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Azazhu Datiko , MD
Definition
The nephrotic syndrome is defined by:
1. Albuminuria >3.5g/1.73m2/day (in practice > 3 to 3.5 g/day)
2. Hypoalbuminemia
3. Edema
4. Hyperlipidemia
The cardinal sign of nephrotic syndrome is “nephrotic-range”
proteinuria;
proteinuria the other manifestations are consequences of the
proteinuria.

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 Nephrotic syndrome results from a marked increase in
glomerular permeability to protein and other macromolecules.
 Hypoalbuminemia is in part a consequence of urinary protein
loss.
 It is also due to the catabolism of filtered albumin by the
proximal tubule, as well as redistribution of albumin within
the body.

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 Edema is the most common presenting symptom of patients
with the nephrotic syndrome.
 The pathophysiology of edema formation in nephrotic
syndrome is poorly understood.
 It may occur through at least two different major mechanisms.
1. Arterial underfilling as the low plasma oncotic pressure leads to
plasma volume depletion (The underfilling hypothesis)
hypothesis
2. Sodium retention directly induced by the renal disease (primary
renal salt and water retention)
retention

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 The underfilling hypothesis
NEPHROTIC SYNDROME

Proteinuria
Hypoalbuminemia

Plasma oncotic pressure

Transcapillary fluid shift

Intravascular volume depletion

Underperfussion of the kidneys

Activation of Activation Release Suppression of

RAAS of SNS of AVP ANP release

EDEM
Renal Na & volume retention
A 5
 Hyperlipidemia is believed to be due to:
o Increased hepatic lipoprotein synthesis that is triggered by reduced
oncotic pressure.
o Increased urinary loss of proteins that regulate lipid homeostasis
o Defective lipid catabolism.

 Low-density lipoproteins and cholesterol are increased in the

majority of patients, whereas very low density lipoproteins
and triglycerides tend to rise in patients with severe disease.
 Hyperlipidemia may accelerate atherosclerosis and
progression of renal disease.

Hyperlipidemia is accompanied by lipiduria  fatty cast in urine 6

 Hypercoagulability is due to:
o Increased urinary loss of antithrombin III
o Altered levels and/or activity of proteins C and S
o Hyperfibrinogenemia due to increased hepatic synthesis
o Impaired fibrinolysis
o Increased platelet aggregability.
 Consequence of these impairments are:
o Spontaneous peripheral arterial or venous thrombosis
o Renal vein thrombosis
o Pulmonary embolism

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 Clinical features that suggest acute renal vein thrombosis
include:
o Sudden onset of flank or abdominal pain
o Gross hematuria
o Left-sided varicocele (the left testicular vein drains into the renal vein)
o Increased proteinuria
o Acute decline in GFR
 Chronic renal vein thrombosis is usually asymptomatic.
 Renal vein thrombosis is particularly common (up to 40%) in
patients with nephrotic syndrome due to membranous
glomerulopathy, MPGN, and amyloidosis.

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Other metabolic complications of nephrotic syndrome include:
Protein malnutrition
Iron-resistant microcytic hypochromic anemia due to transferrin loss.
Hypocalcemia and secondary hyperparathyroidism can occur as a
consequence of vitamin D deficiency due to enhanced urinary excretion
of cholecalciferol-binding protein.
Loss of thyroxine-binding globulin can result in depressed thyroxine
levels.
An increased susceptibility to infection due to low IgG levels as a
result of urinary loss and increased catabolism.
Unpredictable changes in the pharmacokinetics of therapeutic agents
that are normally bound to plasma proteins.

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Clinical condition against or not suggestive of NS
Decrease in renal function is unusual early in the course of
disease.
o A rise in the serum creatinine level is usually a feature of more
advanced disease.
The urinary sediment is typically devoid of red and white cells
or casts and is termed an inactive urinary sediment.
sediment
Pulmonary edema is uncommon in nephrotic syndrome.

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 The etiology of nephrotic syndrome is separated into primary
and secondary causes.
 Primary glomerular diseases make up to 75% of cases of
nephrotic syndrome.
 About a quarter to one-third of adult patients with nephrotic
syndrome have a systemic renal disease such as DM,
amyloidosis, or SLE.

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 The most common primary (IDIOPATHIC) glomerular
diseases that cause nephrotic syndrome in adults are:
1. Minimal change disease [5–10%]
2. Focal segmental glomerulosclerosis [20–25 %]
3. Membranous nephropathy [25–30 %]
4. Membranoproliferative glomerulonephritis [5 %]
5. Other proliferative and sclerosing glomerulonephritides [15–30 %]
 Although these disease entities are usually primary (and
idiopathic), each can also be secondary to an underlying
systemic disease.
 However, the glomerular histology is indistinguishable in
primary and secondary forms.

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 NEPHROTIC SYNDROME ASSOCIATED WITH SPECIFIC CAUSES
(“SECONDARY” NS)

SYSTEMIC DISEASES
Diabetes mellitus
SLE & other collagen diseases
Amyloidosis (amyloid AL or AA associated)
Vasculitic-immunologic disease
INFECTIONS
Bacterial (poststreptococcal, congenital and 20 syphilis, SBE)
Viral (HBV, HCV, HIV infection, infectious mononucleosis, CMV infection)
Parasitic (malaria, toxoplasmosis, schistosomiasis, filariasis)
MEDICATION RELATED
Gold, mercury, and the heavy metals
Penicillamine
NSAID
Lithium
NEOPLASMS
Hodgkin's lymphoma and leukemia-lymphomas (with minimal change lesion)
Solid tumors (with membranous nephropathy)

Diabetes mellitus and amyloidosis are the leading causes of secondary

nephrotic syndrome. 13
 “SECONDARY” NEPHROTIC SYNDROME…

HEREDITARY AND METABOLIC DISEASE

Alport's syndrome
Sickle cell disease
Familial nephrotic syndrome
OTHER
Pregnancy related (includes preeclampsia)
Transplant rejection
Serum sickness
Accelerated hypertensive nephrosclerosis
Unilateral renal artery stenosis
Massive obesity–sleep apnea syndrome
Reflux nephropathy
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 Initial evaluation of a nephrotic patient includes laboratory
tests to define whether the patient has primary, idiopathic
nephrotic syndrome or a secondary cause related to a systemic
disease, toxin, or medication.
 Common screening tests include:
 FBS and glycosylated Hb tests for diabetes
 ANA test for collagen vascular disease
 Serum complement, to screen for many immune complex–mediated
diseases.
 In selected patients, cryoglobulins, hepatitis B and C serology,
ANCA, anti-GBM antibodies, and other tests may be useful.

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 24-h urine for protein; creatinine clearance
o Urine dipstick is easy and can easily pick nephrotic range proteinuria ( 3+ or
4+)
 Serum albumin, cholesterol, complement
 Urine protein electrophoresis
 Rule out SLE, DM
 Review drug exposure
 Renal biopsy
 Consider malignancy (in elderly pt with membranous GN or minimal
change disease)
 Consider renal vein thrombosis (if membranous GN or symptoms of
pulmonary embolism are present)

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 Once secondary causes have been excluded, treatment of an
adult nephrotic patient often requires a renal biopsy.
o Renal biopsy is the best guide to treatment and prognosis

 If renal biopsy is impossible, infectious disease (HBV, HCV,

HIV, syphilis, …) should be effectively ruled out before
thinking of any immune-suppresive therapy.
 Minimal change disease, the commonest type of NS in young
age, is highly responsive to steroid therapy.

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Four principles guide the management of the nephrotic
syndrome.
1.Treat any complications:
 Reduce fluid overload with diuretics & salt restriction
 Provide anticoagulation therapy for patients at high risk for venous
thrombosis (e.g., those with a serum albumin level < 2.0 g)
 Aggressively treat hypertension (BP goal < 130/80 mm Hg)
 Decrease hyperlipidemia with statins.
Lower proteinuria to less than 1 g/24 hr.
Use disease-specific therapy when possible.
Treat the underlying secondary cause if one is present.

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 Nonspecific measures that may reduce proteinuria include
ACE inhibitors, ARBs, and NSAIDs.
 ACE inhibitors and ARBs reduce proteinuria and slow the rate
of progression of renal failure by lowering intraglomerular
pressure and preventing the development of hemodynamically
mediated focal segmental glomerulosclerosis.
 ACE inhibitors are renoprotective in human diabetic
nephropathy and many other proteinuric glomerulopathies.

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 Anticoagulation is indicated for patients with DVT, arterial
thrombosis, and pulmonary embolism.
 Patients may be relatively resistant to heparin as a
consequence of antithrombin III deficiency.
 The potential value of dietary protein restriction for reducing
proteinuria must be balanced against the risk of contributing to
malnutrition.
 Vitamin D supplementation is advisable in patients with
clinical or biochemical evidence of vitamin D deficiency.

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 NS is classically characterized by four clinical features : -
Nephrotic range proteinuria, Hypoalbuminemia, Edema, &
Hyperlipidemia.
 Primary (idiopathic) glomerular diseases make for the
majority of cases of NS.
 Membranous nephropathy is the commonest of NS in adults as
is minimal change disease in children.
 Urinalysis is the single most important screening tool for
nephrotic syndrome.
 Treatment of adult NS should be based on renal biopsy finding
and ruling out secondary causes.

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