Glomerular Diseases-Part 1

Glomerular
diseases
By Dr. Haitham Nabeel
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Introduction to
glomerular diseases

Terminology of glomerular diseases
• Primary: a kidney disease specifically affecting
the glomeruli (e.g., minimal change glomerulonephritis)
• Secondary: a disease affecting the glomeruli in the
context of a systemic disease (e.g., lupus nephritis in SLE)
or a disease affecting another organ (e.g., diabetic
nephropathy)
• Diffuse: > 50% of glomeruli affected (e.g., diffuse
proliferative glomerulonephritis)
• Focal: < 50% of glomeruli affected (e.g., focal segmental
glomerulosclerosis)
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Terminology of glomerular diseases
• Global: entire glomerulus is affected
• Segmental: only part of the glomerulus is affected
• Proliferative: an increased number of cells in the glomerulus
• Membranous: thickening of the glomerular basement
membrane (e.g., membranous nephropathy)
• Sclerosing: scarring of the glomerulus
• Necrotizing: cell death within the glomerulus
• Crescentic: accumulation of cells such
as macrophages, fibroblasts, and epithelial cells in Bowman
space
Glomerular filtration
barrier
The glomerular filtration barrier filters the
blood to form primary urine.
The filtration barrier is composed of three
layers: the fenestrated endothelium of
capillaries, the glomerular basement
membrane, and the podocytes. All three
layers selectively allow passage of particles
of a specific size.
Both the podocytes and negative glycocalyx
of the fenestrated endothelium are
permeable to neutral and cationic particles.

Nephritic and
nephrotic syndromes

Pathophysiology
• The glomerular filtration barrier consists of 3 parts
• Initial segment: Fenestrated glomerular capillary
endothelium prevents large proteins from passing through.
• Second segment: The glomerular basement membrane (GBM)
contains a negative charge produced by heparan sulfate.
• Final segment: Visceral epithelial cells produce/maintain
the GBM and contain intercellular junctions created
by podocytes that prevent further protein loss.
• Damage to the glomeruli → disruption of the glomerular
filtration barrier → can lead to nephritic or nephrotic
syndrome

Pathophysiology of nephrotic syndrome
• Damage to podocytes → structural damage

of glomerular filtration barrier → massive renal loss
of protein.
• Hyperlipidaemia : In response to the low serum
albumin concentrations, the liver increases its
production of numerous proteins, including
lipoproteins, leading to hyperlipidemia

• Edema : occurs for at least two possible reasons. The

first, known as the “underfilling hypothesis,” argues that
low serum albumin concentrations lead to a reduction in
intravascular oncotic pressure. As a result, plasma moves
from the capillary lumen to the interstitium, which leads
to edema. The resulting intravascular depletion activates
the renin-angiotensin-aldosterone system, which
promotes retention of sodium and water and thus
further worsens the edema.
• Edema : The second hypothesis, known as the

“overfilling hypothesis,” argues that there is
primary retention of sodium at the level of the
collecting duct, perhaps triggered by the filtered
proteins themselves, that leads to edema. It
appears probable that both hypotheses are correct,
and that the primary mechanism for edema may
vary across patients and across time
Pathophysiology of
nephrotic syndrome

Pathophysiology of nephritic syndrome
• Inflammatory response within glomeruli → GBM

disruption → loss of renally excreted RBCs
(acanthocytes) and ↓ GFR → hematuria, oliguria,
azotemia, and ↑ renin → edema and hypertension

Nephrotic vs. nephritic syndrome
• Nephritic syndrome and nephrotic syndrome are both common
clinical manifestations of glomerular diseases.
• Both syndromes are composed of characteristic clinical
(e.g., edema, hypertension) and laboratory findings (e.g., glomerular
hematuria, massive proteinuria), which result from damage to
the glomeruli.
• Glomerular diseases are usually categorized by the syndrome they
cause, which is either nephritic or nephrotic.
• Some diseases that manifest with nephritic syndrome can
simultaneously cause nephrotic-range proteinuria (> 3.5 g/day), the
main feature of nephrotic syndrome. When the criteria for both
syndromes are fulfilled, the findings are referred to as
mixed nephritic-nephrotic syndrome.
Classifying the patient's presentation as
nephritic, nephrotic, or mixed nephritic-
nephrotic can help narrow down the list
of likely differential diagnoses.
Clinical pearl!

Presentation
Nephrotic syndrome Nephritic syndrome
•Heavy proteinuria (> 3.5 g/day) •Hematuria
•Hypoalbuminemia •Mild to moderate edema
•Generalized edema •Oliguria
•Hyperlipidemia •Azotemia
•Hypertension

Notes on presentation of nephritic syndrome
• Many patients with glomerulonephritis, particularly those with

milder disease, do not exhibit all of these features; their
combined presence, however, is typical of a rapidly
progressive glomerulonephritis and warrants urgent
investigation.
• Patients with nephritic syndrome may also exhibit varying
degrees of proteinuria, including nephrotic-range proteinuria;
the prominence of haematuria on dipstick should, however,
alert the physician to the possibility of a glomerulonephritis.
• A characteristic feature of glomerular bleeding is an ‘active
urinary sediment’ (the presence of dysmorphic red blood cells
or red cell casts on microscopy); this is not always present,
however.
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Causes
Nephrotic syndrome Nephritic syndrome
Due to primary or secondary podocyte damage Poststreptococcal glomerulonephritis
Minimal change disease IgA nephropathy (Berger disease)
Focal segmental glomerulosclerosis Granulomatosis with polyangiitis
Membranous nephropathy Microscopic polyangiitis
Due to secondary podocyte damage Eosinophilic granulomatosis with polyangiitis
Diabetic nephropathy Goodpasture syndrome (anti-GBM disease)
Amyloid light-chain (AL) amyloidosis, light Alport syndrome (hereditary nephritis)
chain deposition disease Thin basement membrane disease
Lupus nephritis Rapidly progressive glomerulonephritis (RPGN)
Lupus nephritis
Most common causes of nephritic-nephrotic syndrome:

Membranoproliferative glomerulonephritis
Diffuse proliferative glomerulonephritis
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Characteristic features of nephritic
syndrome and nephrotic syndrome do not
always present in isolation, but should be
considered to be the extreme phenotypes
at either end of a spectrum of presentations.
Clinical pearl!

Nephritic and
nephrotic syndrome
At one extreme, specific injury to podocytes
causes proteinuria and nephrotic syndrome. The
histology to the left shows diabetic
nephropathy. At the other end of the spectrum,
inflammation leads to cell damage and
proliferation, breaks form in the glomerular
basement membrane (GBM) and blood leaks
into urine. In its extreme form, with acute
sodium retention and hypertension, such
disease is labelled nephritic syndrome. The
histology to the right shows a glomerulus with
many extra nuclei from proliferating intrinsic
cells, and influx of inflammatory cells leading to
crescent formation (arrows) in response to
severe post-infectious glomerulonephritis.
(FSGS = focal and segmental glomerulosclerosis;
IgA = immunoglobulin A; MCGN =
mesangiocapillary glomerulonephritis; SLE =
systemic lupus erythematosus)

Investigations of nephritic syndrome

In many cases, investigation will
include a renal biopsy to confirm
diagnosis and guide management.
Clinical pearl!

Investigations of nephrotic syndrome
• Investigation of nephrotic syndrome usually involves

renal biopsy, although non-invasive tests may also be
helpful in suggesting the underlying cause.
• In children, minimal change disease is by far the most
common cause of nephrotic syndrome and therefore
renal biopsy is not usually required unless the
patient fails to respond to high-dose glucocorticoid
therapy.

• Similarly, most patients with diabetes presenting with
nephrotic syndrome will have diabetic nephropathy,
and so renal biopsy is usually not performed.
• When to perform renal biopsy in a diabetic
presenting with proteinuria?
• 1-patient has rapidly increasing proteinuria
• 2-patient has rapid detrioration of kidney function
• 3-patient has no evidence of diabetic microvascular
complications in other sites (e.g. daibetic retinopathy)
Nephrotic syndrome

Definitions
• Nephrotic-range proteinuria: proteinuria > 3.5 g/24

hours.
• Nephrotic syndrome: nephrotic-range proteinuria
PLUS hypoalbuminemia and edema

Etiology
• Nephrotic syndrome may be caused by primary glomerular disorders (80–
90% of cases) and/or systemic diseases and toxic exposures (10–20% of
cases).
• Primary (idiopathic) forms:
• Minimal change disease
• Focal segmental glomerulosclerosis
• Membranous nephropathy
• Membranoproliferative glomerulonephritis (can manifest as nephrotic or nephritic
syndrome)
• Secondary forms:
• Diabetic nephropathy
• Amyloid nephropathy: can be associated with multiple myeloma (AL amyloidosis) or
chronic inflammatory disease such as rheumatoid arthritis (AA amyloidosis)
• Lupus nephritis (can manifest as nephrotic or nephritic syndrome)

Renal glomeruli

Pathophysiology
• Damage of glomerular filtration barrier by various
mechanisms.
• Structural damage of glomerular filtration barrier →
massive renal loss of protein (hyperproteinuria) →
reactively increased hepatic protein synthesis.
• Loss of negative charge of glomerular basement
membrane → loss of selectivity of barrier (especially for
negatively charged albumin)
• Podocyte damage and fusion → nonselective proteinuria
(except in minimal change disease, which manifests
with selective glomerular proteinuria)

Pathophysiology
• If protein loss exceeds hepatic synthesis (usually with a loss of
protein > 3.5 g/24 hours) → hypoproteinemia/hypoalbuminemia,
initially with both normal GFR and creatinine.
• ↓ Serum albumin → ↓ colloid osmotic pressure → edema (especially
if albumin levels are < 2.5 g/dL)
• Loss of antithrombin III, protein C and protein S, increased synthesis
of fibrinogen, and loss of fluid into the extravascular
space → hypercoagulability.
• Loss of transport proteins
• Loss of thyroglobulin transport protein → thyroxin deficiency
• Vitamin D binding protein → vitamin D deficiency
• Loss of plasma proteins → ↓ plasma protein binding → increase in free
plasma drug concentration, but drug toxicity is usually not increased

Pathophysiology
• ↑ Plasma levels of cholesterol, LDL, triglycerides,

and lipoproteins (mainly LPA) to compensate for the
loss of albumin → lipiduria (fatty casts)
• Loss of immunoglobulins → increased risk
of infection, especially Streptococcus pneumoniae
infection.
• Sodium retention → possible hypertension

Clinical features
• Classic manifestations
• Massive proteinuria > 3.5 g/24 hours
• Edema
• Typically starts with periorbital edema
• Peripheral edema (pitting)
• Pleural effusion
• Pericardial effusion
• Ascites
• In severe cases, anasarca
• Hypoalbuminemia
• Hyperlipidemia

Unlike edema related to heart failure,
the edema in hypoalbuminemia does not follow
gravity. Instead, it appears throughout the entire body.
The area around the eyes is usually the first clinically
apparent localization of edema because connective
tissue in this area is particularly loose,
making edema very noticeable
That’s why!

Clinical features
• Other clinical features
• Hypercoagulable state with increased risk of thrombosis and
embolic events (e.g., pulmonary embolism, renal vein
thrombosis)
• Increased susceptibility to infection
• Hypertension in some cases
• Possibly frothy urine
• Symptoms of hypocalcemia (e.g., tetany, paresthesia, muscle
spasms)
• Symptoms of the underlying disease (e.g., malar rash in lupus
nephritis)

Differential diagnosis of nephrotic syndrome
• Minimal change disease (lipoid nephrosis)

• Epidemiology:
• Most common cause of nephrotic syndrome in children
• Associations:
• Often idiopathic
• Secondary causes (rare)
• Immune stimulus (e.g., infection, immunization)
• Tumors (e.g., Hodgkin lymphoma)
• Certain drugs (e.g., NSAIDs)

Minimal change disease

• Minimal change disease (lipoid nephrosis)

• Findings:
• LM: no changes
• IM: negative
• EM: effacement of podocyte foot processes
• Selective glomerular proteinuria
• Treatment:
• Responds well to prednisone
• Good prognosis

Podocyte foot processes
fusion in minimal
change disease
Electron micrograph of kidney tissue
The effacement of the foot processes of the
podocytes are visible (examples indicated by
green ellipse) as well as swelling of podocyte
bodies (example indicated by red overlay).
This finding, together with unremarkable
light microscopy, is typical of minimal change
disease.

Minimal change nephropathy
is the most common cause of
nephrotic syndrome in
children.
Clinical pearl!


• Epidemiology:
• Most common cause of nephrotic syndrome in African American adults
and Hispanic populations
• Associations:
• Can be idiopathic Full blown nephrotic syndrome
• Heroin use
• HIV infection
• Sickle cell disease Proteinuria without nephrotic syndrome
• Massive obesity
• Interferon treatment
• Congenital malformations (e.g., Charcot-Marie-Tooth syndrome)

Focal segmental glomerulosclerosis


• Findings:
• LM: segmental sclerosis and hyalinosis
• IM: Most commonly negative
• EM: effacement of podocyte foot processes
• Treatment:
• Prednisone (often shows poor response)
• If necessary, PLUS other immunosuppressants (e.g., cyclosporine,
tacrolimus)
• RAAS inhibitors
• Usually leads to ESRD if left untreated

Focal segmental
glomerulosclerosis
(perihilar type)
Photomicrograph of a kidney biopsy (PAS
stain; very high magnification)
A cross-section of a glomerulus is visible at
the center of the image. The perihilar region
is hypercellular and contains hyaline
deposits. Loss of the capillary lumens and
diffuse sclerosis is also present.
These are the typical features of focal
segmental glomerulosclerosis (perihilar
type).

• Epidemiology:
• Most common cause of nephrotic syndrome in adults of European,
Middle Eastern, or North African descent
• Associations:
• Primary: anti-PLA2R antibodies
• Secondary:
• Infections (HBV, HCV, malaria, syphilis)
• Autoimmune diseases (e.g., SLE)
• Tumors (e.g., lung cancer, prostate cancer)
• Medications (e.g., NSAIDs, penicillamine, gold)

Membranous nephropathy

• Findings:
• LM
• Diffuse thickened glomerular capillary loops and basement membrane
• Granular subepithelial deposits of IgG and C3 (dense deposits) → spike
and dome appearance
• Treatment:
• RAAS inhibitors
• Prednisone (often shows poor response)
• PLUS other immunosuppressants (e.g., cyclophosphamide) in severe
disease
• Usually leads to ESRD if left untreated
Membranous
nephropathy
Photomicrograph of a kidney biopsy sample
(PAS stain; very high magnification)
There is diffuse thickening of the glomerular
basement membrane and capillaries. There is
no evidence of glomerular hypercellularity or
inflammation.
This characteristic finding of membranous
nephropathy is caused by the deposition of
antibodies between podocytes and the
glomerular basement membrane.

Membranous nephropathy is
the most common cause of
nephrotic syndrome in adults!
Clinical pearl!

Minimal change and primary focal segmental
glomerulosclerosis (FSGS) typically present with
fulminant nephrotic syndrome, whereas in
membranous nephropathy and secondary FSGS,
the nephrosis tends to be more indolent in nature
Clinical pearl!

Diagnostics
• Confirmation of nephrotic-range proteinuria

• Qualitative assessment by urine dipstick (commonly used
for screening)
• Usually shows ≥ 3+ proteins
• Hematuria may indicate concomitant glomerulonephritis.
• Quantitative assessment of urine protein excretion
• 24-hour urine protein (test of choice): > 3.5 g/24 hours
• Spot urine protein/creatinine ratio: > 3.5 g/g

Spot urine protein/creatinine ratio is usually more
practical than 24-hour urine collection in the clinical
setting because it is less cumbersome, less prone to
collection errors, and provides quicker results. It is thus
considered an acceptable alternative for
confirming nephrotic-range proteinuria (but not for
monitoring treatment).
Clinical pearl!

Diagnostics
• Additional laboratory studies
• CBC: ↑ Hb/Hct may indicate hemoconcentration
• BMP: ↑ Cr and/or ↑ BUN may be seen; ↓ Na is commonly seen.
• Serum protein: ↓ total protein, ↓ albumin (< 3 g/dL)
• Coagulation factors: ↓ ATIII, ↓ protein S, ↓ plasminogen ;
↑ fibrinogen, ↑ D-dimer
• Lipid profile: Hyperlipidemia (↑ LDL, ↑ triglycerides) may be
present.
• Vitamin D levels: ↓ 25-OH Vit-D
• Inflammatory markers: ↑ ESR, ↑ CRP may suggest underlying
infection, inflammatory condition, or vasculitis.
Diagnostics
• Renal biopsy
• Indication: to confirm the diagnosis when the etiology of
nephrotic syndrome is unclear and/or to guide
management.

Management of symptoms and
complications of nephrotic syndrome
• Edema
• Dietary sodium restriction: < 3 g/day (usually 1.5–2 g/day)
• Fluid restriction: < 1.5 liters/day
• Diuretic therapy
• Options
• First-line: oral loop diuretic (e.g., furosemide)
• Second-line:
• Add oral thiazide or thiazide-like diuretic (e.g., metolazone)
• AND/OR switch to IV loop diuretic (e.g., IV furosemide)
• Consider adjunctive IV albumin

• Proteinuria
• Antiproteinuric therapy
• Indicated in most patients
• RAAS inhibitor: ACEI (e.g., ramipril) or ARB (e.g., losartan) are
commonly used.
• Effects
• Reduces proteinuria
• Treats hypertension
• May slow progression of any underlying renal disease (e.g., diabetic nephropathy)
• Avoid in patients with AKI, hyperkalemia, or abrupt onset of nephrotic
syndrome.
• Dietary protein: avoid very high-protein diet but ensure adequate
protein intake.

• Dyslipidemia
• Lipid-lowering therapy (e.g., atorvastatin)
• Indications similar to those in other patients with a high
risk of cardiovascular disease

• Hypercoagulability
• All patients with nephrotic syndrome are at increased risk
of thromboembolism, and this risk becomes progressively
higher as serum albumin drops below 3.0 g/L.
• Prophylactic anticoagulation

• Infectious risk
• Preventive measures
• Pneumococcal vaccination
• Annual vaccination for influenza

Complications of nephrotic syndrome and
their mangment

Disease-specific measures
• Primary forms of nephrotic glomerulopathies: often treated
with immunosuppressive therapy
• Immunosuppressive therapies may include:
• Glucocorticoids (often used initially)
• Additional immunosuppressants (e.g., cyclophosphamide, calcineurin
inhibitors) in patients with steroid-resistant nephrotic syndrome or severe
disease
• Management in adults is usually guided by biopsy-based histological
diagnosis.
• Children are often treated initially with empiric corticosteroids for
presumed MCD.
• Secondary forms of nephrotic glomerulopathies: Treat the
underlying cause.
• Primary (idiopathic) minimal change disease (MCD)

• Initial management: immunosuppressive therapy
• Prednisone
• Alternative: cyclophosphamide OR calcineurin inhibitor
Most patients respond well to prednisone (approx. 75% achieve complete remission) but
up to a third of adult patients overall subsequently develop frequent relapses
or steroid dependence. However, progressive CKD is not part of the natural history
of MCD and suggests underlying FSGS.

Supportive treatment with RAAS
inhibitors is usually deferred in children
but may be considered in adults, for
whom response to glucocorticoids is
often slower.
Clinical pearl!

Glucocorticoid resistance in
children warrants a
biopsy to exclude an
alternative diagnosis!
Clinical pearl!

• Primary (idiopathic) focal segmental

glomerulosclerosis (FSGS)
• Initial management: supportive therapy including an RAAS
inhibitor (i.e., ACEI or ARB).
• Consider immunosuppressive therapy for all patients with nephrotic
syndrome due to FSGS.
• Prednisone
• Alternative: calcineurin inhibitor (cyclosporin OR tacrolimus)
Responses are varied: Rates of complete remission are reported in 28–74% of
cases and there and the rate of ESRD among nonresponders is high (> 50%).

FSGS frequently recurs in
renal transplants!
Clinical pearl!

Since FSGS is a focal
process, abnormal glomeruli may not be
seen on renal biopsy if only a few are
sampled, leading to an initial diagnosis of
minimal change nephropathy.
Clinical pearl!

• Primary membranous nephropathy

• Initial management: conservative therapy including
an RAAS inhibitor (i.e., ACEI or ARB)
• Consider immunosuppressive therapy for severe or
refractory disease.
• Prednisone AND cyclophosphamide
• Alternatives: cyclosporine, tacrolimus, OR rituximab

Rule of thirds in membranous
nephropathy:
1/3 undergo spontaneous remission
1/3 remain in a nephrotic state
1/3 develop progressive CKD
Clinical pearl!

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Glomerular

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• Damage to podocytes → structural damage

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• Edema : occurs for at least two possible reasons. The

• Edema : The second hypothesis, known as the

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• Inflammatory response within glomeruli → GBM

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• Many patients with glomerulonephritis, particularly those with

Most common causes of nephritic-nephrotic syndrome:

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• Investigation of nephrotic syndrome usually involves

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• Nephrotic-range proteinuria: proteinuria > 3.5 g/24

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• ↑ Plasma levels of cholesterol, LDL, triglycerides,

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• Minimal change disease (lipoid nephrosis)

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• Minimal change disease (lipoid nephrosis)

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• Focal segmental glomerulosclerosis

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• Focal segmental glomerulosclerosis

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• Confirmation of nephrotic-range proteinuria

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