NEPHROTIC SYNDROME

► Nephrotic syndrome is a clinical syndrome defined by massive

proteinuria responsible for hypoalbuminaemia, with resulting
hyperlipidaemia, oedema, and various complications.
► It is caused by increased permeability through the damaged basement
membrane in the renal glomerulus
► It results from an abnormality of glomerular permeability that not only
may be caused by primary (idiopathic) glomerular diseases but also may be
secondary to a large number of identifiable disease.
► Adults sometimes present with only pedal edema and frothing of urine There
may not be any typical signs and symptoms often leading to misdiagnosis
► A BIOPSY must be done in all cases and secondary causes must be ruled out
after biopsy .
NEPHROTIC RANGE PROTEINURIA :

► >3.5gm/24hrs
► URINE PROTEIN CREATENINE RATIO >3.5
► URINE ALBUMIN CREATENINE RATIO >2.2
 HYPOALBUMINEMIA :

► The most common systemic abnormalities associated with

nephrotic proteinuria is hypoalbuminemia.
► Clinical manifestations of the nephrotic syndrome become evident
in patients with levels of proteinuria in excess of 3.5 g/day.
► Albumin accounts for more than 80% of the excreted proteins.
► In patients with the nephrotic syndrome, hypoalbuminemia results
from excessive urinary loss, decreased hepatic synthesis, and
increased rates of albumin catabolism.
HYPERCOAGULABILITY :
• Urinary loss of proteins involved in coagulation cascade and adaptive
increased synthesis of other factors induces a hypercoagulable state

• Loss of Antithrombin III , Protein C and Protein S , Increase in fibrinogen ,

factor V and VII , increased platelet aggregation

• There is an inverse correlation between serum albumin and fibrinogen

levels in the nephrotic syndrome.
• Thromboembolic events are serious complications of the nephrotic
syndrome. The most frequent site of thrombosis is the renal vein.
 EDEMA :
The following are the two hypotheses for the occurrence of edema
in nephrotic syndrome:
❖ UNDERFILL HYPOTHESIS :
Increased glomerular permeability causes albuminuria, eventually
leading to hypoalbuminemia resulting in a decline in plasma colloid osmotic
pressure. Subsequently, this process leads to the development of edema.
❖OVERFILL HYPOTHESIS :
An alternative hypothesis states that an intrinsic defect in the
renal tubules leads to a decline in sodium excretion. This might occur if the
intraluminal protein directly causes renal epithelial sodium reabsorption.
DYSLIPIDEMIA :

► Blood levels of cholesterol are almost always increased and continue

to rise as the severity of the nephrotic syndrome increases
► Levels of triglycerides are more variable and in many patients do not
increase at all
► Two mechanisms contribute to nephrotic dyslipidemia:
overproduction and impaired catabolism/clearance of serum lipids
and lipoproteins
► Hepatic activity of hydroxymethylglutaryl CoA reductase, the rate-
limiting step for hepatic synthesis of cholesterol, is elevated.
► The most important consequence of hyperlipidemia is its potential
for inducing cardiovascular disease.
► REMISSION :
Urinary Albumin Nil for 3 consecutive days OR
Urine ACR < 200 mg/g
► RELASPE :
Persistence of proteinuria in spite of achieving remission for one
month.
► STEROID NON RESPONDERS :
Persistence of proteinuria at the end of 16 weeks even on
full doses of steroids
► STEROID DEPENDENCE :
Development of nephrotic syndrome within 14 days of
stopping steroid or on tapering doses of steroids.
MINIMAL CHANGE DISEASE
► Minimal change disease accounts for nephrotic syndrome in 15-20% of adults , most
common in children.
► Almost all cases are idiopathic , very few have an identifiable cause such as NSAIDS
or Hodgkin's lymphoma
► It presents clinically with Edema predominantly, hypertension (50% of
adults),microscopic hematuria (33% adults ), decreased renal function , atopy or
allergic symptoms in 30 % of adults .
► Nephrotic range proteinuria of about 10 g in 24 hrs with hypoalbuminemia seen
Selective proteinuria occurs , principally contains albumin with minimal amounts of
high molecular weight proteins
► On light microscopy, glomeruli appear normal , there is no significant glomerular
deposition of Igs or complement on immunofluorescence.
► Electron microscopy reveals retraction of the epithelial foot processes along with
obliteration of slit pores.
Treatment
► Corticosteroids are the mainstay of therapy. In adults prednisolone given at
1mg/kg/day (not exceeding 80mg/day ) or 2mg/kg alternate days ( not
exceeding 120mg/day).
► The time of remission in adults is about 16 weeks.
► Steroid resistance is defined as no remission at the end of 16 weeks of
therapy.
► Then in such cases cyclophosphamide (2mg/kg/day) for 12 weeks may be
given to induce a prolonged remission .
► Cyclosporine or tacrolimus or Ritiuximab can also be used in patients with
frequent relapses or steroid dependency.
► Prognosis is usually good in steroid responsive patients .
 FSGS :
❑ Focal segmental glomerulosclerosis (FSGS) is neither a disease nor a
syndrome, but rather a set of clinicopathologic syndromes that has
multiple causes and pathogenic mechanisms
❑ Typically, idiopathic FSGS is seen in patients aged 18 - 45 .
❑ FSGS accounts for approximately 35% of cases in adults idiopathic
nephrotic syndrome.
►PATHOGENESIS :
❑ Podocytes are the principal target of the lesions, leading to the
characteristic sclerotic pattern involving part (focal) of some
(segmental) glomeruli
❑ In FSGS, the presence of a circulating factor that results in
PODOCYTOPATHY in a form of podocyte effacement and disruption
of the glomerular filtration barrier along with decrease in number of
podocytes.

❑ Circulating permeability factors:

i. SUPPAR :Soluble urokinase plasminogen activator receptor
ii. CLC1 : Cardiotropin like cytokine
iii. APOL1
CLASSIFICATION:
 CLINICAL FEATURES :

► Proteinuria in FSGS is typically nonselective, consisting of both small and large proteins,
including albumin.
► Edema, hypoalbuminemia, and hyperlipidemia are typically present in primary FSGS while
less common in other forms.
► Hypertension is common, and decreased glomerular filtration rate GFR is noted in
approximately one-third of patients at presentation.
► Hematuria occurs in over 50% of FSGS patients, and approxiately one-third of patients present
with some degree of renal insufficiency
1. 75%- NEPHROTIC RANGE PREOTEINURIA
1. PRIMARY FSGS: PRESENTS WITH NEPHROTIC SYNDROME
2. SECONDARY FSGS : PRESENTS WITHOUT SYNDROME
2. 25% - ASYMPTOMATIC , MILD HEMATURIA PROTEINURIA
3. 70% - PATIENT MAY DEVELOP CKD AFTER 10YRS
LIGHT MICROSCOPY:
Moderate increase in MESANGIAL matrix with
SEGMENTAL adhesion of glomerular tuft to bowmans
capsule and obliteration of capillary lumina

IMMUNOFLOROSENCE:
irregular segmental staining for C3 corresponding to a site
of segmental sclerosis
 TREATMENT:
► ACE inhibitors and ARBs have been evaluated in the treatment of FSGS. ACE
inhibitors have been shown to decrease proteinuria and the rate of progression
to ESKD in diabetic and nondiabetic kidney disease.
► Initial course of Prednisone of 1mg/kg/ day to be given for nephrotic range
proteinuria for 16 weeks
► In steroid-dependent patients who develop frequent relapses, repeated rounds
of high-dose corticosteroid therapy result in unacceptable cumulative toxicity.
Thus, alternative strategies, such as the addition of cyclosporine, may be
useful.
► FSGS that is resistant to prednisone may be induced into remission by
cyclosporine (5 mg/kg/day)
 MEMBRANOUS NEPHROPATHY :
► Membranous nephropathy (MN) is the most common cause of adult-onset nephrotic syndrome.
► In INDIA 50% of adult nephrotic patients biopsied found to have MN.

❑ PATHOGENESIS :
❖ It is characterized by deposition of immune complexes and complement components in the
glomerular capillary wall and SUBEPITHELIAL in location with basement membrane synthesis.
❖ TARGET Antigens involved:
❖ 1. M TYPE PLA2R: 80% of patients
❖ 2.Thrombospondin 7A
❖ 3.NELL1:Neural Epidermal like growth factor
❖ 4.SOMAPHORIN 3b
❖ 5.MEGALIN AND NCAM

❖ These antigens are present inside podocytes.

❖ Thus Antibodies are formed against these antigens Leading to secondary podocyte injury.
PATHOLOGHY :
► LIGHT MICROSCOPY :
❖ glomeruli appear normal. Increasing the size and number of immune complexes
in the subepithelial space produces a thick GBM . No cell infiltration and
Hypercellularity seen
► SILVER METHINAMINE STAIN :
❖ New basement membrane is formed around the immune complexes producing the
spikes along the epithelial side of the basement membrane.
► IMMUNOFLUORESCENCE MICROSCOPY :
❖ beaded appearance along the GBM (capillary wall), a pattern that is
pathognomonic of MN on immunofluorescence.
► ELECTRON MICROSCOPY :
❖ The majority of cases show extensive podocyte foot process effacement, even at
the early stages
 SECONDARY CAUSES OF MEMBRANOUS NEPHROPATHY :

75% : ARE PRIMARY

MEMBRANOUS

25% : ARE SECONDARY

MEMBRANOUS
CLINICAL FEATURES :

► MN in 70% of cases with features associated with the nephrotic

syndrome, such as edema, proteinuria greater than 3.5 g/day,
hypoalbuminemia, and hyperlipidemia.
► The other 30% of cases present with asymptomatic proteinuria with or
without microhematuria.
► The majority of patients present with NORMAL glomerular filtration
rate (GFR), but about 10% have diminished kidney function.
► Hypertension is UNCOMMON at presentation, occurring in ONLY10%
to 20% of cases.
► Complications of MN include THROMBOEMBOLIC AND
CARDIOVASCULAR EVENTS.
► IN 80% OF PRIMARY MEMBRANOUS ANTI PLA2R POSITIVE
CONFIRMS DIAGNOSIS AND CAN AVOID BIOPSY
TREATMENT :
► Uaually treatment is indicated in patient with Non nephrotic proteinuria with raised sr
creatinine Or Nephrotic range proteinuria > 4 gm/day.
► MODIFIED PONTICELLI REGIMEN :
DIABETIC NEPHROPATHY :
► Diabetic kidney disease (DKD) is a leading cause of end stage renal disease
worldwide.
► Approximately 40% of patients with diabetes develop nephropathy.
► Risk factors for the development of diabetic nephropathy include
hyperglycemia, hypertension, dyslipidemia, smoking, a family history of
diabetic nephropathy
► Even with advanced chronic kidney disease, patients with diabetic
nephropathy will have enlarged kidneys
► The presence of diabetic retinopathy in patients with albuminuria is
strongly suggestive of DKD
 PATHOLOGY :
► Hyperglycemia activates the renin-angiotensin-aldosterone system and also alters
insulin-like growth factor, reactive oxygen species, and endothelin and also the
presence of advanced glycation end products alter Matrix production.
► Multiple lines of evidence support an important role for changes in glomerular
hemodynamics including INCREASES IN GLOMERULAR CAPILLARY
PRESSURE and GLOMERULAR HYPERFILTRATION in these pathologic changes.
► Diabetes upregulates the sodium-glucose cotransporters (SGLT1 and SGLT2) in the
proximal tubule, resulting in decreased distal delivery of sodium to the macula densa
and further glomerular hyperfiltration.
► Sustained GLOMERULAR HYPERTENSION increases matrix production and
alterations in the GBM with disruption in the filtration barrier.
► STAGE 1:
❖ INTERMITTENT MICROALBUMINURIA + HYPERFILTRATION with
glomerular hypertrophy and raised GFR
❖ NO SYMPTOMS AND NORMAL BLOOD PRESSURE
► STAGE 2:
❖ FIXED ALBUMINURIA (30-300mg/g) WITH RAISED GFR and
INTRAGLOMERULAR HYPERTENSION
❖ RAISED BP WITH ABSENCE OF NOCTURNAL DIPPING ON CABPM
► STAGE 3 :
❖ PROTEINURIA (>300mg/g) with FALL IN GFR , EDEMA +
❖ STAGE 4 : RENAL FAILURE
❖ SATGE 5 : ESRD
PATHOLOGY:
•Diffuse uniform thickening of glomerular
basement membrane (GBM)

•Matrix expansion encroaching on the

capillary lumina may be diffuse, nodular or
both

•Nodular lesions are also called Kimmelsteil-

Wilson lesions

• Vascular hyalinosis is a common finding

TREATMENT :
►Advance trial : hba1c 6.5-7.5 and BMI<25 . glycemic control is
very crucial
►Microalbuminuria : increase risk of developing cva and cad
►Drugs with cv benefit and renal safe : insulin , linagliptin ,
SGLT2 inhibitors and liraglutide
►BLOOD PRESSURE CONTROL : TARGET OF 140/90 AND IF
PROTEINURIA >1gm/dl :130/80 . ARB are drug of choice
(FIMSARTAN)
►Statins: LDL >100 in stages 1-4
►Salt restriction
Monoclonal immunoglobulinopathy

⮚ Organized Ig :
Amyloidosis have Lambda Chain Deposition

⮚ Non Organized Ig :
Monoclonal Immunoglobulin Deposition
Disease have Kappa Chain
Deposition
AMYLOIDOSIS :
► It comprises a diverse group of systemic and local diseases characterized
by the extracellular deposition of characteristic eosinophilic fibrillary
proteins called amyloid proteins in various organs.
► 3types of AMYLOID PROTEINS :
► LIGHT CHAIN : AL TYPE / PRIMARY AMYLOIDOSIS
► SERUM AMYLOID A : AA TYPE / SECONDARY AMYLOIDOSIS
► FAMILIAL AMYLOIDOSIS : TRANSTHYRETIN PROTEIN
► Most renal amyloidosis are due to either AL amyloidosis or AA
amyloidosis
► AL amyloidosis are older than 50 years (median age 59–63 )
► Men are affected twice as often as women
► Multisystem organ involvement is typical, with most commonly affected
organs being the kidney (50%)
❑ PRIMARY AMYLOIDOSIS : Multiple Systems Are Involved
▪ Renal : Nephrotic Syndrome
▪ Cardiac : Restrictive Cardiomyopathy
▪ Liver : Hepatomegaly
▪ Autonomic Dysfunction : Postural Hypotension
❑ SECONDARY AMYLOIDOSIS:
▪ Only RENAL Involvement seen
❑ RENAL FEATURES:
▪ Clinical manifestations of renal disease depend on the location and extent of
amyloid deposition
▪ Proteinuria and reduced kidney function are the major kidney manifestations of
AL-type amyloidosis.
▪ Proteinuria is typically nonselective and almost 90% of patients with more than
1 g/day urinary protein will have a monoclonal protein in the urine.
►Light Microscopy ►Congo Red Immunoflorosence

Pas Positive Orange Stain For Detecting Monoclonal

Immunoglobulin
Mesangial Deposits Reaction And Apple Deposits . Most Common
Green Under Of Which Is Lambda
Polarized Light Chain
►Antilambda Antibody : Positive
►Electron Microscopy : Fibrillary Deposits
►Serum And Urine : Protein Electrophoresis
►USG : Most Patients Have Characteristic Normal Size
Kidneys
 TREATMENT :

❑ In general, healthier and younger patients have been offered ASCT

❑ Recent chemotherapeutic agents used successfully in conjunction with
dexamethasone include a number of agents used in myeloma, including
melphalan, lenalidomide,bortezomib, and cyclophosphamide
❑ Patients who are not candidates for HCT often receive bortezomib-
based regimen
❑ The treatment of AA amyloid focuses on the control of the underlying
inflammatory disease process
 SICKLE NEPHROPATHY :
► Renal Disease Associated With Sickle Cell Disease Include Papillary Necrosis, Nephrotic
Syndrome, Renal Infarction
► PATHOGENESIS : 1. Hemolysis
2.Vasooclusion: Renal Medullary Ischemia
3. Tubulointerstitial Damage
► PATTERNS OF GLOMERULAR PATHOLOGY IN SICKLE NEPHROPATHY :
1. FSGS : Most Common : a “collapsing” pattern and an
“expansive” pattern.
2. Membranoproliferative Glomerulopathy
► CLINICAL FEATURES :
1. Albumiuria : Incidence Increases With Age
2. Microscopic Hematuria : Is A Common Finding
3. Gross Hematuria : Indicates Significant Renal Papillary Necrosis
►Mesangial cells are activated by the presence of fragmented red
blood cells in glomerular capillaries. Activated mesangial cells
promote synthesis of matrix proteins and migrate into the peripheral
capillary wall, leading to GBM reduplication
►Current guidelines suggest screening for proteinuria beginning at age
10 and then annually if negative.
►Chronic kidney disease in sickle cell disease: It occurs due to the
fibrosis and is primarily seen in adults.
►Treatment of patients with sickle cell nephropathy with ACE
inhibitors reduces the degree of proteinuria.
 NSAID AND OTHER DRUGS ASSOCIATED
NEPHROTIC SYNDROME
► NSAIDS : The combination of acute interstitial nephritis and nephrotic is
characteristic of this group of compounds
▪ 18 months after initiation of NSAID therapy
▪ Patients may present with edema and oliguria. Proteinuria is usually in the
nephrotic range. The extent of renal dysfunction may be mild to severe.
▪ Membranous nephropathy has also been reported in association with
NSAID use , including the newer COX-2 inhibitors
► OTHER DRUGS :
▪ GOLD , MERCURY
▪ CAPTOPRIL
▪ LITHIUM
▪ INF ALPHA
 VIRAL DISEASES :
► HIV ASSOCIATED NEPHROPATHY (HIVAN):
▪ The term HIVAN is reserved for the characteristic LM pattern of FSGS of the “collapsing” type
▪ The clinical features of HIVAN include presenting features of proteinuria, typically in the nephrotic
range (and often massive), and renal insufficiency
▪ The renal ultrasound in HIVAN shows echogenic kidneys with Preserved or Enlarged size with an
average of over 12 cm in spite of the severe renal insufficiency

►HEPATITIS B AND HEPATITIS C:

▪ Most patients present with proteinuria or the nephrotic syndrome.
▪ Most cases of hepatitis B–associated nephropathy manifest MEMBRANOUS NEPHROPATHY
▪ Specifically, lamivudine was shown to reduce proteinuria and lead to a lesser incidence of ESKD
patients with hepatitis B–associated nephropathy
▪ Renal disease associated with HCV infection includes MPGN with or without associated mixed
cryoglobulinemia and MEMBRANOUS NEPHROPATHY
COMPLICATIONS :
► Anemia : Due To Loss Of Transferrin
► Hypothyroidism : Loss Of Thyroid Binding Globulin
► Hypocalcaemia : Loss Of Vitamin D Binding Globulin And Loss Of 1,25
Dihydroxycholecalciferol
► Infections : 1. Strep. Pnemoniae, Gram Negative Bacteria , Varicella
2. Due To Loss Of Immunoglobulin
3. Decreased Cell Mediated Immunity
4. Treatment With Steroids
► Renal Failure:
► Convulsions : Hypocalcemia And Hyponatremia
► Pericardial Effusion
► Accelerated Atherosclerosis
► Thromboembolism : Renal Vein Thrombosis , Cerebral Vein Thrombosis,
Peripheral Vein Thrombosis
► The prevalence of RVT is highest in patients with membranous
nephropathy,on average 37%
► RVT presents clinically in two ways acute and chronic.
1.Acute RVT is usually unilateral and characterized by acute flank
pain, flank tenderness, macroscopic hematuria, and some
deterioration of renal function.
2.Chronic RVT is usually asymptomatic and occurs in the elderly.
► First-line treatment consists of conventional anticoagulation with low-
molecular-weight heparin and oral vitamin K antagonists
► Prophylactic measures, such as pneumococcal vaccine, are
recommended in adults with severely depressed immunoglobulin levels