Approach to the patient with Glomerular Disease.

‘Approach to the patient with
Glomerular Disease.’
Speaker:
Dr.Farhana Faruque
Indoor Medical Officer, Medicine Unit – II,
SSMC & MH

Introduction:
 Two human kidneys harbor nearly 1.8 million
glomerular capillary tufts. Each glomerular
tuft resides within Bowman’s space.
 The glomerular capillary tuft derives from an
afferent arteriole that forms a branching
capillary bed embedded in mesangial
matrix .

Introduction:
 This capillary network funnels into an efferent
arteriole, which passes filtered blood into
cortical peritubular capillaries or medullary
vasa recta that supply and exchange with a
folded tubular architecture.

Introduction:
 Fenestrated endothelial cells resting on a
glomerular basement membrane (GBM) line
glomerular capillaries. Delicate foot processes
extending from epithelial podocytes shroud
the outer surface of these capillaries, and
podocytes interconnect to each other by
slitpore membranes forming a selective
filtration barrier.

Introduction:
 The glomerular capillaries filter 120–180 L/d of
plasma water containing various solutes for
reclamation or discharge by downstream
tubules. Most large proteins and all cells are
excluded from filtration by a physicochemical
barrier governed by pore size and negative
electrostatic charge.

Pathogenesis:
 There are many forms of glomerular disease
with pathogenesis variably linked to the
presence of genetic mutations, infection,
toxin exposure, autoimmunity, atherosclerosis,
hypertension, emboli, thrombosis, or diabetes
mellitus. Even after careful study, however,
the cause often remains unknown, and the
lesion is called idiopathic.

Pathogenesis:
 Some glomerular diseases result from genetic
mutations producing familial disease or a
founder effect: congenital nephrotic
syndrome from mutations in NPHS1 (nephrin)
and NPHS2 (podocin) affect the slit-pore
membrane at birth, and TRPC6 cation
channel mutations produce focal segmental
glomerulosclerosis (FSGS) in adulthood.

Pathogenesis:
 Systemic hypertension and atherosclerosis can
produce pressure stress, ischemia, or lipid
oxidants that lead to chronic glomerulosclerosis.
 Malignant hypertension can quickly complicate
glomerulosclerosis with fibrinoid necrosis of
arterioles and glomeruli, thrombotic
microangiopathy, and acute renal failure.

Pathogenesis:
 Diabetic nephropathy is an acquired
sclerotic injury associated with thickening of
the GBM secondary to the long-standing
effects of hyperglycemia, advanced
glycosylation end products, and reactive
oxygen species.

Pathogenesis:
 Inflammation of the glomerular capillaries is
called glomerulonephritis. Most glomerular or
mesangial antigens involved in immune
mediated glomerulonephritis are unknown.
Glomerular epithelial or mesangial cells may
shed or express epitopes that mimic other
immunogenic proteins made elsewhere in the
body. Bacteria, fungi, and viruses can directly

Pathogenesis:
 Autoimmune diseases like idiopathic
membranous glomerulonephritis(MGN) or
MPGN are confined to the kidney, whereas
systemic inflammatory diseases like lupus
nephritis or granulomatosis with polyangiitis
(Wegener’s) spread to the kidney, causing
secondary glomerular injury.

Pathogenesis:
 Antiglomerular basement membrane disease
producing Goodpasture’s syndrome primarily
injures both the lung and kidney because of
the narrow distribution of the α3 NC1 domain
of type IV collagen that is the target antigen.

Pathogenesis:
 Local activation of Toll-like receptors on
glomerular cells, deposition of immune
complexes, or complement injury to
glomerular structures induces mononuclear
cell infiltration, which subsequently leads to
an adaptive immune response attracted to
the kidney by local release of chemokines.

Pathogenesis:
 Neutrophils, macrophages, and T cells are
drawn by chemokines into the glomerular
tuft, where they react with antigens and
epitopes on or near somatic cells or their
structures, producingmore cytokines and
proteases that damage the mesangium,
capillaries,and/or the GBM. While the
adaptive immune response is similar to

Pathogenesis:
 that of other tissues, early T cell activation
plays an important role in the mechanism of
glomerulonephritis. Antigens presented by
class II major histocompatibility complex
(MHC) molecules on macrophages and
dendritic cells in conjunction with
associative recognition molecules engage
the CD4/8 T cell repertoire.

Pathogenesis:
 Mononuclear cells by themselves can injure the
kidney, but autoimmune events that damage
glomeruli classically produce a humoral
immune response.

Pathogenesis:
 Post streptococcal glomerulonephritis, lupus
nephritis and idiopathic membranous nephritis
typically are associated with immune deposits
along the GBM, while anti-GBM antibodies
produce the linear binding of anti-GBM disease.

Glomerular disease : commonly
used terms:
 Focal: some, but not all, glomeruli show the
lesion.
 Diffuse (global): most of the glomeruli (>75%)
contain the lesion.
 Segmental: only a part of the glomerulus is
affected (most focal lesions are also segmental,
e.g. focal segmental glomerulosclerosis).

used terms:
 Global: all of the glomerulus is symmetrically
involved.
 Proliferative: an increase in cell numbers due
to hyperplasia of one or more of the resident
glomerular cells with or without inflammation.

used terms:
 Membrane alterations: capillary wall
thickening due to deposition of immune
deposits or alterations in basement
membrane.
 Crescent formation: epithelial cell
proliferation with mononuclear cell
infiltration in Bowman's space.

Describing glomerular disease:
 The nomenclature for glomerular disease
can be confusing, as descriptive terms (as
seen on histology) overlap with clinical
syndromes and more recent molecular
insights into the pathogenesis of disease.
If there is predominant inflammation on
histology, glomerular disease may be
described as a glomerulonephritis.

 If inflammation is absent, glomerulopathy is
more correct. There remains much overlap
between the two, and the terms are often
(wrongly) used interchangeably. It may be
better to think about glomerular disease in terms
of the predominant compartment involved,
where the GBM separates podocytes from
mesangial and endothelial cells.

 Clinical classification of glomerular disease is
also often used, although there is no complete
correlation between histopathological types
and clinical features. Four major glomerular
syndromes are often described:

 Nephrotic syndrome: massive proteinuria (>3.5
g/day), hypoalbuminaemia, oedema,lipiduria
and hyperlipidaemia. Podocyte malfunction or
injury is often causative.

 Glomerulonephritis (nephritic syndrome):
– Acute glomerulonephritis: abrupt onset of
glomerular haematuria (red blood cell casts
or dysmorphic red blood cells), non-
nephrotic-range proteinuria, oedema,
hypertension and transient renal
impairment, or

– Rapidly progressive glomerulonephritis:
features of acute nephritis, focal necrosis with
or without crescents, and rapidly progressive
renal failure over weeks.

 Mixed nephritic/nephrotic presentations:
where glomerulonephritis is part of a systemic
disease (e.g. lupus nephritis,
cryoglobulinaemia and Henoch–Schönlein
purpura), a nephritic syndrome is often
associated with the nephrotic syndrome.
 Asymptomatic haematuria, proteinuria or
both.

Approach to the patient with
Glomerular Disease:
HEMATURIA, PROTEINURIA, AND PYURIA:
Patients with glomerular disease usually have
some hematuria with varying degrees of
proteinuria. Hematuria is typically
asymptomatic.

Glomerular Disease:
 As few as three to five red blood cells in the spun
sediment from first-voided morning urine is
suspicious. The diagnosis of glomerular injury can
be delayed because patients will not realize they
have microscopic hematuria, and only rarely
with the exception of IgA nephropathy and

Glomerular Disease:
sickle cell disease is gross hematuria present.
When working up microscopic hematuria,
perhaps accompanied by minimal proteinuria
(<500 mg/24 h), it is important to exclude
anatomic lesions, such as malignancy of the
urinary tract, particularly in older men.
Microscopic hematuria may also appear with

Glomerular Disease:
the onset of benign prostatic hypertrophy,
interstitial nephritis, papillarynecrosis,
hypercalciuria, renal stones, cystic kidney
diseases or renal vascular injury. However, when
red blood cell casts or dysmorphic red blood cells
are found in the sediment, glomerulonephritis is
likely.

Glomerular Disease:
 Sustained proteinuria >1–2 g/24 h is also
commonly associated with glomerular disease.
Patients often will not know they have
proteinuria unless they become edematous or
notice foaming urine on voiding.

Glomerular Disease:
 Sustained proteinuria has to be distinguished
from lesser amounts of so-called benign
proteinuria in the normal population .

Glomerular Disease:
Urine Assays for Albuminuria/Proteinuria
24-Hour
Albumina
(mg/24 h)
Albumina
/Creatinine
Ratio (mg/g)
Dipstick
Proteinuria
24-Hour
Urine
Proteinb
(mg/24 h)
Normal 8–10 <30 − <150
Microalbumi
nuria
30–300 30–300 −/Trace/1+ −
Proteinuria >300 >300 Trace−3+ >150

Glomerular Disease:
 This latter class of proteinuria is nonsustained,
generally <1 g/24 h and is sometimes called
functional or transient proteinuria. Fever,
exercise, obesity, sleep apnea, emotional stress,
and congestive heart failure can explain
transient proteinuria.

Glomerular Disease:
 Proteinuria only seen with upright posture is
called orthostatic proteinuria and has a benign
prognosis. Isolated proteinuria sustained over
multiple clinic visits is found in many glomerular
lesions.

Glomerular Disease:
 Proteinuria in most adults with glomerular
disease is nonselective, containing albumin
and a mixture of other serum proteins,
whereas in children with minimal change
disease,the proteinuria is selective and
composed largely of albumin.

Glomerular Disease:
 Some patients with inflammatory glomerular
disease, such as acute poststreptococcal
glomerulonephritis or MPGN, have pyuria
characterized by the presence of
considerable numbers of leukocytes.
This latter finding has to be distinguished

Clinical Syndromes:
 Various forms of glomerular injury can also
be parsed into several distinct syndromes on
clinical grounds. These syndromes, however,
are not always mutually exclusive.

Clinical Syndromes:
 There is an acute nephritic syndrome
producing 1–2 g/24 h of proteinuria,
hematuria with red blood cell casts, pyuria,
hypertension, fluid retention, and a rise in
serum creatinine associated with a reduction
in glomerular filtration.

Clinical Syndromes:
 If glomerular inflammation develops slowly,
the serum creatinine will rise gradually over
many weeks, but if the serum creatinine rises
quickly, particularly overa few days, acute
nephritis is sometimes called rapidly
progressive glomerulonephritis (RPGN);

Clinical Syndromes:
 the histopathologic term crescentic
glomerulonephritis is the pathologic
equivalent of the clinical presentation of
RPGN.

Clinical Syndromes:
 When patients with RPGN present with lung
hemorrhage from Goodpasture’s syndrome,
antineutrophil cytoplasmic antibodies
(ANCA)-associated small-vessel vasculitis,
lupus erythematosus, or cryoglobulinemia,
they are often diagnosed
as having a pulmonary-renal syndrome.

Clinical Syndromes:
 Nephrotic syndrome describes the onset of
heavy proteinuria (>3.0 g/24 h), hypertension,
hypercholesterolemia, hypoalbuminemia,
edema/anasarca and microscopic
hematuria; if only large amounts of
proteinuria are present without clinical
manifestations, the condition is sometimes

Clinical Syndromes:
 called nephrotic-range proteinuria. The
glomerular filtration rate (GFR) in these
patients may initially be normal or, rarely,
higher than normal, but with persistent
hyperfiltration and continued nephron loss, it
typically declines over months to years.

Clinical Syndromes:
 Patients with a basement membrane syndrome
either have genetically abnormal basement
membranes (Alport’s syndrome) or an
autoimmune response to basement membrane
collagen IV (Goodpasture’s syndrome)
associated with microscopic hematuria, mild to
heavy proteinuria, and hypertension with
variable elevations in serum creatinine.

Clinical Syndromes:
 Glomerular–vascular syndrome describes
patients with vascular injury producing
hematuria and moderate proteinuria.Affected
individuals can have vasculitis, thrombotic
microangiopathy,antiphospholipid syndrome,
or, more commonly, a systemic disease such

Clinical Syndromes:
 as atherosclerosis, cholesterol emboli,
hypertension, sickle cell anemia, and
autoimmunity. Infectious disease–associated
syndrome is most important if one has a global
perspective.

Clinical Syndromes:
 Save for subacute bacterial endocarditis in
the Western Hemisphere,malaria and
schistosomiasis may be the most common
causes of glomerulonephritis throughout the
world, closely followed by HIV and chronic
hepatitis B and C.

Clinical Syndromes:
 These infectious diseases produce a variety
of inflammatory reactions in glomerular
capillaries, ranging from nephrotic syndrome
to acute nephritic injury, and urinalyses that
demonstrate a combination of hematuria
and proteinuria.

Clinical Syndromes:
 These six general categories of syndromes are
usually determined at the bedside with the help
of a history and physical examination, blood
chemistries, renal ultrasound, and urinalysis.

Clinical Syndromes:
 These initial studies help frame further
diagnostic workup that typically involves testing
of the serum for the presence of various
proteins (HIV and hepatitis B and C antigens),
antibodies (anti-GBM, antiphospholipid,
antistreptolysin O [ASO], anti-DNAse,

Clinical Syndromes:
 antihyaluronidase, ANCA, anti-DNA, cryoglobulins,
anti-HIV, and anti-hepatitis B and C antibodies) or
depletion of complement components (C3 and
C4). The bedside history andphysical examination
can also help determine whether the
glomerulonephritis is isolated to the kidney
(primary glomerulonephritis)

Clinical Syndromes:
 or is part of a systemic disease (secondary
glomerulonephritis). When confronted with an
abnormal urinalysis and elevated serum
creatinine, with or without edema or
congestive heart failure,one must consider
whether the glomerulonephritis is acute or
chronic.

Clinical Syndromes:
 This assessment is best made by careful history
(last known urinalysis or serum creatinine during
pregnancy or insurance physical, evidence of
infection, or use of medication or recreational
drugs);

Clinical Syndromes:
 the size of the kidneys on renal ultrasound
examination; and how the patient feels at
presentation. Chronic glomerular disease
often presents with decreased kidney size.

Clinical Syndromes:
 Patients who quickly develop renal failure are
fatigued and weak and often have uremic
symptoms associated with nausea, vomiting,
fluid retention,and somnolence. Primary
glomerulonephritis presenting with

Clinical Syndromes:
 renal failure that has progressed slowly,
however, can be remarkably asymptomatic,
as are patients with acute glomerulonephritis
without much loss in renal function. Once this
initial information is collected, selected

Clinical Syndromes:
 patients who are clinically stable, have
adequate blood clotting parameters, and
are willing and able to receive treatment are
encouraged to have a renal biopsy.

Approach to the patient with Glomerular Disease.

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