucocorticoids with cyclophosphamide
or calcineurin inhibitors (cyclosporine or tacrolimus)
may be used.

Treatment
Other options for relapsing or refractory
disease include mycophenolate mofetil,
adrenocorticotropic hormone, and the
antiB-cell antibody rituximab.
For secondary causes of MG treat the
underlying cause like treatment of
hepatitis B virus infection with antiviral
agents

Minimal Change Glomerulopathy

Minimal change disease is the most common cause of
idiopathic nephrotic syndrome in children and
accounts for approximately 10% of cases in adults.
The pathogenesis of MCG is not fully understood but
is thought to be related to production of cytokines by
immune cells that lead to podocyte dysfunction.
A history of viral respiratory infection, atopy, or
immunization preceding the onset of edema
may be present.

Minimal Change Glomerulopathy

Primary form (Idiopathic)
secondary :
Medications (such as NSAIDs, lithium,
pamidronate, rifampin and the interferons)
Malignancies (such as Hodgkin
lymphoma , other lymphoproliferative
disorders and thymoma)
Infections: Infectious Mononucleosis and TB

Clinical Manifestations
Patients with MCG typically present
with acute onset of edema and
weight gain due to fluid retention.
Urine protein levels tend to be
significantly elevated (urine proteincreatinine ratio typically 5000-10,000
mg/g).

MCD
Diagnosis
Normal glomeruli on both light and
immunofluorescence microscopy.
The tubules may show lipid accumulation.
On electron microscopy, the GBM is
normal with extensive effacement of
visceral epithelial foot processes.

Treatment
Patients typically respond to glucocorticoids (1mg/kg/d or
2mg/kg every other day )within 8 to 16 weeks.
Complete remission achieved in around 70 %
Relapse is common, and in up to 40% of patients, the
course of MCG is one of remission followed by relapse.
For frequently relapsing or glucocorticoid-dependent
disease, treatment options include cyclophosphamide,
calcineurin inhibitors (tacrolimus or cyclosporine),
mycophenolate mofetil, and rituximab.

Diabetic Nephropathy
Diabetic nephropathy (DN) is the
leading cause of ESKD in the United
States
The strongest clinical indicator for
progressive kidney disease is the
level of urine albumin.

Risk factors for developing DN

older age
race (American Indian, Mexican American,
and black)
poor glycemic control
hypertension
cigarette smoking
family history of kidney disease

Clinical Manifestations
Moderately increased albuminuria (formerly known
as microalbuminuria), defined as a urine albumincreatinine ratio of 30 to 300 mg/g, is typically the first
abnormality seen in patients with type 1 and type 2
diabetes.

Overt nephropathy (formerly known as overt

proteinurea) (urine protein-creatinine ratio >300 mg/g)
occurs around 10 to 15 years from disease onset in
approximately 50% of patients with moderately
increased albuminuria and progresses to ESKD in most
patients.

Diagnosis
Annual testing for albuminuria should begin at
the time of diagnosis in type 2 diabetes and 5
years after diagnosis in type 1 diabetes.
Kidney biopsy is not indicated unless there is
a suspicion of another glomerular disease.
On electron microscopy, the GBM is normal
with extensive effacement of visceral
epithelial foot processes.
Moderately increased albuminuria defined as
a urine albumin-creatinine ratio of 30 to 300
mg/g
Overt nephropathy (urine proteincreatinine ratio >300 mg/g)

Indications for kidney biopsy

acute onset of the nephrotic syndrome
findings of another systemic disease
short duration from onset of diabetes to onset
of proteinuria
abnormal serologies
rapid rate of progression of kidney
dysfunction

Pathology
DN affects every compartment of the kidney.
In the glomerulus, there is expansion of the
mesangium and thickening of the basement
membrane, followed by focal (nodular) sclerosis
(the Kimmelstiel-Wilson lesion) then global
sclerosis of the glomerulus.
Interstitial fibrosis, tubular atrophy with
thickened tubular basement membranes, and
arteriolosclerosis are also seen.

Treatment
Achieving targets of glycemic control
(hemoglobin A1c<7%) and blood
pressure (<140/90 mm Hg.
In patients who have diabetes with
moderately increased albuminuria or
severely increased albuminuria , ACE
inhibitors or ARBs have been shown to
slow progression.

Read about

MPGN
Amylodosis
Multiple Myloma
HIV associated nephropathy
Hepatitis B associated kidney disease

References