Case presentation

• A 55 yr old lady ms. Manju who is a known case
of hypertension since 8yrs and hypothyroidism
since 6 yrs was on tab. Losartan once daily and
tab thyronorm 50mcg once daily
• Admitted with a chief complaint of
• swelling of face and followed by swelling of both
the lower limbs since one month
• Dyspnea on exertion since twenty days
• Decrease in appetite

• No h/o
• Chest pain
• Pnd
• Orthopnea
• Palpitations
• Jaundice
• Viral hepatitis

• Abdominal distention
• Decreased urine output
• Weigt loss
• Fever
• Rash
• Photosensitivity
• Oral ulcers
• Drug abuse

• D/d
• CHF
• Chronic liver disese
• Loss of protein in urine(? nephrotic synd )
• Protein losing enteropathy
• Decreased absorption of protein in the gut

• Investigations
• CBC
• Hb : 8.6
• TLC : 8500
• PLT : 172000
• ESR : 112

• KFT
• S.urea : 32
• S. creat : 1.3
• S. k+ : 5.2
• S. Na+ : 138
• S. ca++ : 7.7
• S . Phos :4.7
• S . Alb : 2.4

• Urine R/M : protein ++++
• S . Cholestrol : 236
• S . T protein : 6.4
• Spot urine protein / creatinine ratio : 23.41

LFT : WNL
HbsAg : neg
Anti HCV : neg
HIV : neg

• ANA : negative
• C3 : 168.7
• C4 : 39.3
• SPEP : WNL

• Renal biopsy description :
• Sections of renal tissue core show 8 glomeruli,
one of which appears sclerosed. The remaining
glomeruli show congestion and mild mesangial
expansion.
• Any segmental sclerosis, hypercellularity or
capillary basement membrane thickening is not
seen.
• No significant fibrosis is present.
• Few tubules are dilated and show presence of
hyaline casts

igG , igA, igM, C3, C1Q, fibrinogen : all
negative
Comments :
Minimal change disease needs to be considered

Approach to proteinuria
• The magnitude of proteinuria and its
composition in the urine depend on the
mechanism of renal injury that leads to
protein losses.

• Normally healthy individuals excrete <150
mg/d of total protein and <30 mg/d of
albumin.

MECHANISM OF PROTEINURIA
• Filtration of blood occurs in glomerulus.
• Glomerular filtration barrier consists of :
• -capillary endothelium
• -glomerular basement membrane
• -visceral epithelium with foot process

• Types
• 1) Glomerular
• 2) Tubular
•

• 1) Glomerular :
• Predominantly selective loss of albumin (
mininal change disease)
• Loss of albumin and other plasma proteins (
immune complex deposition)

• 2) Tubular :
• Secreted by tubules , tamm horsfall, IgA,
urokinase , beta2 microglobulin , apoproteins ,
enzymes, and peptide hormones .
• Excessive production of abnormal protein in
• Multiple myeloma, amyloidosis, lymphomas

Detecting and quantifying proteinuria
• 1) DIPSTICK MEASUREMENT
• Detects only albumin.
• False positive :
• With Alkaline urine
• With highly concentrated urine
• With gross hematuria
• False negative :
• Dilute urine

• Proteinuria that is not predominantly due to
albumin will be missed by dipstick screening.
• Eg : bence jones proteins in patients with
multiple myeloma

• 2) albumin to creatinine ratio :
• Spot urine sample ( ideally from a first
morning void)

• 24-Hour Protein Excretion
• The 24-hour urine collection for protein excretion remains the reference
• (gold standard) method. It is based on chemical assay (e.g.,
• biuret or Folin-Lowry reaction), turbidimetric technique (e.g.,
trichloroacetic acid, benzethonium chloride, ammonium chloride), or
• dye-binding technique (e.g., ponceau S, Coomassie brilliant blue
• G-250, pyrogallol red molybdate), which quantify total proteins
• rather than simply albumin.
• The 24-hour protein excretion averages the variation of proteinuria
caused by the circadian rhythm and is the most accurate for monitoring of
proteinuria during treatment.
• However, it can be impractical in some settings (e.g., children, outpatients,
• elderly patients) and is subject to error from overcollection
• or undercollection.

• Microalbuminuria Defined as the presence of albumin in the urine
• in a range of 30 to 299 mg/24 h, microalbuminuria identifies
diabetic
• patients at increased risk of developing overt diabetic nephropathy.
• Also, in the general population, microalbuminuria identifies patients
• at increased risk of chronic kidney disease, cardiovascular
morbidity,
• and overall mortality.
• The 24-hour urine collection, initially considered
• the gold standard method for the detection of microalbuminuria,
• currently has been replaced by the use of early-morning urine,
• which minimizes the changes caused by diurnal volume variations.
• .

• A number of semiquantitative dipstick tests
are available to screen for microalbuminuria.
• Once microalbuminuria is found by dipstick, a
standard quantitative method is then used for
confirmation, usually immunoassay.
• Because of its great simplicity,
immunoturbidometry is the method most
frequently used

• Tubular Proteins
• Low-molecular-weight tubular proteins such as α1-
microglobulin, retinol-binding protein, and β2-
microglobulin are identified by a qualitative analysis of
urine proteins, using electrophoresis on cellulose acetate or
agarose after protein concentration
• or using very sensitive stains such as silver and gold.
• Sodium dodecyl sulfate–polyacrylamide gel electrophoresis
(SDS-PAGE) can be used to identify tubular proteins in the
urine of patients with glomerular diseases, which may have
therapeutic and prognostic implications.

• Selectivity of Proteinuria
• Selectivity can be assessed in nephrotic patients
by the ratio of the clearance of IgG (molecular
weight of 160,000 d) to the clearance of
transferrin (88,000 d).
• Although now used infrequently, highly selective
proteinuria (ratio <0.1) in nephrotic children
suggests the diagnosis of minimal change disease
and predicts corticosteroid responsiveness

• NEPHROTIC SYNDROME

Manifestations
:
• Proteinuria of >3.5gm/day
• Generalised Edema
• Hypoalbuminemia
• Hyperlipidemia and lipiduria
• Susceptibility to infections
• Thrombotic complications
• Microcytic anemia , altered Thyroid function
tests

ETIOLOGY

Treatment of nephrotic syndrome
• Treat specific cause
• Treatment of complications
Hypertension
Proteinuria
Nephrotic edema
Thrombosis
Risk of infections

Minimal change disease in adults
• Most frequent cause of nephrotic syndrome in
children, but it is less common in adults
• Diffuse effacement of foot processes of
epithelial cells
• Dramatic response to corticosteroid therapy

Pathogenesis
• ?immune mediated
• ANGPTL (angiopoietin like protein) – having
high positive charge – deposited in Podocytes
• Secondary MCD – hodgkins lymphoma ,
NSAIDS
• Finnish type – nephrin mutations

Clinical course
• 75% of adults with MCD are steroid responsive
• >50% of adult MCD patients will experience
relapses
• Up to a third of patients may become FR or
SD.
• 10% of adult MCD patients are steroid-
resistant

• Steroid resistance – failure to achieve remission after 16 weeks of
steroid therapy
• Steroid dependence- Two consecutive relapses during
corticosteroid therapy, or within 14 days of ceasing therapy
• Frequent relapsers –not defined in adults
• Remission -uPCR <200 mg/g or <1+ of protein on urine dipstick for
3 consecutive days
• Relapse -uPCR >2000 mg/g or >3+ protein on urine dipstick for 3
consecutive days

Treatment of idiopathic MCD

Steroid resistant MCD
• Biopsy should be repeated

FSGS
• Lesion is characterized by sclerosis of some,
but not all, glomeruli (thus, it is focal); and in
the affected glomeruli, only a portion of the
capillary tuft is involved (thus, it is segmental)
• IDIOPATHIC
• SECONDARY

Secondary FSGS
• Infections – HIV,Hep B , parvovirus
• Reflux nephropathy
• Hypertesive nephropathy
• Renal agenesis, post nephrectomy
• Drugs – Analgesics, Heroin , pamidronate
• Sickle cell disease
• Radiation nephritis

HISTOPATHOLOGY
• Light microscopy - In the sclerotic segments-
collapse of basement membranes, increase in
matrix, and segmental insudation of plasma
proteins
• Electron microscopy-Both sclerotic and
nonsclerotic areas - diffuse effacement of foot
processes & focal detachment of the
epithelial cells with damage to underlying
GBM

• Immunofluorescence -IgM and C3 may be
present in the sclerotic areas and/or in the
mesangium

Treatment
• Complete remission-↓ proteinuria to 300mg/d
or 300 mg/g of ACR
• Relapse - Proteinuria >3.5 g/d or >3500 mg/g of
ACR after complete remission has been obtained
• Steroid-dependent -Two relapses during or within
2 weeks of completing steroid therapy
• Steroid-resistant --Persistence of proteinuria
despite prednisone 1 mg/kg/d or 2 mg/kg every
other day for >4 months

Rx of Idiopathic FSGS
Initial treatment
• Prednisone - 1 mg/kg/d ( max 80 mg/d) or
A/D prednisone 2 mg/kg (up to 120 mg)
• For at least 4 weeks and for max of 4 months
• In case of a complete remission, taper
prednisone: e.g., reduce dose by 10mg per 2
weeks down to 0.15 mg/kg/d, then taper dose
every 2–4 weeks by 2.5 mg.

Rx of SR FSGS
• Therapy for SR FSGS
• Cyclosporine
• 3–5 mg/kg/d: in two divided doses (initial target levels 125–175 ng/ml
[104–146 nmol/l]); in case of a remission continue treatment for 1 year
then try to slowly taper cyclosporine: reduce cyclosporine dose by 25%
every 2 months. If no remission by 6 months, discontinue cyclosporine
treatment.
• Or
• Tacrolimus
0.1–0.2 mg/kg/d in two divided doses (initial target levels 5–10 ng/ml
[6–12 nmol/l]); in case of remission see advice for cyclosporine.
• And
• Prednisone
0.15 mg/kg/d for 4–6 months, then taper off over 4–8 weeks.

Membranous nephropathy
• Common cause of the nephrotic syndrome in
adults. ( 25-30% of cases)
• MC cause of Nephrotic syndrome in elderly
• Diffuse thickening of the glomerular capillary
wall and the accumulation of electron-dense,
Ig deposits along the subepithelial side of the
basement membrane

• Peak incidence – 30-50 years
• M:F -2:1
• 70-75% of cases idiopathic or primary
• 25-30 % of cases associated with malignancies
, infections, autoimmune diseases

Pathogenesis
• Immune complex mediated
• Resembles experimental model of heymann
nephritis
• Newer studies – Idiopathic MGN – antibodies
to phospholipase A2 receptor

Histopathology
• Light microscopy- Thickening of the basement
membrane along the peripheral capillary
loops
• Electrom microscopy-Electron-dense
subepithelial deposits
• Immunoflorescence-diffuse granular deposits
of IgG and C3
• IgG 4 predominant in Idiopathic MGN

Course
• 20-33% of cases – spontaneous remission
• 30% - relapsing with normal renal function
• 30% - renal failure
• MGN – highest incidence of thrombotic
complications

Treatment of Idiopathic MGN
• First 6 months – supportive with
antihypertensives & antiproteinuric drugs
• Monitoring of serum creatinine, eGFR, urine
protein excretion , for other compliactions of
NS

Indications of immunosuppression
• urinary protein excretion persistently exceeds
4 g/d AND remains at over 50% of the
baseline value, AND does not show
progressive decline, during antihypertensive
and antiproteinuric therapy of at least 6
months
• The presence of severe, disabling, or
lifethreatening symptoms related to the
nephrotic syndrome

Indications of immunosuppression
• SCr has risen by 30% or more within 6 to 12
months from the time of diagnosis AND this
change is not explained by superimposed
complications.

Immunosuppression
• Initial therapy consist of a 6-month course of
alternating monthly cycles of oral and i.v.
corticosteroids, and oral alkylating agents
• Manage conservatively for at least 6 months
following the completion of this regimen
before being considered a treatment failure if
there is no remission,

• Complete Remission: Urinary protein
excretion<0.3 g/d (uPCR<300 mg/ g ),
confirmed by two values at least 1 week apart,
accompanied by a normal serum albumin
concentration, and a normal SCr.

Alternate regimen
• Cyclosporine: 3.5–5.0 mg/kg/d given orally in two
equally divided doses 12 hours apart, with
prednisone 0.15 mg/kg/d, for 6 months.
• Tacrolimus: 0.05–0.075 mg/kg/d given orally in
two divided doses 12 hours apart, without
prednisone, for 6–12 months.
• *Discontinue CNIs in patients who do not
achieve complete or partial remission after 6
months of treatment.

Treatment of resistant cases
• In case of relapse – we can use primary
regimen which induced remission
• In case of resistance – we can use alternate
regimen

• Patients with IMN and nephrotic syndrome,
with marked reduction in serum albumin (<2.5
g/dl ) and additional risks for thrombosis, be
considered for prophylactic anticoagulant
therapy, using oral warfarin.

MPGN
• Characterized histologically by alterations in
the basement membrane, proliferation of
glomerular cells, and leukocyte infiltration
• Also called as mesangiocapillary GN
• Accounts for 10% to 20% of cases of nephrotic
syndrome in children and young adults

Types of MPGN

Pathogenesis
• Type 1 is mainly due to ag-ab complex mediated
• Type 2 & 3 – due to activation of alternate
pathway of complement
• Light microscope – GBM thickening & mesangial
proliferation in both types & double contour
/tram track app in type 1
• Electron microscopy- subendothelial deposits in
type 1 & dense deposits along GBM in type 2

Treatment
• Idiopathic MPGN with nephrotic syndrome
AND progressive decline of kidney function -
oral cyclophosphamide or MMF plus low-dose
alternate-day or daily corticosteroids with
initial therapy limited to less than 6 months.
• There is very low–quality evidence to suggest
the benefit

Diabetic nephropathy
• Diabetic nephropathy is the single most
common cause of chronic renal failure
accounting for 45% of patients receiving RRT
• 40% of patients with types 1 or 2 diabetes
develop nephropathy
• Risk factors -Hyperglycemia, hypertension,
dyslipidemia, smoking, a family history of
diabetic nephropathy

Pathogenesis
• Metabolic changes – increased collagen
synthesis & decreased heparin sulfate
• Hemodynamic changes – increased
glomerular capillary pressure and glomerular
hypertrophy

Pathogenesis
• Thickening of the glomerular capillary
basement membrane
• Diffuse increase in mesangial matrix. There
can be mild proliferation of mesangial cells.
• Kimmelstiel-Wilson disease OR nodular
glomerulosclerosis

Stages of DN
Stage 1 – hyperfiltration – GFR ↑
Stage 2 – silent phase – GFR →
Stage 3 – micoalbuminuria 30-300mg/g
Stage 4 – macroalbuminuria >300mg/g ( 500mg-25gm/d)
Stage 5 – ESRD

• Screening for microalbuminuria -5 years after
diagnosis in type 1 DM, at the time of
diagnosis in type 2 DM
• More than 90% of patients with type 1
diabetes and DN have DR
• Only 60% of patients with type 2 diabetes
with nephropathy have DR
• Patients with advanced DN have normal to
enlarged kidneys

Treatment
• (1) Normalization of glycemia
• (2) Strict blood pressure control
• (3) Administration of ACE inhibitors or ARBs

Thankyou