1
MED II-B Group 6 Notes
Level II Block V Module 2 – URINARY SYSTEM
Case 1: “Puffy Raffy”
1. Recall the anatomic and histologic features of the kidneys.
• Each human adult kidney weighs about 150 gm.
• As the ureter enters the kidney at the hilum, it dilates into a
funnel-shaped cavity, the pelvis, from which derive two or
three main branches, the major calyces; each of these
subdivides again into three or four minor calyces.
• There are about 12 minor calyces in the human kidney.
• On the cut surface, the kidney is made up of a cortex and a
medulla, the former 1.2 to 1.5 cm in thickness.
• The medulla consists of renal pyramids, the apices of which
are called papillae, each related to a calyx.
• Cortical tissue extends into spaces between adjacent
pyramids as the renal columns of Bertin.
• From the standpoint of its diseases, the kidney can be
divided into four components: blood vessels, glomeruli,
tubules, and interstitium.
Blood Vessels
• The kidney is richly supplied by blood vessels, and although
both kidneys make up only 0.5% of the total body weight,
they receive about 25% of the cardiac output. The cortex is
by far the most richly vascularized part of the kidney,
receiving 90% of the total renal blood supply.
• The main renal artery divides into anterior and posterior
sections at the hilum.
• From these, interlobar arteries emerge, course between
lobes, and give rise to the arcuate arteries, which arch
between cortex and medulla, in turn giving rise to the
interlobular arteries.
• From the interlobular arteries, afferent arterioles enter the
glomerular tuft, where they progressively subdivide into 20
to 40 capillary loops arranged in several units or lobules
architecturally centered by a supporting mesangial stalk.
• Capillary loops merge to exit from the glomerulus as efferent
arterioles.
• In general, efferent arterioles from superficial nephrons form
a rich vascular network that encircles cortical tubules
(peritubular vascular network), and deeper juxtamedullary
glomeruli give rise to the vasa recta, which descend as
straight vessels to supply the outer and inner medulla.
• These descending arterial vasa recta then make several
loops in the inner medulla and ascend as the venous vasa
recta.
• The anatomy of renal vessels has several important
implications.
• First, because the arteries are largely end-arteries, occlusion
of any branch usually results in infarction of the specific area
it supplies.
• Glomerular disease that interferes with blood flow through
the glomerular capillaries has profound effects on the
tubules, within both the cortex and the medulla, because all
tubular capillary beds are derived from the efferent
arterioles.
• The peculiarities of the blood supply to the renal medulla
render them especially vulnerable to ischemia; the medulla
does not have its own arterial blood supply but is dependent
on the blood emanating from the glomerular efferent
arterioles.
• The blood in the capillary loops in the medulla has a
remarkably low level of oxygenation.
• Thus, minor interference with the blood supply of the
medulla may result in medullary necrosis from ischemia.
Glomeruli
• The glomerulus consists of an anastomosing network of
capillaries lined by fenestrated endothelium invested by two
layers of epithelium.
• The visceral epithelium is incorporated into and becomes an
intrinsic part of the capillary wall, separated from endothelial
cells by a basement membrane.
• The parietal epithelium, situated on Bowman's capsule, lines
the urinary space, the cavity in which plasma filtrate first
collects.
• The glomerular capillary wall is the filtering membrane and
consists of the following structures:
 A thin layer of fenestrated endothelial cells, each
fenestrum being about 70 to 100 nm in diameter.
 A glomerular basement membrane (GBM) with a thick
electron-dense central layer, the lamina densa, and
thinner electron-lucent peripheral layers, the lamina
rara interna and lamina rara externa. The GBM consists
of collagen (mostly type IV), laminin, polyanionic
proteoglycans (mostly heparan sulfate), fibronectin,
entactin, and several other glycoproteins. Type IV
collagen forms a network suprastructure to which other
glycoproteins attach. The building block (monomer) of
this network is a triple-helical molecule made up of
three α-chains, composed of one or more of six types of
α-chains (α1 to α6 or COL4A1 to COL4A6), the most
common consisting of α1, α2, α1. Each molecule
consists of a 7S domain at the amino terminus, a triple-
helical domain in the middle, and a globular
noncollagenous domain (NC1) at the carboxyl terminus.
The NC1 domain is important for helix formation and for
assembly of collagen monomers into the basement
membrane suprastructure. Glycoproteins (laminin,
entactin) and acidic proteoglycans (heparan sulfate,
perlecan) attach to the collagenous suprastructure3-5.
These biochemical determinants are critical to
understanding glomerular diseases. For example, as we
shall see, the antigens in the NC1
 2

domain are the targets of antibodies in anti-GBM nephritis;

genetic defects in the α-chains underlie some forms of
hereditary nephritis; and the acidic porous nature of the
GBM determines its permeability characteristics.
 The visceral epithelial cells (podocytes), are structurally
complex cells that possess interdigitating processes
embedded in and adherent to the lamina rara externa
of the basement membrane. Adjacent foot processes
(pedicels) are separated by 20- to 30-nm-wide filtration
slits, which are bridged by a thin diaphragm.
 The entire glomerular tuft is supported by mesangial
cells lying between the capillaries. Basement
membrane-like mesangial matrix forms a meshwork
through which the mesangial cells are centered (Fig.
20-1). These cells, of mesenchymal origin, are
contractile, phagocytic, and capable of proliferation, of
laying down both matrix and collagen, and of secreting
a number of biologically active mediators. Biologically,
they are most akin to vascular smooth muscle cells and
pericytes. They are, as we shall see, important players
in many forms of human glomerulonephritis.
• The major characteristics of normal glomerular filtration are
an extraordinarily high permeability to water and small
solutes, because of the highly fenestrated nature of the
endothelium, and impermeability to proteins, such as
molecules of the size of albumin (+3.6-nm radius; 70
kilodaltons [kDa] molecular weight) or larger.
• The latter property, called glomerular barrier function,
discriminates among various protein molecules, depending
on their size (the larger, the less permeable) and charge (the
more cationic, the more permeable).
• This size- and charge-dependent barrier function is
accounted for by the complex structure of the capillary wall,
the collagenous porous and charged structure of the GBM,
and the many anionic moieties present within the wall,
including the acidic proteoglycans of the GBM and the
sialoglycoproteins of epithelial and endothelial cell coats.
• The charge-dependent restriction is important in the virtually
complete exclusion of albumin from the filtrate, because
albumin is an anionic molecule of a pI 4.5. The visceral
epithelial cell, also known as a podocyte, is important for the
maintenance of glomerular barrier function; its slit
diaphragm presents a size-selective distal diffusion barrier to
the filtration of proteins, and it is the cell type that is largely
responsible for synthesis of GBM components.
• The structure of renal tubular epithelial cells varies
considerably at different levels of the nephron and, to a
certain extent, correlates with function.
• For example, the highly developed structure of the proximal
tubular cells, with their abundant long microvilli, numerous
mitochondria, apical canaliculi, and extensive intercellular
interdigitations, is correlated with their major functions:
reabsorption of two-thirds of filtered sodium and water as
well as glucose, potassium, phosphate, amino acids, and
proteins.
• The proximal tubule is particularly vulnerable to ischemic
damage.
• Furthermore, toxins are frequently reabsorbed by the
proximal tubule, rendering it also susceptible to chemical
injury.
• The juxtaglomerular apparatus snuggles closely against the
glomerulus where the afferent arteriole enters it.
• The juxtaglomerular apparatus consists of:
1. The juxtaglomerular cells, modified granulated smooth
muscle cells in the media of the afferent arteriole that
contain renin.
2. The macula densa, a specialized region of the distal
tubule as it returns to the vascular pole of its parent
glomerulus, where the tubular cells are more crowded
and the cells are somewhat shorter and possess distinct
patterns of interdigitation between adjacent
membranes.
3. The lacis cells or nongranular cells, which reside in the
area bounded by the afferent arteriole, the macula
densa, and the glomerulus.
• They resemble mesangial cells and appear to be continuous
with them.
• The juxtaglomerular apparatus is a small endocrine organ,
the juxtaglomerular cells being the principal sources of renin
production in the kidney.

• Proteins located in the slit diaphragm control glomular

permeability.
Interstitium

• While the details are imcomplete, three important proteins

have been identified (Fig. 20-5). Nephrin is a transmembrane
protein with a large extracellular portion made up of
immunoglobulin (Ig)-like domains. Nephrin molecules extend
towards each other from neighboring foot processes and
dimerize across the slit diaphragm.
• Within the cytoplasm of the foot processes, nephrin forms
molecular connections with podocin, CD2-associated protein,
and ultimately the actin cytoskeleton. The importance of
these proteins in maintaining glomerular permeability is
demonstrated by the observation that mutations in the
genes encoding them give rise to nephrotic syndrome
(discussed later).
• In the normal cortex, the interstitial space is compact, being
occupied by the fenestrated peritubular capillaries and a
small number of fibroblast-like cells. Any obvious expansion
of the cortical interstitium is usually abnormal; this
expansion can be due to edema or infiltration by acute
inflammatory cells, as in acute interstitial diseases, or it may
be caused by accumulation of chronic inflammatory cells and
fibrous tissue, as in chronic interstitial diseases.
• The amounts of proteoglycans in the interstitial tissue of the
medulla increase with age and in the presence of ischemia.

• This has resulted in renewed appreciation of the importance

of the slit diaphragm in glomerular barrier function and its
(Robbins and Cotran Pathologic Basis of Therapeutics 7th Edition)
contribution to protein leakage in disease states.

2. Identify Acute Glomerulonephritis as to:

Tubules
 3

2.1 Pathophysiology  IgG/anti-IgG immune complexes are formed and then

collect in the glomeruli.

 In addition, elevations of antibody titers to other

 Although we know little of etiologic agents and antigens, such as antistreptolysin O or
triggering events, it is clear that immune mechanisms antihyaluronidase, DNAase-B, and streptokinase,
underlie most forms of primary and many of the provide evidence of a recent streptococcal infection.
secondary glomerular disorders.

 Glomerulonephritis can be readily induced

experimentally by antigen-antibody reactions. (http://www.emedicine.com/emerg/topic219.htm)

 Furthermore, glomerular deposits of immunoglobulins,

often with various components of complement, are
found in the majority of patients with 2.2 Incidence
glomerulonephritis.

 Cell-mediated immune reactions also clearly play a role,

usually in concert with antibody-mediated events. Frequency

 We therefore begin this discussion with a review of

antibody-instigated injury.
United States
 Two forms of antibody-associated injury have been
established: (1) injury by antibodies reacting in situ
within the glomerulus, either with insoluble fixed
(intrinsic) glomerular antigens or with molecules
planted within the glomerulus, and (2) injury resulting  Glomerulonephritis represents 10-15% of glomerular
from deposition of circulating antigen- antibody diseases.
complexes in the glomerulus. In addition, there is
experimental evidence that cytotoxic antibodies  Variable incidence has been reported due in part to the
directed against glomerular cell components may cause subclinical nature of the disease in more than one half
glomerular injury. the affected population.

 These pathways are not mutually exclusive, and in  Despite sporadic outbreaks, incidence of
humans, all may contribute to injury. poststreptococcal glomerulonephritis has fallen over
the last few decades.
 In this form of injury, antibodies react directly with
intrinsic tissue antigen, or antigens "planted" in the  Factors responsible for this decline may include better
glomerulus from the circulation. health care delivery and improved socioeconomic
conditions.
 There are two well-established experimental models for
anti-tissue antibody-mediated glomerular injury, for
which there are counterparts in human disease:
antiglomerular basement membrane (anti-GBM) International
antibody- induced nephritis and Heymann nephritis.

 With some exceptions, a reduction in the incidence of

(Robbins and Cotran Pathologic Basis of Therapeutics 7th poststreptococcal glomerulonephritis has occurred in
Edition) most western countries.

 It remains much more common in regions such as

Africa, the Caribbean, India, Pakistan, Malaysia, Papua
 Glomerular lesions in acute glomerulonephritis are the New Guinea, and South America.
result of glomerular deposition or in situ formation of
immune complexes.
 Immunoglobulin A (IgA) nephropathy
glomerulonephritis (ie, Berger disease) is the most
 On gross appearance, the kidneys may be enlarged up
common cause of glomerulonephritis worldwide.
to 50%.

(http://www.emedicine.com/emerg/topic219.htm)
 Histopathologic changes include swelling of the
glomerular tufts and infiltration with
polymorphonucleocyte.  Incidence of AGN is decreasing in western countries,
and it is typically sporadic.
 Immunofluorescence reveals deposition of
immunoglobulins and complement.  Epidemic cases are still seen, though less commonly.

 With the exception of poststreptococcal  Typically affects children between the ages of 2 and 14
glomerulonephritis, the exact triggers for the formation years old, but 10% of the patients are older than 40 y.o.
of the immune complexes are unclear.
 More common in males and the familial or cohabitant
 In streptococcal infection, involvement of derivatives of incidence is high as 40%.
streptococcal proteins has been reported.

 A streptococcal neuramidase may alter host

immunoglobulin G (IgG). (Harrison’s Principles of Medicine 16th Edition)

 IgG combines with host antibodies. 2.3 Clinical Manifestation


 Classic presentation is acute nephritic picture with
hematuria, pyuria,, RBC casts, edema , HPN, and
oliguric renal failure which may be severe enough to
appear as RPGN
 Systemic SX include headache, malaise, anorexia, and
flank pain are reported in as many as 50% of cases
 5% of children and 20% of adults have proteinuria in
the nephritic change
 In the 1st week of Sx, 90% of patients will have a
depressed CH50 and decreased levels of C3 with
normal levels of C4
 A subclinical disease is reported in some series to be
four or five times as common as clinical nephritis, and
these latter cases are characterized by asymptomatic
microscopic hematuria with low level serum
complement levels.
(Harrison’s Principles of Medicine 16th Edition)
 A thorough history should focus on the identification of
an underlying systemic disease (if any) or recent
infection.
 Most often, the patient is a boy, aged 2-14 years, who
suddenly develops puffiness of the eyelids and facial
edema in the setting of a poststreptococcal infection.
The urine is dark and scanty, and the blood pressure
may be elevated.
 Onset of symptoms is usually abrupt.
 Nonspecific symptoms include weakness, fever,
abdominal pain, and malaise.
 In the setting of a postinfectious acute nephritis, a
latent period of up to 3 weeks occurs before onset of
symptoms. However, the latent period may vary;
typically 1-2 weeks for postpharyngitis cases and 2-4
weeks for cases of postdermal infection (ie, pyoderma).
 Onset of nephritis within 1-4 days of streptococcal
infection suggests preexisting renal disease.
 Symptoms of acute glomerulonephritis include the
following:
o Hematuria is a universal finding, even if it is
microscopic. Gross hematuria is reported in 30%
of pediatric patients.
o Oliguria
o Edema (peripheral or periorbital) is reported in
approximately 85% of pediatric patients; edema
may be mild (involving only the face) to severe,
bordering on a nephrotic appearance.
o Headache may occur secondary to hypertension;
confusion secondary to malignant hypertension
may be seen in as many as 5% of patients.
o Shortness of breath or dyspnea on exertion
secondary to heart failure or pulmonary edema;
usually uncommon, particularly in children.
o Possible flank pain secondary to stretching of the
renal capsule.
4
 Patients may also present with symptoms specific to an
underlying systemic disease that can precipitate an
acute glomerulonephritis.
 These disease entities are briefly described in Causes.
 Classic presentations include the following:
o Triad of sinusitis, pulmonary infiltrates, and
nephritis suggesting Wegener granulomatosis
o Nausea/vomiting, abdominal pain, and purpura
observed with Henoch-Schönlein purpura
o Arthralgias associated with systemic lupus
erythematosus (SLE)
o Hemoptysis occurring with Goodpasture syndrome
or idiopathic progressive glomerulonephritis
o Skin rashes observed with a hypersensitivity
vasculitis or systemic lupus erythematosus; also
possibly due to the purpura that can occur in
hypersensitivity vasculitis, cryoglobulinemia, and
Henoch-Schönlein purpura.
Physical Examination
 This description does not include all the physical
findings that can be associated with the nonnephritic
features of an infectious process (eg, fever), renal
etiology, or systemic etiology, as such a description is
beyond the scope of this article.
 Patients often have a normal physical examination and
blood pressure; most frequently, however, patients
present with a combination of edema, hypertension,
and oliguria.
o Edema frequently involves the face, specifically
the periorbital area.
o Hypertension is seen in as many as 80% of
affected patients.
o Hematuria, either macroscopic (gross) or
microscopic, may be noted.
o Skin rashes (ie, malar rash frequently seen with
lupus nephritis) may be observed.
o Abnormal neurologic examination or altered level
of consciousness occurring because of malignant
hypertension or hypertensive encephalopathy.
o Arthritis may be noted.
o Other signs:
 Pharyngitis
 Impetigo
 Respiratory infection
 Pulmonary hemorrhage
 Heart murmur may indicate endocarditis
 Scarlet fever
 Weight gain
 5

 Abdominal pain  It has both primary and secondary causes.

 Anorexia  Diagnosis is based on history, physical examination,

and sometimes renal biopsy.
 Back pain
 Treatment and prognosis vary by cause.
 Skin pallor
 Nephritic syndrome is a manifestation of glomerular
 Palpable purpura in patients with Henoch- inflammation (glomerulonephritis [GN]) and occurs at
Schönlein purpura any age.

 Oral ulcers  Causes differ by age and mechanisms differ by cause.

Acute and chronic forms exist.
(http://www.emedicine.com/emerg/topic219.htm)
 Postinfectious GN is the prototype of acute GN, but the
condition may be caused by other glomerulopathies
2.4 Differentiate nephrotic syndrome from nephritic syndrome.
and by systemic diseases such as connective tissue
disorders and paraproteinemias.

 Glomerular Diseases: Causes of Glomerulonephritis

 The nephrotic syndrome is characterized by heavy
proteinuria (more than 3.5 gm/day), hypoalbuminemia,
severe edema, hyperlipidemia, and lipiduria (lipid in the  Chronic GN has features similar to acute GN but
urine) while nephritic syndrome (acute) is a glomerular develops slowly and may display mild to moderate
syndrome dominated by the acute onset of usually proteinuria.
grossly visible hematuria (red blood cells in urine), mild
to moderate proteinuria, and hypertension; it is the  Examples include IgA nephropathy and hereditary
classic presentation of acute poststreptococcal nephritis.
glomerulonephritis.
(www.merk.com)

(Robbins and Cotran Pathologic Basis of Therapeutics 7th

Edition) 3. Identify the morphology and pathogenesis of the different causes
of acute glomerulonephritis.

3.1 Primary Causes

NEPHROTIC SYNDROME
3.1.1Acute Diffuse Proliferative Glomerulonephritis

3.1.1.1 Post-streptococcal
 Nephrotic syndrome is urinary excretion of > 3 g of
protein/day due to glomerular disease. 3.1.1.2 Viral

 It is more common in children and has both primary 3.1.1.3 Fungal and Parasitic
and secondary causes.

 Diagnosis is by measurement of a spot urine

protein/creatinine ratio or a 24-h urinary protein; (3.1.1-3.1.1.3 Fused)
underlying causes are diagnosed based on history,
physical examination, and renal biopsy.
ACUTE GLOMERULONEPHRITIS
 Treatment and prognosis vary by cause.

 Nephrotic syndrome is urinary excretion of > 3 g of Mechanisms of Chronic Tubulointerstitial Injury in

protein/day due to glomerular disease. Glomerulonephritis

 It is more common in children and has both primary

and secondary causes.
o Various components of the protein-rich filtrate and
cytokines derived from leukocytes cause tubular
 Diagnosis is by measurement of a spot urine
cell activation and secretion of cytokines, growth
protein/creatinine ratio or a 24-h urinary protein;
factors, and other mediators.
underlying causes are diagnosed based on history,
physical examination, and renal biopsy.
o These, together with products of macrophages,
incite interstitial inflammation and fibrosis.
 Treatment and prognosis vary by cause.
o ET-1, endothelin-1, PAI-1, plasminogen activator
inhibitor-1; TIMP-1, tissue inhibitor of
metalloproteinases
NEPHRITIC SYNDROME
o This group of glomerular diseases is characterized
anatomically by inflammatory alterations in the
glomeruli and clinically by the syndrome of acute
 Nephritic syndrome is defined by hematuria and RBC nephritis.
casts on microscopic examination of urinary sediment.
o The nephritic patient usually presents with
 Often one or more elements of mild to moderate hematuria, red cell casts in the urine, azotemia,
proteinuria, edema, hypertension, elevated serum oliguria, and mild to moderate hypertension.
creatinine, and oliguria are also present.

o The patient also commonly has proteinuria and
edema, but these are not as severe as those
encountered in the nephrotic syndrome, discussed
later.
o The acute nephritic syndrome may occur in such
multisystem diseases as SLE and microscopic
polyarteritis.
o Typically, however, it is characteristic of acute
proliferative glomerulonephritis and is an
important component of crescentic
glomerulonephritis, which is described later.
Acute Proliferative (Poststreptococcal,
Postinfectious) Glomerulonephritis
o As the name implies, this cluster of diseases is
characterized histologically by diffuse proliferation
of glomerular cells, associated with influx of
leukocytes.
o These lesions are typically caused by immune
complexes.
o The inciting antigen may be exogenous or
endogenous.
o The prototypic exogenous antigen-induced disease
pattern is postinfectious glomerulonephritis,
whereas that produced by an endogenous antigen
is the nephritis of systemic lupus erythematosus.
o The most common infections are streptococcal,
but the disorder has also been associated with
other infections.
Poststreptococcal Glomerulonephritis
o This glomerular disease is decreasing in frequency
in the United States but continues to be a fairly
common disorder worldwide.47 It usually appears
1 to 4 weeks after a streptococcal infection of the
pharynx or skin (impetigo).
o Skin infections are commonly associated with
overcrowding and poor hygiene.
o Poststreptococcal glomerulonephritis occurs most
frequently in children 6 to 10 years of age, but
adults of any age can be affected.
Etiology and Pathogenesis
o Only certain strains of group A β-hemolytic
streptococci are nephritogenic, more than 90% of
cases being traced to types 12, 4, and 1, which
can be identified by typing of M protein of the cell
wall.
o Poststreptococcal glomerulonephritis is an
immunologically mediated disease.
o The latent period between infection and onset of
nephritis is compatible with the time required for
the production of antibodies and the formation of
immune complexes.
o Elevated titers of antibodies against one or more
streptococcal antigens are present in a great
majority of patients.
6
o Serum complement levels are low, compatible
with activation of the complement system and
consumption of complement components.
o The presence of granular immune deposits in the
glomeruli demonstrates an immune complex-
mediated mechanism, and so does the finding of
electron-dense deposits.
o The streptococcal antigenic component
responsible for the immune reaction has eluded
identification for years.
o A cytoplasmic antigen called endostreptosin and
several cationic antigens, including a proteinase
(nephritis strain-associated protein, NSAP) related
to streptokinase and unique to nephritogenic
strains of streptococci, can be present in affected
glomeruli.
o It is not known if these represent planted antigens,
part of circulating immune complexes, or both.
GBM proteins altered by streptococcal enzymes
have also been implicated as antigens at one time
or another.
Morphology
o The classic diagnostic picture is one of enlarged,
hypercellular glomeruli.
o The hypercellularity is caused by (1) infiltration by
leukocytes, both neutrophils and monocytes; (2)
proliferation of endothelial and mesangial cells;
and (3) in severe cases by crescent formation.
o The proliferation and leukocyte infiltration are
diffuse, that is, involving all lobules of all
glomeruli.
o There is also swelling of endothelial cells, and the
combination of proliferation, swelling, and
leukocyte infiltration obliterates the capillary
lumens.
o There may be interstitial edema and inflammation,
and the tubules often contain red cell casts.
o By immunofluorescence microscopy, there are
granular deposits of IgG, IgM, and C3 in the
mesangium and along the basement membrane.
o Although almost universally present, they are
often focal and sparse.
o The characteristic electron microscopic findings
are discrete, amorphous, electron-dense deposits
on the epithelial side of the membrane, often
having the appearance of "humps", presumably
representing the antigen- antibody complexes at
the epithelial cell surface.
o Subendothelial and intramembranous deposits are
also commonly seen, and mesangial deposits may
be present.
o There is often swelling of endothelial and
mesangial cells.
Clinical Course

o In the classic case, a young child abruptly
develops malaise, fever, nausea, oliguria, and
hematuria (smoky or cocoa-colored urine) 1 to 2
weeks after recovery from a sore throat.
o The patients exhibit red cell casts in the urine,
mild proteinuria (usually less than 1 gm/day),
periorbital edema, and mild to moderate
hypertension.
o In adults, the onset is more likely to be atypical,
with the sudden appearance of hypertension or
edema, frequently with elevation of BUN.
o During epidemics caused by nephritogenic
streptococcal infections, glomerulonephritis may
be asymptomatic, discovered only on screening for
microscopic hematuria. Important laboratory
findings include elevations of antistreptococcal
antibody (ASO) titers and a decline in the serum
concentration of C3 and other components of the
complement cascade and the presence of
cryoglobulins in the serum.
o More than 95% of affected children eventually
recover totally with conservative therapy aimed at
maintaining sodium and water balance.
o A small minority of children (perhaps less than 1%)
do not improve, become severely oliguric, and
develop a rapidly progressive form of
glomerulonephritis (described later). Some of the
remaining patients may undergo slow progression
to chronic glomerulonephritis with or without
recurrence of an active nephritic picture.
o Prolonged and persistent heavy proteinuria and
abnormal GFR mark patients with an unfavorable
prognosis.
o In adults, the disease is less benign.
o Although the overall prognosis in epidemics is
good, in only about 60% of sporadic cases do the
patients recover promptly. In the remainder, the
glomerular lesions fail to resolve quickly, as
manifested by persistent proteinuria, hematuria,
and hypertension.
o In some of these patients, the lesions eventually
clear totally, but others develop chronic
glomerulonephritis.
o Some patients will develop a syndrome of rapidly
progressive glomerulonephritis.
Nonstreptococcal Acute Glomerulonephritis
(Postinfectious Glomerulonephritis)
o A similar form of glomerulonephritis occurs
sporadically in association with other bacterial
infections (e.g., staphylococcal endocarditis,
pneumococcal pneumonia, and
meningococcemia), viral disease (e.g., hepatitis B,
hepatitis C, mumps, human immunodeficiency
virus [HIV] infection, varicella, and infectious
mononucleosis), and parasitic infections (malaria,
toxoplasmosis).
o In this setting, granular immunofluorescent
deposits and subepithelial humps characteristic of
immune complex nephritis are present.
(Robbins and Cotran Pathologic Basis of Therapeutics
7th Edition)
Morphology:
7
o Typical findings on immunofluorescence
microscopy of renal biopsy specimens from
patients with anti-glomerular basement membrane
antibody disease, immune complex–mediated
glomerulonephritis, and pauci-immune
glomerulonephritis.
o Specimens in the upper and middle panels were
stained for immunoglobulin and show the classic
linear “ribbon-like” pattern of anti-GBM disease (A)
and granular pattern of immune complex–
mediated glomerulonephritis (B).
o Immunoglobulin is sparse or absent in patients
with pauci-immune glomerulonephritis (not
shown); however, abundant fibrin is detected in
crescents (C). (Micrographs courtesy of Dr. Helmut
Rennke.)
CLINICAL PRESENTATIONS
ACUTE NEPHRITIC SYNDROME AND RAPIDLY
PROGRESSIVE GLOMERULONEPHRITIS CLINICAL
FEATURES AND CLINICOPATHOLOGIC
CORRELATES
o The acute nephritic syndrome is the clinical
correlate of acute glomerular inflammation.
o In its most dramatic form, the acute nephritic
syndrome is characterized by sudden onset (i.e.,
over days to weeks) of acute renal failure and
oliguria (400 mL/day of urine).
o Renal blood flow and GFR fall as a result of
obstruction of the glomerular capillary lumen by
infiltrating inflammatory cells and proliferating
resident glomerular cells.
o Renal blood flow and GFR are further
compromised by intrarenal vasoconstriction and
mesangial cell contraction that result from local
imbalances of vasoconstrictor (e.g., leukotrienes,
platelet-activating factor, thromboxanes,
endothelins) and vasodilator substances (e.g.,
nitric oxide, prostacyclin) within the renal
microcirculation.
o Extracellular fluid volume expansion, edema, and
hypertension develop because of impaired GFR
and enhanced tubular reabsorption of salt and
water. As a result of injury to the glomerular
capillary wall, urinalysis typically reveals red blood
cell casts, dysmorphic red blood cells, leukocytes,
and subnephrotic proteinuria of <3.0 g per 24 h
(“nephritic urinary sediment”). Hematuria is often
macroscopic.
o The classic pathologic correlate of the nephritic
syndrome is proliferative glomerulonephritis.
o The proliferation of glomerular cells is due initially
to infiltration of the glomerular tuft by neutrophils
and monocytes and subsequently to true
proliferation of resident glomerular endothelial and
mesangial cells (endocapillary proliferation).
o In its most severe form, the nephritic syndrome is
associated with acute inflammation of most
glomeruli, i.e., acute diffuse proliferative
glomerulonephritis.
o When less vigorous, <50% of glomeruli may be
involved, i.e., focal proliferative
glomerulonephritis.
o In milder forms of nephritic injury, cellular
proliferation may be confined to the mesangium,
i.e., mesangioproliferative glomerulonephritis.

o RPGN is the clinical correlate of more subacute
glomerular inflammation.
o Patients develop renal failure over weeks to
months in association with a nephritic urinary
sediment, subnephrotic proteinuria and variable
oliguria, hypervolemia, edema, and hypertension.
o The classic pathologic correlate of RPGN is
crescent formation involving most glomeruli
(crescentic glomerulonephritis).
o In practice, the clinical term rapidly progressive
glomerulonephritis and the pathologic term
crescentic glomerulonephritis are often used
interchangeably.
o In addition to classic crescentic
glomerulonephritis, in which crescents dominate
the glomerular pathology, crescents can also
develop concomitantly with proliferative
glomerulonephritis or as a complication of
membranous glomerulopathy and other more
indolent forms of glomerular inflammation.
o The acute nephritic syndrome and RPGN are part
of a spectrum of presentations of immunologically
mediated proliferative glomerulonephritis.
o Studies of experimental models suggest that
nephritic syndrome and diffuse proliferative
glomerulonephritis represent an acute immune
response to a sudden large antigen load, whereas
RPGN and crescentic glomerulonephritis represent
a more subacute immune response to a smaller
antigen load in presensitized individuals.
o At the other end of the spectrum, chronic low-
grade immune injury presents with slowly
progressive renal insufficiency or asymptomatic
hematuria in association with focal proliferative or
mesangioproliferative glomerulonephritis.
o These more indolent forms of immune-mediated
glomerulonephritis are discussed later in this
chapter.
ETIOLOGY AND DIFFERENTIAL DIAGNOSIS
o Acute nephritic syndrome and RPGN can result
from renal-limited primary glomerulopathy or from
secondary glomerulopathy complicating systemic
disease.
o In general, rapid diagnosis and prompt treatment
are critical to avoid the development of
irreversible renal failure.
o Renal biopsy remains the “gold standard” for
diagnosis. Immunofluorescence microscopy is
particularly helpful and identifies three major
patterns of deposition of immunoglobulin that
define three broad diagnostic categories:
1. Scattered granular deposits of
immunoglobulin, a hallmark of
immunecomplex glomerulonephritis.
2. More discrete linear deposition of
immunoglobulin along the GBM,
characteristic of anti-GBM disease.
3. Paucity or absence of immunoglobulin—
pauci-immune glomerulonephritis
8
o Most patients (>70%) with full-blown acute
nephritic syndrome have immune-complex
glomerulonephritis.
o Pauci-immune glomerulonephritis is less common
in this setting (<30%), and anti-GBM disease is
rare (<1%).
o Among patients with RPGN, immune-complex
glomerulonephritis and pauci-immune
glomerulonephritis are equally prevalent (~45%
each), whereas anti- GBM disease again accounts
for a minority of cases (<10%).
o Three serologic markers often predict the
immunofluorescence microscopy findings in
nephritic syndrome and RPGN and may obviate
the need for renal biopsy in classic cases.
o They are the serum C3 level and titers of anti-GBM
antibody and ANCA.
o As discussed in previous sections, the kidney is
host to immune attack in immune-complex
glomerulonephritis, most cases being initiated
either by in situ formation of immune complexes
or less commonly by glomerular trapping of
circulating immune complexes.
o These patients typically have
hypocomplementemia (low C3 in 90%) and
negative anti-GBM and ANCA serology, the major
exception being IgA nephropathy/Henoch
Scho¨nlein purpura where complement levels are
typically normal.
o The glomerulus is the direct target of immune
attack in anti-GBM disease, glomerular
inflammation being initiated by an autoantibody
directed at a 28-kDa autoantigen on the alpha3
chain of type IV collagen.
o Approximately 90 to 95% of patients with anti-
GBM disease have circulating anti-GBM
autoantibodies detectable by immunoassay;
serum complement levels are typically normal,
and ANCA are usually not detected.
o The pathogenesis of pauci-immune
glomerulonephritis is still being defined; however,
most patients have circulating ANCA. Serum
complement levels are typically normal, and anti-
GBM titers are usually negative in ANCA-
associated renal disease.
o It should be noted, however, that there may be
some serologic overlap, with as many as 20% of
patients with immune complex or anti-GBM
glomerulonephritis also having at least low levels
of circulating ANCA.
NEPHRITIC SYNDROME AND RPGN DUE TO
IMMUNE-COMPLEX GLOMERULONEPHRITIS
o Nephritic syndrome induced by immune- complex
glomerulonephritis may be (1) be idiopathic, (2)
represent a response to a known antigenic
stimulus (e.g., glomerulonephritis triggered by
bacterial endocarditis or streptococcal infection, or
hepatitis B or C infection in cryoglobulinemic
glomerulonephritis), or (3) form part of a
multisystem immune-complex disorder (e.g., lupus
nephritis, Henoch-Scho¨nlein purpura)
INFECTION-ASSOCIATED GLOMERULONEPHRITIS
INCLUDING GLOMERULONEPHRITIS ASSOCIATED WITH
 9

STREPTOCOCCAL INFECTION AND INFECTIVE o The serum creatinine is often mildly elevated at
ENDOCARDITIS presentation.

o Serum C3 levels and CH50 are depressed within 2

weeks in ~90% of cases.
o A variety of infections can precipitate immune-
complex glomerulonephritis. o C4 levels are characteristically normal, indicating
activation of the alternate pathway of
complement.
o The most common clinicopathologic lesion in this
setting is acute diffuse proliferative
glomerulonephritis presenting as the acute o Complement levels usually return to normal within
nephritic syndrome; however, depending on the 6 to 8 weeks. Persistently depressed levels after
speed of onset and site and extent of immune this period should suggest another cause, such as
complex formation, infection-associated immune the presence of a C3 nephritic factor (see
complex formation can trigger “Membranoproliferative Glomerulonephritis,” p.
mesangioproliferative, focal proliferative, 1687).
membranoproliferative, or membranous
glomerulopathy. o The majority of patients (>75%) have transient
hypergammaglobulinemia and mixed
o Poststreptococcal glomerulonephritis is the cryoglobulinemia.
prototypical postinfectious glomerulonephritis and
a leading cause of acute nephritic syndrome. o The antecedent streptococcal infection may still be
evident or may have resolved either
o Most cases are sporadic, though the disease can spontaneously or in response to antibiotic therapy.
occur as an epidemic.
o Most patients (>90%) have circulating antibodies
o Glomerulonephritis develops, on average, 10 days against streptococcal exoenzymes such as
after pharyngitis or 2 weeks after a skin infection antistreptolysin O (ASO), anti-deoxyribonuclease B
(impetigo) with a nephritogenic strain of group A (anti-DNAse B), antistreptokinase (ASKase), anti-
beta-hemolytic streptococcus. nicotinyl adenine dinucleotidase (anti-NADase),
and antihyaluronidase (AHase).
o The known nephritic strains include M types 1, 2,
4, 12, 18, 25, 49, 55, 57, and 60. o Acute poststreptococcal glomerulonephritis is
usually diagnosed on clinical and serologic
o Immunity to these strains is type-specific and grounds, without resort to renal biopsy, especially
long-lasting, and repeated infection and nephritis in children with a typical antecedent history. The
are rare. characteristic lesion on light microscopy is diffuse
proliferative glomerulonephritis.
o Epidemic poststreptococcal glomerulonephritis is
most commonly encountered in children of 2 to 6 o Crescents are uncommon, and extraglomerular
years of age with pharyngitis during the winter involvement is usually mild. Immunofluorescence
months. microscopy reveals diffuse granular deposition of
IgG and C3, giving rise to a “starry sky”.
o This entity appears to be decreasing in frequency,
possibly due to more widespread and prompt use o The characteristic finding on electron microscopy
of antibiotics. is the presence of large electron-dense immune
deposits in the subendothelial, subepithelial, and
mesangial areas.
o Poststreptococcal glomerulonephritis in
association with cutaneous infections usually o In addition to poststreptococcal
occurs in a setting of poor personal hygiene or glomerulonephritis, the nephritic syndrome and
streptococcal superinfection of another skin RPGN can complicate acute immune-complex
disease. glomerulonephritis due to other viral, bacterial,
fungal, and parasitic infections.
o The classic clinical presentation of
poststreptococcal glomerulonephritis is full-blown o Diffuse proliferative immune-complex
nephritic syndrome with oliguric acute renal glomerulonephritis is a well-described
failure; however, most patients have milder complication of acute and subacute infective
disease. Indeed, subclinical cases outnumber overt endocarditis and is usually associated with
cases by four- to tenfold during epidemics. hypocomplementemia.

o Patients with overt disease present with gross
hematuria (red or “smoky” urine), headache, and
generalized symptoms such as anorexia, nausea,
vomiting, and malaise. Swelling of the renal
capsule can cause flank or back pain.
o The glomerular lesion typically resolves following
eradication of the cardiac infection.
(Harrison’s Principles of Internal Medicine 16th Edition)

o Physical examination reveals hypervolemia,

edema, and hypertension.
3.1.2Rapidly Progressive (Cresentric Glomerulonephritis)
o The urinary sediment is nephritic, with dysmorphic
red blood cells, red cell casts, leukocytes,
occasionally leukocyte casts, and subnephrotic
proteinuria. RAPIDLY PROGRESSIVE (CRESCENTIC)
GLOMERULONEPHRITIS
o Fewer than 5% of patients develop nephrotic-
range proteinuria. The latter may only manifest as
acute nephritis resolves and renal blood flow and
GFR recover. o Rapidly progressive glomerulonephritis (RPGN) is a
syndrome associated with severe glomerular injury
o Coexistent rheumatic fever is extremely rare.

and does not denote a specific etiologic form of
glomerulonephritis.
o It is characterized clinically by rapid and
progressive loss of renal function associated with
severe oliguria and (if untreated) death from renal
failure within weeks to months.
o Regardless of the cause, the classic histologic
picture is characterized by the presence of
crescents in most of the glomeruli (crescentic
glomerulonephritis).
o As discussed earlier, these are produced in part by
proliferation of the parietal epithelial cells lining
Bowman capsule and in part by infiltration of
monocytes and macrophages.
Classification and Pathogenesis
o RPGN may be caused by a number of different
diseases, some restricted to the kidney and others
systemic.
o Although no single mechanism can explain all
cases, there is little doubt that in most cases, the
glomerular injury is immunologically mediated.
o Thus, a practical classification divides RPGN into
three groups on the basis of immunologic findings
(Table 20-7). In each group, the disease may be
associated with a known disorder, or it may be
idiopathic.
o The first type of RPGN is best remembered as anti-
GBM antibody-induced disease and hence is
characterized by linear deposits of IgG and, in
many cases, C3 in the GBM, as previously
described.48 In some of these patients, the anti-
GBM antibodies cross-react with pulmonary
alveolar basement membranes to produce the
clinical picture of pulmonary hemorrhage
associated with renal failure (Goodpasture
syndrome).
o Plasmapheresis to remove the pathogenic
circulating antibodies is usually part of the
treatment, which also includes therapy to
suppress the underlying immune response.
o The Goodpasture antigen, as was noted earlier, is
a peptide within the noncollagenous portion of the
α3-chain of collagen type IV.
o What triggers the formation of these antibodies is
unclear in most patients. Exposure to viruses or
hydrocarbon solvents (found in paints and dyes)
has been implicated in some patients, as have
various drugs and cancers.
o There is a high prevalence of certain HLA subtypes
and haplotypes (e.g., HLA-DRB1) in affected
patients, a finding consistent with the genetic
predisposition to autoimmunity.
o The second type of RPGN is the result of immune
complex-mediated disease.
o It can be a complication of any of the immune
complex nephritides, including postinfectious
glomerulonephritis, SLE, IgA nephropathy, and
Henoch-Schönlein purpura.
o In all of these cases, immunofluorescence studies
reveal the granular pattern of staining
characteristic of immune complex deposition.
10
These patients cannot usually be helped by
plasmapheresis, and they require treatment for
the underlying disease.
o The third type of RPGN, also called pauci-immune
type, is defined by the lack of anti-GBM antibodies
or immune complexes by immunofluorescence and
electron microscopy.
o Most patients with this type of RPGN have
antineutrophil cytoplasmic antibodies (ANCA), of
cytoplasmic (C) or perinuclear (P) patterns, in the
serum, which, as we have seen (Chapter 11), play
a role in some vasculitides.
o Hence, in some cases, this type of RPGN is a
component of a systemic vasculitis such as
Wegener granulomatosis or microscopic
polyarteritis.
o In many cases, however, pauci-immune crescentic
glomerulonephritis is isolated and hence
idiopathic.
o More than 90% of such idiopathic cases have c-
ANCA or p-ANCA in the sera.
o The presence of circulating ANCAs in both
idiopathic RPGN and cases of RPGN that occur as a
component of systemic vasculitis, and the similar
pathologic features in either setting, have led to
the idea that these disorders are pathogenetically
related.
o According to this concept, all cases of RPGN of the
pauci-immune type are manifestations of small
vessel vasculitis or polyangiitis, which is limited to
glomerular and perhaps peritubular capillaries in
cases of idiopathic crescentic glomerulonephritis.
o The clinical distinction between systemic vasculitis
with pauci-immune renal involvement and
idiopathic crescentic glomerulonephritis
accordingly has become deemphasized, as these
entities are viewed as part of a spectrum of
vasculitic disease.
o ANCAs have proved to be invaluable as a highly
sensitive diagnostic marker for pauci-immune
RPGN, but proof of their role as a direct cause of
RPGN has been elusive.
o Recent strong evidence of their pathogenic
potential has been obtained by studies in which
antibodies against myeloperoxidase (the target
antigen of most p-ANCAs) are transferred into
mice.
o To summarize, all three types of RPGN may be
associated with a well-defined renal or extrarenal
disease, but in many cases (approximately 50%),
the disorder is idiopathic. Of the patients with this
syndrome, about one fifth have anti-GBM
antibody-induced disease without lung
involvement; another one fourth have immune
complex-mediated disease RPGN; and the
remainder are of the pauci-immune type.
o The common denominator in all types of RPGN is
severe glomerular injury.
Morphology
o The kidneys are enlarged and pale, often with
petechial hemorrhages on the cortical surfaces.
 11

o Depending on the underlying cause, the glomeruli

may show focal necrosis, diffuse or focal
endothelial proliferation, and mesangial (Robbins and Cotran Pathologic Basis of Disease 7th
proliferation. Edition)

o The histologic picture, however, is dominated by

the formation of distinctive crescents.
3.1.3Membranous Glomerulopathy
o Crescents are formed by proliferation of parietal
cells and by migration of monocytes and
macrophages into the urinary space.
MEMBRANOUS GLOMERULOPATHY (MEMBRANOUS
o Neutrophils and lymphocytes may be present. NEPHROPATHY)

o The crescents eventually obliterate Bowman space

and compress the glomerular tuft.
o Membranous glomerulopathy is the most common
o Fibrin strands are prominent between the cellular cause of the nephrotic syndrome in adults.
layers in the crescents; indeed, as discussed
earlier, the escape of fibrin into Bowman space is o It is characterized by diffuse thickening of the
an important contributor to crescent formation.
glomerular capillary wall and the accumulation of
electron-dense, immunoglobulin-containing
o Electron microscopy may, as expected, disclose deposits along the subepithelial side of the
subepithelial deposits in some cases, but in many basement membrane.
cases, it shows distinct ruptures in the GBM, the
severe injury that allows leukocytes, proteins, and o Membranous glomerulopathy occurring in
inflammatory mediators into the urinary space,
association with other systemic diseases and a
where they trigger the crescent formation.
variety of identifiable etiologic agents is referred
to as secondary membranous glomerulopathy.
o In time, most crescents undergo sclerosis, but
restoration of normal glomerular architecture o The most notable such associations are as follows:
marks a successful clinical outcome in some
patients, particularly those with an infection-
associated immune complex etiology.  Drugs (penicillamine, captopril, gold,
nonsteroidal anti-inflammatory drugs
[NSAIDs]): 1% to 7% of patients with
o By immunofluorescence microscopy, postinfec-
rheumatoid arthritis treated with
tious cases exhibit granular immune deposits;
penicillamine or gold (drugs now used
Goodpasture syndrome cases show linear
infrequently for this purpose) develop
fluorescence for immunoglobulin and complement,
membranous glomerulopathy. NSAIDs, as we
and pauci-immune cases have little or no
shall see, also cause minimal change disease.
deposition of immune reactants.

 Underlying malignant tumors, particularly

carcinoma of the lung and colon and
melanoma. According to some investigators,
Clinical Course these are present in up to 5% to 10% of
adults with membranous glomerulopathy.

 SLE: About 15% of glomerulonephritis in SLE

o The renal manifestations of all forms include is of the membranous type.
hematuria with red cell casts in the urine,
moderate proteinuria occasionally reaching the
 Infections (chronic hepatitis B, hepatitis C,
nephrotic range, and variable hypertension and
syphilis, schistosomiasis, malaria)
edema.

 Other autoimmune disorders, such as

o In Goodpasture syndrome, the course may be
thyroiditis
dominated by recurrent hemoptysis or even life-
threatening pulmonary hemorrhage.
o In about 85% of patients, no associated condition
can be uncovered, and the disease is considered
o Serum analyses for anti-GBM antibodies,
idiopathic.
antinuclear antibodies, and ANCA are helpful in the
diagnosis of specific subtypes.

o Although milder forms of glomerular injury may

subside, the renal involvement is usually Etiology and Pathogenesis
progressive over a matter of weeks and
culminates in severe oliguria.

o Recovery of renal function may follow early
intensive plasmapheresis (plasma exchange)
combined with steroids and cytotoxic agents in
Goodpasture syndrome.
o This therapy appears to reverse both pulmonary
hemorrhage and renal failure.
o Other forms of RPGN also respond well to steroids
and cytotoxic agents.
o Despite therapy, patients may eventually require
chronic dialysis or transplantation.
o Membranous glomerulopathy is a form of chronic
immune complex-mediated disease. In secondary
membranous glomerulopathy, particular antigens
can sometimes be identified in the immune
complexes.
o For example, membranous glomerulopathy in SLE
is associated with deposition of autoantigen-
antibody complexes.
o Exogenous (hepatitis B, Treponema antigens) or
endogenous (thyroglobulin) antigens have been
identified within deposits in some patients.

o The lesions bear a striking resemblance to those of
experimental Heymann nephritis, which, as you
might recall, is induced by antibodies to a megalin
antigenic complex.
o A similar but still unidentified antigen is presumed
to be present in most cases of idiopathic
membranous glomerulopathy in humans.
o Susceptibility to Heymann nephritis in rats and
membranous glomerulopathy in humans is linked
to the MHC locus, which influences the ability to
produce antibodies to the nephritogenic antigen.
o Thus, idiopathic membranous glomerulopathy, like
Heymann nephritis, is considered an autoimmune
disease linked to susceptibility genes and caused
by antibodies to a renal autoantigen.
o How does the glomerular capillary wall become
leaky in membranous glomerulopathy?
o There is a paucity of neutrophils, monocytes, or
platelets in glomeruli and the virtually uniform
presence of complement, and experimental work
suggests a direct action of C5b-C9, the pathway
leading to the formation of the membrane attack
complex.
o C5b-C9 causes activation of glomerular epithelial
and mesangial cells, inducing them to liberate
proteases and oxidants, which cause capillary wall
injury and increased protein leakage.
Morphology
o By light microscopy, the glomeruli either appear
normal in the early stages of the dis-ease or
exhibit uniform, diffuse thickening of the
glomerular capillary wall.
o By electron microscopy, the thickening is seen to
be caused by irregular dense deposits between
the basement membrane and the overlying
epithelial cells, the latter having effaced foot
processes.
o Basement membrane material is laid down
between these deposits, appearing as irregular
spikes protruding from the GBM.
o These spikes are best seen by silver stains, which
color the basement membrane black.
o In time, these spikes thicken to produce domelike
protrusions and eventually close over the immune
deposits, burying them within a markedly
thickened, irregular membrane.
Immunofluorescence microscopy demonstrates
that the granular deposits contain both
immunoglobulins and various amounts of
complement.
o As the disease advances, the membrane
thickening progressively encroaches on the
capillary lumens, and sclerosis of the mesangium
may occur; in the course of time, glomeruli may
become totally sclerosed.
o The epithelial cells of the proximal tubules contain
protein reabsorption droplets, and there may be
considerable mononuclear cell interstitial
inflammation.
Clinical Course
12
o In a previously healthy individual, this disorder
usually begins with the insidious onset of the
nephrotic syndrome or, in 15% of patients, with
non-nephrotic proteinuria.
o Hematuria and mild hypertension are present in
15% to 35% of cases.
o It is necessary in any patient to first rule out the
secondary causes described earlier, since
treatment of the underlying condition (malignant
neoplasm, infection, or SLE) or discontinuance of
the offending drug can reverse progression.
o The course of the disease is variable but generally
indolent.
o In contrast to minimal change disease, described
later, the proteinuria is nonselective and does not
usually respond well to corticosteroid therapy.
o Progression is associated with increasing sclerosis
of glomeruli, rising BUN reflecting renal
insufficiency, and development of hypertension.
o Although proteinuria persists in more than 60% of
patients, only about 10% die or progress to renal
failure within 10 years, and no more than 40%
eventually develop renal insufficiency. Concurrent
sclerosis of glomeruli in the renal biopsy at the
time of diagnosis is a predictor of worse prognosis.
o Spontaneous remissions and a relatively benign
outcome occur more commonly in women and in
those with proteinuria in the non-nephrotic range.
o Because of the variable course of the disease, it
has been difficult to evaluate the overall
effectiveness of corticosteroids or other
immunosuppressive therapy in controlling the
proteinuria or progression.
(Robbins and Cotran Pathologic Basis of Disease 7th
Edition)
o MGN, or membranous nephropathy as it is
sometimes called, accounts for approximately
30% of cases of nephrotic syndrome in adults, with
a peak incidence between the ages of 30–50 years
and a male to female ratio of 2:1.
o It is rare in childhood and by far the most common
cause of nephrotic syndrome in the elderly.
o In 25–30% of cases, MGN is secondary to
malignancy (solid tumors of the breast, lung,
colon), infection (hepatitis B, malaria,
schistosomiasis), or rheumatologic disorders like
lupus or rarely rheumatoid arthritis (Table 277-6).
o Uniform thickening of the basement membrane
along the peripheral capillary loops is seen by light
microscopy on renal biopsy, this thickening needs
to be distinguished from that seen in diabetes and
amyloidosis.
o Immunofluorescence demonstrates diffuse
granular deposits of IgG and C3, and electron
microscopy typically reveals electron-dense
subepithelial deposits.
o While different stages (I–V) of progressive
membranous lesions have been described, some
published analyses indicate the degree of tubular

atrophy or interstitial fibrosis is more predictive of
progression than is the stage of glomerular
disease.
o The presence of subendothelial deposits or the
presence of tubuloreticular inclusions strongly
points to a diagnosis of membranous lupus
nephritis, which may precede the extrarenal
manifestations of lupus.
o Work in Heyman nephritis, an animal model of
MGN, suggests that glomerular lesions result from
in situ formation of immune complexes with
megalin receptor–associated protein as the
putative antigen.
o This antigen is not found in human podocytes, but
human antibodies have been described against
neutral endopeptidase expressed by podocytes,
hepatitis antigens B/C, Helicobacterpylori
antigens, tumor antigens, and thyroglobulin.
o Eighty percent of patients with MGN present with
nephrotic syndrome and nonselective proteinuria.
o Microscopic hematuria is seen in up to 50% of
patients. Spontaneous remissions occur in 20–33%
of patients and often occur late in the course after
years of nephrotic syndrome.
o One-third of patients continue to have relapsing
nephrotic syndrome but maintain normal renal
function, and approximately another third of
patients develop renal failure or die from the
complications of nephrotic syndrome. Male
gender, older age, hypertension, and the
persistence of proteinuria are associated with
worse prognosis.
o Although thrombotic complications are a feature of
all nephrotic syndromes, MGN has the highest
reported incidences of renal vein thrombosis,
pulmonary embolism, and deep vein thrombosis.
Prophylactic anticoagulation is controversial but
has been recommended for patients with severe
or prolonged proteinuria in the absence of risk
factors for bleeding.
o In addition to the treatment of edema,
dyslipidemia, and hypertension, inhibition of the
renin-angiotensin system is recommended.
o Therapy with immunosuppressive drugs is also
recommended for patients with primary MGN and
persistent proteinuria (>3.0 g/24 h).
o The choice of immunosuppressive drugs for
therapy is controversial, but current
recommendations based on small clinical studies
are to treat with steroids and cyclophosphamide,
chlorambucil, or cyclosporine.
o Experience with mycophenolate mofetil or anti-
CD20 antibody is even more limited.
(Harrison’s Principles of Internal Medicine 17th Edition)
3.1.4Minimal Change
MINIMAL CHANGE DISEASE (LIPOID NEPHROSIS)
13
o This relatively benign disorder is the most frequent
cause of nephrotic syndrome in children, but it is
less common in adults.
o It is characterized by diffuse effacement of foot
processes of epithelial cells in glomeruli that
appear virtually normal by light microscopy.
o The peak incidence is between 2 and 6 years of
age.
o The disease sometimes follows a respiratory
infection or routine prophylactic immunization.
o Its most characteristic feature is its usually
dramatic response to corticosteroid therapy.
Etiology and Pathogenesis
o Although the absence of immune deposits in the
glomerulus excludes classic immune complex
mechanisms, several features of the disease point
to an immunologic basis, including (1) the clinical
association with respiratory infections and
prophylactic immunization; (2) the response to
corticosteroids and/or other immunosuppressive
therapy; (3) the association with other atopic
disorders (e.g., eczema, rhinitis); (4) the increased
prevalence of certain HLA haplotypes in patients
with minimal change disease associated with
atopy (suggesting a genetic predisposition); (5)
the increased incidence of minimal change disease
in patients with Hodgkin disease, in whom defects
in T cell-mediated immunity are well recognized;
and (6) reports of proteinuria-inducing factors in
the plasma or lymphocyte supernatants of
patients with minimal change disease and focal
glomerulosclerosis.
o The current leading hypothesis is that minimal
change disease involves some immune
dysfunction, eventually resulting in the elaboration
of a cytokine that damages visceral epithelial cells
and causes proteinuria.
o The ultrastructural changes point to a primary
visceral epithelial cell injury, and studies in animal
models suggest the loss of glomerular polyanions.
o Thus, defects in the charge barrier may contribute
to the proteinuria.
o The actual route by which protein traverses the
epithelial cell portion of the capillary wall remains
an enigma.
o Possibilities include transcellular passage through
the epithelial cells, passage through residual
spaces between remaining but damaged foot
processes, or leakage through foci in which the
epithelial cells have become detached from the
basement membrane.
o Additional insight into mechanisms by which
epithelial cell injury results in proteinuria in
minimal change disease, focal and segmental
glomerulosclerosis, and related entities should
come from the recent discovery of mutations in
several glomerular proteins, including nephrin,
discussed in the section on focal
glomerulosclerosis below.
o A mutation in the nephrin gene causes a
hereditary form of congenital nephrotic syndrome
(Finnish type) with minimal change glomerular
morphology.

o Such mutations and the proteinuria they engender
demonstrate that at least some cases of nephrotic
syndrome with minimal change disease
morphology can occur in the absence of abnormal
responses of the immune system.
Morphology
o The glomeruli are normal by light microscopy.
o By electron microscopy, the basement membrane
appears normal, and no electron-dense material is
deposited.
o The principal lesion is in the visceral epithelial
cells, which show a uniform and diffuse
effacement of foot processes, these being
replaced by a rim of cytoplasm often showing
vacuolization, swelling, and hyperplasia of villi.
o This change, often incorrectly termed "fusion" of
foot processes, actually represents simplification
of the epithelial cell architecture with flattening,
retraction, and swelling of foot processes.
o Foot process effacement is also present in other
proteinuric states (e.g., membranous
glomerulopathy, diabetes); it is only when
effacement is associated with normal glomeruli by
light microscopy that the diagnosis of minimal
change disease can be made.
o The visceral epithelial changes are completely
reversible after corticosteroid therapy,
concomitant with remission of the proteinuria.
o The cells of the proximal tubules are often laden
with lipid and protein, reflecting tubular
reabsorption of lipoproteins passing through
diseased glomeruli (thus, the historical term lipoid
nephrosis).
o Immunofluorescence studies show no
immunoglobulin or complement deposits.
Clinical Course
 Despite massive proteinuria, renal function
remains good, and there is commonly no
hypertension or hematuria.
 The proteinuria usually is highly selective, most of
the protein consisting of albumin.
 Most children (more than 90%) with minimal
change disease respond rapidly to corticosteroid
therapy.
 However, the nephrotic phase may recur, and
some patients may become steroid dependent or
resistant.
 Nevertheless, the long-term prognosis for patients
is excellent, and even steroid-dependent disease
resolves when children reach puberty.
 Although adults are slower to respond, the long-
term prognosis is also excellent.
 As has been noted, minimal change disease in
adults can be associated with Hodgkin disease
14
and, less frequently, other lymphomas and
leukemias.
(Robbins and Cotran Pathologic Basis of Disease 7th
Edition)
Minimal Change Disease
o MCD, sometimes known as nil lesion, causes 70–
90% of nephrotic syndrome in childhood but only
10–15% of nephrotic syndrome in adults.
o MCD usually presents as a primary renal disease
but can be associated with several other
conditions, including Hodgkin's disease, allergies,
or use of nonsteroidal anti-inflammatory agents;
significant interstitial nephritis often accompanies
cases associated with nonsteroidal use.
o MCD on renal biopsy shows no obvious glomerular
lesion by light microscopy and is negative for
deposits by immunofluorescent microscopy, or
occasionally shows small amounts of IgM in the
mesangium.
o Electron microscopy, however, consistently
demonstrates an effacement of the foot process
supporting the epithelial podocytes with
weakening of slit-pore membranes.
o The pathophysiology of this lesion is uncertain.
o Most agree there is a circulating cytokine, perhaps
related to a T cell response that alters capillary
charge and podocyte integrity.
o The evidence for cytokine-related immune injury is
circumstantial and is suggested by the presence of
preceding allergies, altered cell-mediated
immunity during viral infections, and the high
frequency of remissions with steroids.
o MCD presents clinically with the abrupt onset of
edema and nephrotic syndrome accompanied by
acellular urinary sediment.
o Less common clinical features include
hypertension (30% in children, 50% in adults),
microscopic hematuria (20% in children, 33% in
adults), atopy or allergic symptoms (40% in
children, 30% in adults), and decreased renal
function (<5% in children, 30% in adults).
o The appearance of acute renal failure in adults is
usually caused by intrarenal edema (nephrosarca)
that is responsive to intravenous albumin and
diuretics.
o This presentation must be distinguished from
acute renal failure secondary to hypovolemia.
o In children, the abnormal urine principally contains
albumin with minimal amounts of higher molecular
weight proteins, and is sometimes called selective
proteinuria.
o Although up to 30% of children have a
spontaneous remission, all children today are
treated with steroids; only children who are
nonresponders are biopsied in this setting.
o Primary responders are patients who have a
complete remission (<0.2 mg/24 h of proteinuria)
after a single course of prednisone; steroid-

dependent patients relapse as their steroid dose is
tapered. Frequent relapsers have two or more
relapses in the 6 months following taper, and
steroid-resistant patients fail to respond to steroid
therapy.
o Ninety to 95% of children will develop a complete
remission after 8 weeks of steroid therapy, and
80–85% of adults will achieve complete remission,
but only after a longer course of 20–24 weeks.
o Patients with steroid resistance can develop FSGS
on repeat biopsy.
o Some hypothesize that if the first renal biopsy
does not have a sample of deeper glomeruli, then
the correct early diagnosis of FSGS may be
missed.
o Relapses occur in 70–75% of children after the first
remission, and early relapse predicts multiple
subsequent relapses.
o The frequency of relapses decreases after puberty,
although there is an increased risk of relapse
following the rapid tapering of steroids in all
groups.
o Relapses are less common in adults but are more
resistant to subsequent therapy.
o Prednisone is first-line therapy, and other
immunosuppressive drugs, such as
cyclophosphamide, chlorambucil, and
mycophenolate mofetil, are saved for frequent
relapsers, steroid-dependent, or steroid-resistant
patients.
o Cyclosporine can induce remission, but relapse is
also common when cyclosporine is withdrawn. The
long-term prognosis in adults is less favorable
when acute renal failure or steroid resistance
occurs.
(Harrison’s Principles of Internal Medicine 17th Edition)
3.1.5Focal Segmental Glomerulosclerosis
FOCAL SEGMENTAL GLOMERULOSCLEROSIS
o As the name implies, this 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).
o Focal segmental glomerulosclerosis is frequently
accompanied clinically by the nephrotic syndrome
or heavy proteinuria.
Classification and Types
o Focal segmental glomerulosclerosis (FSGS) occurs
in the following settings:
 In association with other known conditions,
such as HIV infection (HIV nephropathy),
15
heroin addiction (heroin nephropathy), sickle
cell disease, and massive obesity
 As a secondary event, reflecting glomerular
scarring, in cases of focal glomerulonephritis
(e.g., IgA nephropathy)
 As a component of the adaptive response to
loss of renal tissue (renal ablation, described
earlier) in advanced stages of other renal
disorders, such as reflux nephropathy,
hypertensive nephropathy, or with unilateral
renal agenesis
 In certain inherited forms of nephrotic
syndrome where the disease, in some
pedigrees, has been linked to mutations in
genes encoding nephrin, podocin, or α-actinin
4
 As a primary disease (idiopathic focal
segmental glomerulosclerosis)
o Idiopathic focal segmental glomerulosclerosis
accounts for up to 10% and 35% of cases of
nephrotic syndrome in children and adults in many
series, respectively. FSGS (both primary and
secondary forms) has increased in incidence and is
now the most common cause of nephrotic
syndrome in adults in the United States.
o It is a particularly common cause of nephrotic
syndrome in Hispanic and African American
patients.
o The clinical signs differ from those of minimal
change disease in the following respects: (1) there
is a higher incidence of hematuria, reduced GFR,
and hypertension; (2) proteinuria is more often
nonselective; (3) there is poor response to
corticosteroid therapy; (4) there is progression to
chronic glomerulosclerosis, with at least 50%
developing end-stage renal disease within 10
years; and (5) immunofluorescence microscopy
may show nonspecific deposition ("trapping") of
IgM and C3 in the sclerotic segment.
Morphology
o By light microscopy, the segmental lesions may
involve only a minority of the glomeruli and may
be missed if the biopsy specimen contains an
insufficient number of glomeruli.
o The lesions initially tend to involve the
juxtamedullary glomeruli, although they
subsequently become more generalized.
o In the sclerotic segments, there is collapse of
basement membranes, increase in matrix, and
segmental insudation of plasma proteins along the
capillary wall (hyalinosis), which may extend to
aggregates within glomerular capillaries that
occlude the lumina.
o Lipid droplets and foam cells are often present.
o Glomeruli that do not exhibit segmental lesions
either appear normal on light microscopy or may
show increased mesangial matrix and mesangial
proliferation.
o On electron microscopy, both sclerotic and
nonsclerotic areas show the diffuse effacement of
foot processes characteristic of minimal change
disease, but in addition, there may be focal

detachment of the epithelial cells with denudation
of the underlying GBM.
o By immunofluorescence microscopy, IgM and C3
may be present in the sclerotic areas and/or in the
mesangium. In addition to the focal sclerosis,
there may be pronounced hyalinosis and
thickening of afferent arterioles.
o With the progression of the disease, increased
numbers of glomeruli become involved, sclerosis
spreads within each glomerulus, and there is an
increase in mesangial matrix.
o In time, this leads to total sclerosis of glomeruli,
with pronounced tubular atrophy and interstitial
fibrosis.
o A morphologic variant of focal segmental
glomerulosclerosis, called collapsing
glomerulopathy, is characterized by collapse and
sclerosis of the entire glomerular tuft in addition to
the usual focal segmental glomerulosclerosis
lesions.
o A characteristic feature is proliferation and
hypertrophy of glomerular visceral epithelial cells.
o This lesion may be seen in situations in which it is
idiopathic, but it is the most characteristic lesion
of HIV-associated nephropathy.
o In both cases, there is associated prominent
tubular injury with formation of microcysts. It has a
particularly poor prognosis.
Pathogenesis
o Whether idiopathic focal segmental
glomerulosclerosis represents a distinct disease or
is simply a phase in the evolution of a subset of
patients with minimal change disease remains
unresolved.
o The characteristic degeneration and focal
disruption of visceral epithelial cells are thought to
represent an accentuation of the diffuse epithelial
cell change typical of minimal change disease.
o It is this epithelial damage that is the hallmark of
focal segmental glomerulosclerosis.
o The hyalinosis and sclerosis represent entrapment
of plasma proteins in extremely hyperpermeable
foci with increased ECM deposition.
o The recurrence of proteinuria, sometimes within
24 hours after transplantation, suggests that a
circulating factor, perhaps a cytokine, may be the
cause of the epithelial damage.
o An approximately 50-kDa nonimmunoglobulin
factor causing proteinuria has been isolated from
sera of such patients.
o The recent discovery of a genetic basis for some
cases of FSGS has improved the understanding of
the pathogenesis of proteinuria in the nephrotic
syndrome and has provided new methods for
diagnosis and prognosis of affected patients.
o The first relevant gene to be identified, NPHS1,
maps to chromosome 19q13 and encodes the
protein nephrin.
16
o Nephrin is a key component of the slit diaphragm,
the zipper-like structure between podocyte foot
processes that might control glomerular
permeability.
o Several types of mutations of the NPHS1 gene
have been identified, and they give rise to
congenital nephrotic syndrome of the Finnish type.
o Prenatal diagnosis of CNF is now possible based on
analysis of the NPHS1 gene.
o A distinctive pattern of autosomal recessive FSGS
results from mutations in the NPHS2 gene, which
maps to chromosome 1q25-31 and encodes the
protein product podocin.
o Podocin has also been localized to the slit
diaphragm.
o Mutations in NPHS2 result in a syndrome of
steroid-resistant nephrotic syndrome of childhood
onset.
o Affected children usually show pathologic features
of FSGS but sometimes of minimal change
disease.
o Podocin mutations may account for up to 30% of
cases of steroid-resistant nephrotic syndrome in
children.
o A third set of mutations in the gene encoding the
podocyte actin-binding protein α-actinin 4
underlies some cases of autosomal dominant
FSGS, which can be insidious in onset but has a
high rate of progression to renal insufficiency.
o What these proteins have in common is their
localization to the slit diaphragm and to adjacent
podocyte cytoskeletal structures such as actin.
o Their specific functions and interactions are
incompletely understood, but it is clear that the
integrity of each is necessary to maintain the
normal glomerular filtration barrier.
o Additional components of the podocyte/slit
diaphragm apparatus, such as CD2-associated
protein (CD2AP), have been identified that may
also contribute to proteinuria, as has been
suggested in studies of knockout mice (but not yet
demonstrated in humans).
o While identification of these genetic defects has
clarified the pathogenesis of some cases of the so-
called idiopathic nephrotic syndrome, many other
factors contribute to permeability defects.
o These include cell-cell and cell-matrix interactions,
particularly those mediated by α3β1 integrins and
dystroglycans. Defects in these interactions may
also cause a loss of podocyte adhesion to the
glomerular basement membrane.
o Renal ablation focal segmental glomerulosclerosis
occurs as a complication of glomerular and
nonglomerular diseases causing reduction in
functioning renal tissue, particularly reflux
nephropathy and unilateral agenesis.
o These may lead to progressive glomerulosclerosis
and renal failure.
o The pathogenesis of focal segmental
glomerulosclerosis in this setting has been
described earlier in this chapter.

Clinical Course
o There is little tendency for spontaneous remission
in idiopathic focal segmental glomerulosclerosis,
and responses to corticosteroid therapy are
variable.
o In general, children have a better prognosis than
adults do.
o Progression of renal failure occurs at variable
rates.
o About 20% of patients follow an unusually rapid
course, with intractable massive proteinuria
ending in renal failure within 2 years.
o Recurrences are seen in 25% to 50% of patients
receiving allografts.
(Robbins and Cotran Pathologic Basis of Disease 7th
Edition)
o FSGS refers to a pattern of renal injury
characterized by segmental glomerular scars that
involve some but not all glomeruli; the clinical
findings of FSGS largely manifest as proteinuria.
o When the secondary causes of FSGS are
eliminated (Table 277-5), the remaining patients
are considered to have FSGS.
o The incidence of this disease is increasing, and it
now represents up to one-third of cases of
nephrotic syndrome in adults and one-half of
cases of nephrotic syndrome in African Americans,
in whom it is seen more commonly.
o The pathogenesis of FSGS is probably
multifactorial.
o Possible mechanisms include a T cell–mediated
circulating permeability factor, TGF-–mediated
cellular proliferation and matrix synthesis, and
podocyte abnormalities associated with genetic
mutations.
o The pathologic changes of FSGS are most
prominent in glomeruli located at the
corticomedullary junction (Fig. e9-2), so if the
renal biopsy specimen is from superficial tissue,
the lesions can be missed, which sometimes leads
to a misdiagnosis of MCD.
o In addition to focal and segmental scarring, other
variants have been described, including cellular
lesions with endocapillary hypercellularity and
heavy proteinuria; collapsing glomerulopathy (Fig.
e9-3) with segmental or global glomerular collapse
and a rapid decline in renal function; or the
glomerular tip lesion, which seems to have a
better prognosis.
o FSGS can present with any level of proteinuria,
hematuria, hypertension, or renal insufficiency.
Nephrotic range proteinuria, African-American
race, and renal insufficiency are associated with a
poor outcome, with 50% of patients reaching renal
failure in 6–8 years.
17
o FSGS rarely remits spontaneously, but treatment-
induced remission of proteinuria significantly
improves prognosis.
o Treatment of patients with primary FSGS should
include inhibitors of the renin-angiotensin system.
Based on retrospective studies, patients with
nephrotic range proteinuria can be treated with
steroids but respond far less often than patients
with MCD.
o Proteinuria remits in only 20–45% of patients
receiving a course of steroids over 6–9 months.
o Limited evidence suggests that the use of
cyclosporine in steroid-responsive patients helps
ensure remissions, while other cytotoxic agents
confer little added benefit over steroid therapy.
Primary FSGS recurs in 25–40% of patients given
allografts at end-stage disease, leading to graft
loss in half of those cases.
o The treatment of secondary FSGS typically
involves treating the underlying cause and
controlling proteinuria. There is no role for steroids
or other immunosuppressive agents in secondary
FSGS.
(Harrison’s Principles of Internal Medicine 17th Edition)
3.2 Systemic Causes
3.2.1Wegener Granulomatosis
o Wegener’s granulomatosis is a distinct
clinicopathologic entity characterized by
granulomatous vasculitis of the upper and lower
respiratory tracts together with
glomerulonephritis.
o In addition, variable degrees of disseminated
vasculitis involving both small arteries and veins
may occur.
o Renal injury occurs in 80% of patients with
Wegener’s granulomatosis and varies from
indolent smoldering inflammation to rapidly
progressive renal failure.
o Cytoplasmic ANCA are detected at presentation in
80% of patients with renal disease and in 10%
more on follow-up.
o Renal biopsy typically reveals focal, segmental,
necrotizing pauci-immune glomerulonephritis with
crescent formation.
o In contrast to the lung, granulomas are rarely seen
in the kidney.
(Harrison’s Principles of Internal Medicine 16th Edition)
3.2.2Hypersensitivity
o Most noninfectious vasculitides appear to be
initiated by one of several immunologic
mechanisms.
o Such processes often induce relatively distinctive
clinicopathologic entities, in which the vasculitis is
widespread.
o Of these so-called systemic necrotizing
vasculitides, several types affect the aorta and

medium-sized vessels; most affect vessels smaller
than arteries, such as arterioles, venules, and
capillaries (designated small vessel vasculitis).
Immune Complexes
o The evidence for involvement of immune
complexes in vasculitides can be summarized as
follows:
o The vascular lesions resemble those found in
experimental immune complex-mediated
conditions, such as the local Arthus phenomenon
and serum sickness.
o Immune reactants and complement can be
detected in the serum or vessels of patients with
vasculitis.
o For example, DNA-anti-DNA complexes are
present in the vascular lesions of systemic lupus
erythematosus-associated vasculitis; IgG, IgM, and
complement in cryoglobulinemic vasculitis; and a
number of other antigens in isolated cases.
o Hypersensitivity to drugs causes approximately
10% of vasculitic skin lesions.
o Some, such as penicillin conjugate serum proteins,
whereas others such as streptokinase are foreign
proteins; both can lead to vascular deposits of
immune complexes.
o The most impressive evidence comes from
vasculitis associated with viral infections,
particularly hepatitis.
o There is a high incidence of hepatitis B antigen
(HBsAg) and HBsAg-anti-HBsAg immune
complexes in the serum and, with complement, in
the vascular lesions of some patients with
vasculitis, particularly those with large vessel
polyarteritis nodosa and less commonly in those
with membranous or membranoproliferative
glomerulonephritis or leukocytoclastic vasculitis.
o Importantly, immunosuppressive treatment results
in a remission of the vasculitis but perpetuates the
hepatitis B virus infection.
o Chronic hepatitis C virus (HCV) infection leads to
glomerulonephritis, in which HCV/RNA and
cryoprecipitates containing anti-HCV antibodies
are detected in glomeruli.
Antineutrophil Cytoplasmic Antibodies
o Serum from many patients with vasculitis in small
vessels reacts with cytoplasmic antigens in
neutrophils, indicating the presence of
antineutrophil cytoplasmic autoantibodies (ANCA).
o ANCA comprise a heterogeneous group of
autoantibodies against enzymes mainly found
within the azurophil or primary granules in
neutrophils but also found in the lysosomes of
monocytes and in endothelial cells.
o ANCA can be detected in serum by
immunofluorescent microscopy of ethanol-fixed
neutrophils and by immunochemical assays.
3.2.3Cryoglobulinemia
18
o Two main patterns of immunofluorescent staining
distinguish different ANCA types.
o One ANCA type shows cytoplasmic localization of
the staining (c-ANCA), and the most common
target antigen is proteinase 3 (PR-3), a neutrophil
granule constituent.
o The second type shows perinuclear staining (p-
ANCA) and is usually specific for myeloperoxidase
(MPO).
o Either ANCA specificity may occur in a patient with
ANCA-associated small vessel vasculitis, but c-
ANCA (PR-3 specificity) are typically found in
Wegener granulomatosis and p-ANCA (MPO
specificity) are found in most cases of microscopic
polyangiitis and Churg-Strauss syndrome.
Approximately 10% of patients with these
disorders, however, do not demonstrate ANCA by
typical assays.
o ANCA serve as useful quantitative diagnostic
markers for these disorders, and their discovery
has led to segregation of a group of these
disorders as the ANCA-associated vasculitides.
o The close association between ANCA titers and
disease activity, particularly c-ANCA in Wegener
granulomatosis, suggests that they may be
important in the pathogenesis of this disease, but
the precise mechanisms by which ANCA induce
injury are unknown.
o One scenario currently being pursued postulates
the following events:
o An autoimmune process of yet uncertain cause
and mechanism initiates the formation of ANCA.
o Proinflammatory cytokines produced during an
infection, by malignancy, or possibly triggered by
drugs induce surface expression of the ANCA
target antigens PR-3 and MPO on susceptible cells,
thereby making them accessible to the respective
antibodies.
o Binding of circulating ANCA to these antigens
leads to neutrophil degranulation and endothelial
cell injury with subsequent vascular damage.
Other Mechanisms
o Antibodies to endothelial cells, perhaps induced by
defects in immune regulation, may predispose to
certain vasculitides, such as those associated with
systemic lupus erythematosus and Kawasaki
disease.
o Additionally, in Goodpasture syndrome the
glomerulitis and pneumonitis are caused by anti-
glomerular basement membrane antibodies.
o Finally, there is experimental evidence that certain
viruses (e.g., herpes, coxsackievirus) may cause
vasculitis by immune mechanisms involving T-cell
action and gamma-interferon.
(Robbins and Cotran Pathologic Basis of Disease 7th
Edition)

o Renal involvement is most common with the
mixed cryoglobulinemias (types II and III), which
are more common in females and usually begin in
the sixth decade.
o Most patients present with a variable combination
of leukocytoclastic vasculitis, skin ulcerations,
arthralgias, fatigue, and Raynaud’s phenomenon.
o Renal disease is a complication in 50% of patients
and usually develops after 12 to 24 months.
o The typical clinical renal manifestations are
nephrotic-range proteinuria, microscopic
hematuria, and hypertension.
o Acute nephritic syndrome occurs in 20 to 30%,
and oliguric acute renal failure in about 5% of
patients with renal disease.
o Circulating levels of C3, C4, and CH50 are
depressed in about 80% of patients with renal
involvement, and a transient ANA (speckled
pattern) is sometimes detected. Hepatitis C virus
(HCV) RNA has been isolated from the serum of
patients with essential mixed cryoglobulinemia
(EMC).
th
(Harrison’s Principles of Internal Medicine 16 Edition)
3.2.4Systemic Lupus Erythematous
o Renal involvement is clinically evident in 40 to
85% of patients with SLE; it varies from isolated
abnormalities of the urinary sediment to full-blown
nephritic or nephrotic syndrome or chronic renal
failure.
o Most glomerular injury is triggered by the
formation of immune complexes within the
glomerular capillary wall; however, thrombotic
microangiopathy may be the dominant reason for
renal dysfunction in a small subset of patients with
the antiphospholipid antibody syndrome.
o Renal biopsy has proven very useful for identifying
the different patterns of immune-complex
glomerulonephritis in SLE, which are diverse,
portend different prognoses, and do not
necessarily correlate with the clinical findings.
o Indeed, clinically silent lupus nephritis is well
described as having a urinalysis virtually normal
but renal biopsy demonstrating varying degrees of
injury.
o Patients with active lupus nephritis have a range
of serologic abnormalities. Hypocomplementemia
is present in 75 to 90% of patients and is most
striking with diffuse proliferative
glomerulonephritis.
o Antinuclear antibodies (ANA) are usually detected
(95 to 99%), although not specific for SLE. ANA
titers tend to fall with treatment, and ANA may not
be detected during remissions.
o Anti-double-stranded DNA (dsDNA) antibodies are
highly specific for SLE, and changes in their titers
correlate with the activity of lupus nephritis.
o Patients with the lupus-related antiphospholipid
antibody syndrome can develop a variable degree
of renal impairment due to thrombotic
microangiopathy.
o The latter typically affects the interlobular arteries,
arterioles, and glomerular capillaries and is
characterized by intravascular microthrombi and
swelling of endothelial cells.
o Decreased levels of tissue plasminogen activator
and increased levels of α2-antiplasmin, both of
which would tend to promote thrombosis, have
been described in this syndrome.
(Harrison’s Principles of Internal Medicine 16th Edition)
3.2.5Polyarteritis nodosa
19
o Polyarteritis nodosa is a systemic vasculitis
manifested by transmural necrotizing
inflammation of small or medium-sized muscular
arteries, typically involving renal and visceral
vessels and sparing the pulmonary circulation.
o Neither glomerulonephritis nor vasculitis of
arterioles, capillaries, or venules is present.
o The involvement is peculiarly focal, random, and
episodic. It often produces irregular aneurysmal
dilation, nodularity, and vascular obstruction and
sometimes infarctions.
o To differentiate this disorder from other similar
vasculitides, which are now thought to be distinct
entities, the term classic is sometimes added to
the designation.
MORPHOLOGY
o In classic cases, polyarteritis nodosa involves
arteries of medium to small size in any organ, with
the possible exception of the lung.
o The distribution of lesions, in descending order of
frequency is kidneys, heart, liver, and
gastrointestinal tract, followed by pancreas,
testes, skeletal muscle, nervous system, and skin.
o Individual lesions are sharply segmental, may
involve only a portion of the vessel circumference,
and have a predilection for branching points and
bifurcations.
o Segmental erosion with weakening of the arterial
wall owing to the inflammatory process may cause
aneurysmal dilation or localized rupture that is
perceived clinically as a palpable nodule and can
be demonstrated by arteriography.
o Impairment of perfusion causing ulcerations,
infarcts, ischemic atrophy, or hemorrhages in the
area supplied by these vessels may provide the
first clue to the existence of the underlying
disorder. Sometimes, however, the lesions are
exclusively microscopic and produce no gross
changes.
o Histologically the vasculitis during the acute phase
is characterized by transmural inflammation of the
arterial wall with a heavy infiltrate of neutrophils,
eosinophils, and mononuclear cells, frequently
accompanied by fibrinoid necrosis of the inner half
of the vessel wall.
o Typically the inflammatory reaction permeates the
adventitia.
o The lumen may become thrombosed.
o In some lesions, only a portion of the
circumference is affected, leaving segments of
normal arterial wall juxtaposed to areas of
vascular inflammation.
o At a later stage, the acute inflammatory infiltrate
begins to disappear and is replaced by fibrous
thickening of the vessel wall accompanied by a
mononuclear infiltrate.
o The fibroblastic proliferation may extend into the
adventitia, contributing to the firm nodularity that
sometimes marks the lesions.

o At a still later stage, all that remains is marked
fibrotic thickening of the affected vessel, devoid of
significant inflammatory infiltration. Particularly
characteristic of polyarteritis nodosa is that all
stages of activity may coexist in different vessels
or even within the same vessel. Thus, whatever
the inflammatory insult, it is apparently recurrent
and strangely haphazard.
Clinical Course
o Classic polyarteritis nodosa is a disease of young
adults, although it may occur in children and older
individuals.
o The course may be acute, subacute, or chronic
and is frequently remittent, with long symptom-
free intervals.
o Because the vascular involvement is widely
scattered, the clinical signs and symptoms of this
disorder may be varied and puzzling.
o The most common manifestations are malaise,
fever of unknown cause, and weight loss;
hypertension, usually developing rapidly;
abdominal pain and melena (bloody stool) owing
to vascular lesions in the alimentary tract; diffuse
muscular aches and pains; and peripheral neuritis,
which is predominantly motor.
o Renal involvement is one of the prominent
manifestations of polyarteritis nodosa and a major
cause of death.
o Because small vessel involvement is absent,
however, there is no glomerulonephritis.
o About 30% of patients with polyarteritis nodosa
have hepatitis B antigen in their serum. Unlike
microscopic polyarteritis (microscopic polyangiitis,
see later), classic polyarteritis nodosa has little
association with ANCA.
o The diagnosis can usually be definitely established
by the identification of necrotizing arteritis on
tissue biopsy specimens, particularly medium-
sized arteries of clinically involved tissue, such as
kidney and nodular skin lesions.
o Angiography shows vascular aneurysms or
occlusions of main visceral arteries in 50% of
cases. Untreated, the disease is fatal in most
cases, either during an acute fulminant attack or
after a protracted course, but therapy with
corticosteroids and cyclophosphamide results in
remissions or cures in 90%.
o Effective treatment of the hypertension is a
prerequisite for a favorable prognosis.
(Robbins and Cotran Pathologic Basis of Disease 7th
Edition)
3.2.6 Henoch-Schӧlein Purpura
o This syndrome consists of purpuric skin lesions
characteristically involving the extensor surfaces
of arms and legs as well as buttocks; abdominal
manifestations including pain, vomiting, and
intestinal bleeding; nonmigratory arthralgia; and
renal abnormalities.
20
o The renal manifestations occur in one-third of
patients and include gross or microscopic
hematuria, proteinuria, and nephrotic syndrome.
o A small number of patients, mostly adults, develop
a rapidly progressive form of glomerulonephritis
with many crescents.
o Not all components of the syndrome need to be
present, and individual patients may have
purpura, abdominal pain, or urinary abnormalities
as the dominant feature.
o The disease is most common in children 3 to 8
years old, but it also occurs in adults, in whom the
renal manifestations are usually more severe.
o There is a strong background of atopy in about
one-third of patients, and onset often follows an
upper respiratory infection. IgA is deposited in the
glomerular mesangium in a distribution similar to
that of IgA nephropathy.
o This has led to the concept that IgA nephropathy
and Henoch-Schönlein purpura are spectra of the
same disease.68
Morphology
o On histologic examination, the renal lesions vary
from mild focal mesangial proliferation to diffuse
mesangial proliferation to crescentic
glomerulonephritis.
o Whatever the histologic lesions, the prominent
feature by fluorescence microscopy is the
deposition of IgA, sometimes with IgG and C3, in
the mesangial region.
o The skin lesions consist of subepidermal
hemorrhages and a necrotizing vasculitis involving
the small vessels of the dermis.
o IgA is also present in such vessels.
o Vasculitis also occurs in other organs, such as the
gastrointestinal tract, but is rare in the kidney.
o The course of the disease is variable, but
recurrences of hematuria may persist for many
years after onset.
o Most children have an excellent prognosis.
o Patients with the more diffuse lesions, crescents,
or the nephrotic syndrome have a somewhat
poorer prognosis.
(Robbins and Cotran Pathologic Basis of Disease 7th
Edition)
3.2.7Goodpasture Syndrome
o Goodpasture syndrome, microscopic polyarteritis,
and Wegener granulomatosis (Chapter 11) are
commonly associated with glomerular lesions, as
described in the discussion of these diseases.

o Suffice it to say here that the glomerular lesions in
these three conditions can be histologically similar
and are principally characterized by foci of
glomerular necrosis and crescent formation.
o In the early or mild forms of involvement, there is
focal and segmental, sometimes necrotizing,
glomerulonephritis, and most of these patients will
have hematuria with mild decline in GFR.
o In the more severe cases associated with RPGN,
there is more extensive necrosis, fibrin deposition,
and extensive formation of epithelial (cellular)
crescents, which can become organized to form
fibrocellular and fibrous crescents if the glomerular
injury evolves into segmental or global scarring
(sclerosis).
(Robbins and Cotran Pathologic Basis of Disease 7 th
Edition)
3.3 Renal Diseases
3.3.1Membranoproliferative Glomerulonephritis
o Membranoproliferative glomerulonephritis (MPGN)
is characterized histologically by alterations in the
basement membrane, proliferation of glomerular
cells, and leukocyte infiltration.
o Because the proliferation is predominantly in the
mesangium, a frequently used synonym is
mesangiocapillary glomerulonephritis.
o MPGN accounts for 10% to 20% of cases of
nephrotic syndrome in children and young adults.
o Some patients present only with hematuria or
proteinuria in the non-nephrotic range, and others
have a combined nephrotic-nephritic picture.
o Like many other glomerulonephritides, MPGN
either can be associated with other systemic
disorders and known etiologic agents (secondary
MPGN) or may be idiopathic (primary MPGN).
o Primary MPGN is divided into two major types on
the basis of distinct ultrastructural,
immunofluorescent, and pathologic findings: type I
and type II MPGN (dense-deposit disease).
Morphology
o By light microscopy, both types are similar.
o The glomeruli are large and hypercellular.
o The hypercellularity is produced both by
proliferation of cells in the mesangium and so-
called endocapillary cell proliferation involving
capillary endothelium and infiltrating leukocytes.
Parietal epithelial crescents are present in many
cases.
o The glomeruli have a "lobular" appearance
accentuated by the proliferating mesangial cells
and increased mesangial matrix
21
o The GBM is clearly thickened, often focally; this is
most evident in the peripheral capillary loops.
o The glomerular capillary wall often shows a
"double-contour" or "tram-track" appearance,
especially evident in silver or PAS stains.
o This is caused by "duplication" of the basement
membrane, usually as the result of new basement
membrane synthesis.
o Within the besement membrane there is inclusion
or interposition of cellular elements, which can be
of mesangial, endothelial, or leukocytic origin.
o Such interposition gives rise to the appearance of
"split" basement membranes.
o Types I and II MPGN differ in their ultrastructural
and immunofluorescent features (Fig. 20-24).
o Type I MPGN (the great majority of cases) is
characterized by the presence of subendothelial
electron-dense deposits. Mesangial and occasional
subepithelial deposits may also be present (Fig.
20-24A). By immunofluorescence, C3 is deposited
in a granular pattern, and IgG and early
complement components (C1q and C4) are often
also present, suggesting an immune complex
pathogenesis.
o In dense-deposit disease (type II MPGN) a
relatively rare entity, the lamina densa of the GBM
is transformed into an irregular, ribbon-like,
extremely electron-dense structure because of the
deposition of dense material of unknown
composition in the GBM proper, giving rise to the
term dense-deposit disease.
o C3 is present in irregular granular or linear foci in
the basement membranes on either side but not
within the dense deposits.
o C3 is also present in the mesangium in
characteristic circular aggregates (mesangial
rings).
o IgG is usually absent, as are the early-acting
complement components (C1q and C4).
Pathogenesis
o In most cases of type I MPGN there is evidence of
immune complexes in the glomerulus and
activation of both classical and alternative
complement pathways.
o The antigens involved in idiopathic MPGN are
unknown.
o In many cases, they are believed to be proteins
derived from infectious agents such as hepatitis C
and B viruses, which presumably behave either as
"planted" antigens after first binding to or
becoming trapped within glomerular structures or
are contained in preformed immune complexes
deposited from the circulation.
o Most patients with dense-deposit disease (type II
MPGN) have abnormalities that suggest activation
of the alternative complement pathway.
o These patients have a consistently decreased
serum C3 but normal C1 and C4, the immune
complex-activated early components of
complement.

o They also have diminished serum levels of factor B
and properdin, components of the alternative
complement pathway.
o In the glomeruli, C3 and properdin are deposited,
but IgG is not. Recall that in the alternative
complement pathway, C3 is directly cleaved to
C3b (Fig. 20-25; see also Chapter 2, Fig. 2-14).
o The reaction depends on the initial interaction of
C3 with such substances as bacterial
polysaccharides, endotoxin, and aggregates of IgA
in the presence of factors B and D.
o This leads to the generation of C3bBb, the
alternative pathway C3 convertase.
o This C3 convertase is labile, being degraded by
factors I and H, but it can be stabilized by
properdin.
o More than 70% of patients with dense-deposit
disease have a circulating antibody termed C3
nephritic factor (C3NeF), which is an autoantibody
that binds to the alternative pathway C3
convertase.
o Binding of the antibody stabilizes the convertase,
protecting it from enzymatic degradation and thus
favoring persistent C3 degradation and
hypocomplementemia.
o There is also decreased C3 synthesis by the liver,
further contributing to the profound
hypocomplementemia.
o Precisely how C3NeF is related to glomerular injury
and the nature of the dense deposits is unknown.
o C3NeF activity also occurs in some patients with a
genetically determined disease, partial
lipodystrophy, some of whom develop dense-
deposit disease (type II MPGN).
Clinical Course
o The principal mode of presentation is the
nephrotic syndrome occurring in older children or
young adults (idiopathic MPGN type I and cases of
type II), but usually with a nephritic component
manifested by hematuria or, more insidiously, as
mild proteinuria.
o Few remissions occur spontaneously in either
type, and the disease follows a slowly progressive
but unremitting course.
o Some patients develop numerous crescents and a
clinical picture of RPGN.
o About 50% develop chronic renal failure within 10
years.
o Treatments with steroids, immunosuppressive
agents, and antiplatelet drugs have not been
proved to be materially effective. There is a high
incidence of recurrence in transplant recipients,
particularly in dense-deposit disease; dense
deposits may recur in 90% of such patients,
although renal failure in the allograft is much less
common.
Secondary MPGN
22
o Secondary MPGN (invariably type I) is more
common in adults and arises in the following
settings:
 Chronic immune complex disorders, such as
SLE; hepatitis B infection; hepatitis C
infection, usually with cryoglobulinemia;
endocarditis; infected ventriculoatrial shunts;
chronic visceral abscesses; HIV infection; and
schistosomiasis
 α1-Antitrypsin deficiency
 Malignant diseases (chronic lymphocytic
leukemia and lymphoma)
 Hereditary deficiencies of complement
regulatory proteins
o The mechanisms underlying the process of
immune complex deposition in the last three
categories above remain unknown.
(Robbins and Cotran Pathologic Basis of Disease 7th
Edition)
3.3.2Berger Disease (IgG-immunoglobulin A [IgA]
nephropathy)
IGA NEPHROPATHY (BERGER DISEASE)
o This form of glomerulonephritis is characterized by
the presence of prominent IgA deposits in the
mesangial regions, detected by
immunofluorescence microscopy.
o The disease can be suspected by light microscopic
examination, but diagnosis is made only by
immunocytochemical techniques.
o IgA nephropathy is a frequent cause of recurrent
gross or microscopic hematuria and is probably
the most common type of glomerulonephritis
worldwide.
o Mild proteinuria is usually present, and the
nephrotic syndrome may occasionally develop.
o Rarely, patients may present with rapidly
progressive crescentic glomerulonephritis.
o Whereas IgA nephropathy is typically an isolated
renal disease, similar IgA deposits are present in a
systemic disorder of children, Henoch-Schönlein
purpura, to be discussed later, which has many
overlapping features with IgA nephropathy.
o In addition, secondary IgA nephropathy occurs in
patients with liver and intestinal diseases, as
discussed in the section on pathogenesis.
Pathogenesis
 23

o IgA, the main immunoglobulin in mucosal
secretions, is at low levels in normal serum, where
it is present mostly in monomeric form, the
polymeric forms being catabolized in the liver.
o In patients with IgA nephropathy, serum polymeric
IgA is increased, and circulating IgA-containing
immune complexes are present in some patients.
o However, it is clear that increased production of
IgA cannot itself cause this disease.
o The mesangial widening may be the result of cell
proliferation, accumulation of matrix, or both.
o Healing of the focal proliferative lesion may lead to
focal segmental sclerosis.
o The characteristic immunofluorescent picture is of
mesangial deposition of IgA often with C3 and
properdin and lesser amounts of IgG or IgM.
o Early complement components are usually absent.

o Although there are two subclasses of IgA o Electron microscopy confirms the presence of
molecules in humans (IgA1 and IgA2), only IgA1 electron-dense deposits in the mesangium.
forms the nephritogenic deposits of IgA
nephropathy.

o A genetic influence is suggested by the occurrence

Clinical Course
of this condition in families and in HLA-identical
brothers and the increased frequency of certain
HLA and complement phenotypes in some
populations.
o The disease affects people of any age, but older
o The prominent mesangial deposition of IgA children and young adults are most commonly
suggests entrapment of IgA immune complexes in affected.
the mesangium, and the presence of C3 combined
with the absence of C1q and C4 in glomeruli points o Many patients present with gross hematuria after
to activation of the alternative complement an infection of the respiratory or, less commonly,
pathway. gastrointestinal or urinary tract; 30% to 40% have
only microscopic hematuria, with or without
o Taken together, these clues suggest a genetic or proteinuria; and 5% to 10% develop a typical
acquired abnormality of immune regulation acute nephritic syndrome.
leading to increased mucosal IgA synthesis in
response to respiratory or gastrointestinal o The hematuria typically lasts for several days and
exposure to environmental agents (e.g., viruses, then subsides, only to return every few months.
bacteria, food proteins).
o The subsequent course is highly variable.
o IgA1 and IgA1-containing immune complexes are
then trapped in the mesangium, where they o Many patients maintain normal renal function for
activate the alternative complement pathway and decades.
initiate glomerular injury.
o Slow progression to chronic renal failure occurs in
o In support of this scenario, IgA nephropathy occurs 15% to 40% of cases over a period of 20 years.
with increased frequency in patients with gluten
enteropathy (celiac disease), in whom intestinal
o Onset in old age, heavy proteinuria, hypertension,
mucosal defects are well defined, and in liver
and the extent of glomerulosclerosis on biopsy are
disease, in which there is defective hepatobiliary
clues to an increased risk of progression.
clearance of IgA complexes (secondary IgA
nephropathy).
o Recurrence of IgA deposits in transplanted kidneys
o The nature of the initiating antigens is unknown, is frequent.
and several infectious agents and food products
have been implicated. o In approximately 15% of those with recurrent IgA
deposits, there is resulting clinical disease, which
o The deposited IgA appears to be polyclonal, and it most frequently runs the same indolent, slowly
may be that a variety of antigens are involved in progressive course as that of the primary IgA
the course of the disease. Alternatively, there is nephropathy.
evidence that qualitative alterations in the IgA1
molecule itself, specifically a defect in normal
galactosylation, make it more likely to bind to
mesangial antigens or form mesangial deposits
(Robbins and Cotran Pathologic Basis of Disease 7th
owing to other as yet unidentified mechanisms.
Edition)

Morphology
4. Identify the different diagnostic modalities for patients with
glomerulonephritis.

o On histologic examination, the lesions vary

considerably. 4.1 Laboratory Work-up

o The glomeruli may be normal or may show

mesangial widening and proliferation
(mesangioproliferative glomerulonephritis),
segmental proliferation confined to some  Complete blood cell count
glomeruli (focal proliferative glomerulonephritis),
or rarely, overt crescentic glomerulonephritis. o A decrease in hematocrit may demonstrate a
dilutional anemia.
o The presence of leukocytes within glomerular
capillaries is a variable feature.
 24

o In the setting of an infectious etiology, pleocytosis o Bedside renal ultrasonography may be appropriate
may be evident. to evaluate kidney size as well as to determine the
extent of fibrosis.
 Electrolytes, including BUN and creatinine (to estimate
the glomerular filtration rate [GFR]): The BUN and  A kidney size of less than 9 cm is suggestive of
creatinine levels will exhibit a degree of renal extensive scarring and a low likelihood of reversibility.
compromise.
(http://www.emedicine.com/emerg/topic219.htm)
 Urinalysis
4.3 Serology and Complement Levels
o Urine is dark.

o Specific gravity is greater than 1020 osm.

4.3.1 Antinuclear Antibody
o Proteinuria is observed.

o RBCs and red cell casts are present.

o Immunofluorescence microscopy is particularly
o Although not indicated in the ED setting, a 24-hour helpful and identifies three major patterns of
urine protein excretion and creatinine clearance deposition of immunoglobulin that define three
may be helpful to document the degree of renal broad diagnostic categories: (1) scattered granular
dysfunction and proteinuria. deposits of immunoglobulin, a hallmark of
immunecomplex glomerulonephritis; (2) more
 Streptozyme test: This test includes many streptococcal discrete linear deposition of immunoglobulin along
antigens that are sensitive for screening but are not the GBM, characteristic of anti-GBM disease; and
quantitative. (3) paucity or absence of immunoglobulin—pauci-
immune glomerulonephritis.
 Antistreptolysin O (ASO)
o Most patients (>70%) with full-blown acute
o This quantitative titer is increased in 60-80% of nephritic syndrome have immune-complex
patients. glomerulonephritis.

o Increase begins in 1-3 weeks, peaks in 3-5 weeks, o Pauci-immune glomerulonephritis is less common
and returns to normal in 6 months. in this setting (<30%), and anti-GBM disease is
rare (<1%).
o Antistreptolysin O titer is unrelated to severity,
duration, or prognosis of renal disease. o Among patients with RPGN, immune-complex
glomerulonephritis and pauci-immune
 Erythrocyte sedimentation ratio (ESR) usually is
o glomerulonephritis are equally prevalent (~45%
increased.
each), whereas anti-GBM disease again accounts
for a minority of cases (<10%).
 Urine or plasma creatinine level greater than 40;
decreased renin level is noted.
o Three serologic markers often predict the
immunofluorescence microscopy findings in
 Cultures of throat and skin lesions to rule out nephritic syndrome and RPGN and may obviate
Streptococcus species may be obtained. the need for renal biopsy in classic cases.

 Blood cultures o They are the serum C3 level and titers of anti-GBM
antibody and ANCA
o Indicated in patients with fever,
immunosuppression, intravenous drug use history, o As discussed in previous sections, the kidney is
indwelling shunts, or catheters. host to immune attack in immune-complex
glomerulonephritis, most cases being initiated
o Blood culture may indicate hypertriglyceridemia, either by in situ formation of immune complexes
decreased glomerular filtration rate, or anemia. or less commonly by glomerular trapping of
circulating immune complexes.
(http://www.emedicine.com/emerg/topic219.htm)
o These patients typically have
4.2 Imaging Studies hypocomplementemia (low C3 in 90%) and
negative anti-GBM and ANCA serology, the major
exception being IgA nephropathy/Henoch
Schonlein purpura where complement levels are
Radiography typically normal.

o The glomerulus is the direct target of immune

attack in anti-GBM disease, glomerular
 Chest radiography is needed in patients with a cough, inflammation being initiated by an autoantibody
with or without hemoptysis (ie, Wegener directed at a 28-kDa autoantigen on the α3 chain
granulomatosis, Goodpasture syndrome, pulmonary of type IV collagen.
congestion).
o Approximately90 to 95% of patients with anti-GBM
 Abdominal radiographic imaging (ie, computed disease have circulating anti-GBM autoantibodies
tomography) is needed if visceral abscesses are detectable by immunoassay; serum complement
suspected; also look for chest abscesses. levels are typically normal, and ANCA are

o Echocardiography in patients with a new cardiac o usually not detected.

murmur or a positive blood culture to rule out
endocarditis or a pericardial effusion.
 25

o The pathogenesis of pauci-immune deposits, or reduplication or splitting of the basement

glomerulonephritis is still being defined; however, membrane.
most patients have circulating ANCA.
 In the other regions of the biopsy, the vasculature
o Serum complement levels are typically normal, surrounding glomeruli and tubules can show
and anti-GBM titers are usually negative in ANCA- angiopathy, vasculitis, the presence of fibrils, or
associated renal disease. thrombi.

o It should be noted, however, that there may be
some serologic overlap, with as many as 20% of
patients with immune complex or anti-GBM
glomerulonephritis also having at least low levels
of circulating ANCA.
 The tubules can be assessed for adjacency to one
another; separation can be the result of edema, tubular
dropout, or collagen deposition resulting from
interstitial fibrosis. Interstitial fibrosis is an ominous
sign of irreversibility and progression to renal failure.

(Harrison’s Principles of Internal Medicine 16th Edition) (Harrison’s Principles of Internal Medicine 17th Edition)

4.4 Renal Biopsy

 Renal biopsy remains the gold standard” for
diagnosis.

 A renal biopsy in the setting of glomerulonephritis can

quickly identify the type of glomerular injury and often
suggests a course of treatment. (Harrison’s Principles of Internal Medicine 16th Edition)

CLINICAL INDICATIONS FOR A RENAL BIOPSY

 The biopsy is processed for light microscopy using
stains for hematoxylin and eosin (H&E) to assess
cellularity and architecture, periodic acid-Schiff (PAS) to
stain carbohydrate moieties in the membranes of the
glomerular tuft and tubules, Jones-methenamine silver
to enhance basement membrane structure,
 Congo red for amyloid deposits, and Masson's trichrome
to identify collagen deposition and assess the degree of
glomerulosclerosis and interstitial fibrosis.
 Biopsies are also processed for direct
immunofluorescence using conjugated antibodies
against IgG, IgM, and IgA to detect the presence of
"lumpy-bumpy" immune deposits or "linear" IgG or IgA
antibodies bound to GBM, antibodies against trapped
complement proteins (C3 and C4), or specific antibodies
against a relevant antigen. High-resolution electron
microscopy can clarify the principal location of immune
deposits and the status of the basement membrane.
 Proteinuria with impairment of renal function
 Symptomless isolated proteinuria if more than 2g/day
 Nephrotic syndrome in adults
In children it is most likely to be due to steroid sensitive
minimal change g/n so trial of steroids is less risky than
biopsy.
 Persistent haematuria with proteinuria especially if
there is renal impairment.
 Acute renal failure if likely to be renal on origin, as
opposed to pre-renal (hypovolaemic shock) or post-
renal (obstructive) in origin.
 Chronic renal failure with normal sized kidneys
 Renal transplant dysfunction
 Systemic disorders with features that include
haematuria, proteinuria and renal failure.

 Each region of a renal biopsy is assessed separately. SOME CONTRA-INDICATIONS FOR A RENAL BIOPSY

 By light microscopy, glomeruli (at least 10 and ideally

20) are reviewed individually for discrete lesions; <50%
involvement is considered focal, and >50% is diffuse.  Asymmetric kidneys
Injury in each glomerular tuft can be segmental,  Tiny shrunken kidneys
involving a portion of the tuft, or global, involving most  Obstructive renal disease
of the glomerulus.  Coagulation defects
 Acute infections
 Glomeruli can have proliferative characteristics,
showing increased cellularity. When cells in the
capillary tuft proliferate, it is called endocapillary, and (Dr. Bigornia’s Lecture)
when cellular proliferation extends into Bowman's
space, it is called extracapillary.

 Synechiae are formed when epithelial podocytes attach

Additional Information
to Bowman's capsule in the setting of glomerular injury;
crescents, which in some cases may be the extension of
synechiae, develop when fibrocellular/fibrin collections  Electron microscopy makes some important
fill all or part of Bowman's space; and sclerotic
contributions
glomeruli show acellular, amorphous accumulations of
proteinaceous material throughout the tuft with loss of
functional capillaries and normal mesangium. o To the understanding of the glomerulus in health.
o To the understanding of mechanisms of disease in
 Since age-related glomerulosclerosis is common in diagnosis.
adults, one can estimate the background percentage of
sclerosis by dividing the patient's age in half and
subtracting 10.
 In diagnostic pathology transmission electron
 Immunofluorescent and electron microscopy can detect microscopy is usually used, rather than scanning
the presence and location of electron microscopy.
subepithelial,subendothelial, or mesangial immune
 26

 Although immune complexes can be identified by

immunofluoresence, it is sometimes helpful to know
exactly where these deposits are in relation to the Example 2:
basement membranes.
Which immune reactants?
o Sub-epithelial deposits in post-streptococcal g/n.
IgG +/- IgM
Complement C3
o Deposits within thickened basement membranes
in membranous g/n. Where?

In walls of glomerular capillaries.

IMMUNOLOGY Pattern?

Linear

 Antibodies are prepared, specific for abnormal things Interpretation?

that might be present in the diseased glomerulus.
 A fluorescent molecule is attached to the back end of Anti-basement membrane disease (Goodpasture’s).
the antibody molecule so that the molecule will be
visible down the light microscope under ultra-violet
light.
 Thin sections are cut from the frozen fresh material. Example 3:
 These are then “stained” using specific antibodies
prepared in the laboratory. Which immune reactants?
 The “stained” sections are viewed under ultra-violet
light.
IgA
 Positive “staining” appears as green fluorescence on a Complement C3
black background
Where?
Usually three variables are scored.
In mesangial stalks.

Pattern?
1. Identity of abnormal materials in glomerulus.
Granular
Interpretation ?

Berger’s IgA disease

o Usually patient’s own immune reactants eg. IgG,
IgM, IgA, C3.

CLINICAL INDICATIONS FOR A RENAL BIOPSY

2. Where is it?

o Eg. In capillary loops. In mesangium.  Proteinuria with impairment of renal function

 Symptomless isolated proteinuria if more than 2g/day
 Nephrotic syndrome in adults
In children it is most likely to be due to steroid sensitive
minimal change g/n so trial of steroids is less risky than
3. What is it like? biopsy.
 Persistent haematuria with proteinuria especially if
o Eg. lumpy-bumpy granular, linear. there is renal impairment.
 Acute renal failure if likely to be renal on origin, as
opposed to pre-renal (hypovolaemic shock) or post-
renal (obstructive) in origin.
 Chronic renal failure with normal sized kidneys
Example 1:
 Renal transplant dysfunction
 Systemic disorders with features that include
Which immune reactants? haematuria, proteinuria and renal failure.

IgG +/- IgM

Complement C3 SOME CONTRA-INDICATIONS FOR A RENAL BIOPSY

Where?

In walls of glomerular capillaries.  Asymmetric kidneys

 Tiny shrunken kidneys
Pattern?  Obstructive renal disease
 Coagulation defects
Lumpy-bumpy granular  Acute infections

Interpretation?
(Dr. Bigornia’s Lecture)
Immune complex deposition

5. Identify the different treatment modalities for acute
glomerulonephritis.
5.1 Antibiotics Therapy
Streptococcal Pharyngitis (Including Scarlet Fever)
 This is the most common disease produced by S.
pyogenes (group A b-hemolytic streptococcus).
 Penicillin-resistant isolates have yet to be observed for
S. pyogenes.
 The preferred oral therapy is with penicillin V, 500 mg
every 6 hours for 10 days.
 Equally good results are produced by the administration
of 600,000 units of penicillin G procaine intramuscularly
once daily for 10 days or by a single injection of 1.2
million units of penicillin G benzathine.
 Parenteral therapy is preferred if there are questions of
patient compliance.
 Penicillin therapy of streptococcal pharyngitis reduces
the risk of subsequent acute rheumatic fever; however,
current evidence suggests that the incidence of
glomerulonephritis that follows streptococcal infections
is not reduced to a significant degree by treatment with
penicillin.
 The administration of penicillin to individuals exposed
to S. pyogenes affords protection from infection.
 The oral ingestion of 200,000 units of penicillin G or
penicillin V twice a day or a single injection of 1.2
million units of penicillin G benzathine is effective.
 Indications for this type of prophylaxis include
outbreaks of streptococcal disease in closed
populations, such as boarding schools or military bases.
Patients with extensive deep burns are at high risk of
severe wound infections with S. pyogenes; "low dose"
prophylaxis for several days appears to be effective in
reducing the incidence of this complication.
(Goodman and Gilman’s The Pharmacological Basis of
Therapeutics 11th Edition)
 Therapy must cover all likely pathogens in the context
of the clinical setting.
 Penicillin is the DOC in treating acute
glomerulonephritis of a poststreptococcal group A beta-
hemolytic etiology.
Drug Name Penicillin V (Veetids)
Description Derivative of 6-aminopenicillanic
acid with a beta-lactam ring
structure essential for bactericidal
activity.
Inhibits enzymes and cell wall
receptors, resulting in cell wall
synthesis inhibition. Other autolytics
enzymes are also activated,
degrading the bacterial cell wall.
Bacterial resistance via beta-
lactamase can be prevented with
addition of clavulanic acid,
27
sulbactam, or tazobactam. Other
forms of bacterial resistance include
alteration of bacterial PBPs and
decreased permeability of cell wall
to penicillin.
Adult Dose 500 mg PO q6h
<12 years: 40 mg/kg/d PO divided
Pediatric Dose q4-6h; not to exceed adult dose
>12 years: Administer as in adults
Documented hypersensitivity; renal
function impairment; bleeding
Contraindication disorder; congestive heart failure;
s cystic fibrosis; GI disease or
antibiotic-associated colitis;
mononucleosis
Probenecid may increase
effectiveness by decreasing
clearance; tetracyclines are
Interactions
bacteriostatic, causing decrease in
effectiveness of penicillins when
administered concurrently
C - Fetal risk revealed in studies in
animals but not established or not
Pregnancy
studied in humans; may use if
benefits outweigh risk to fetus
Precautions Caution in renal impairment
(http://www.emedicine.com/emerg/topic219.htm)
5.2 Non-selective β-blocker with Cardioselective α-1 Blocker
β-ADRENERGIC RECEPTOR AGONISTS
Introduction
 β-adrenergic receptor agonists have been utilized in
many clinical settings but now play a major role only in
the treatment of bronchoconstriction in patients with
asthma (reversible airway obstruction) or chronic
obstructive pulmonary disease (COPD).
 Minor uses include management of preterm labor,
treatment of complete heart block in shock, and short-
term treatment of cardiac decompensation after
surgery or in patients with congestive heart failure or
myocardial infarction.
 Epinephrine first was used as a bronchodilator at the
beginning of the past century, and ephedrine was
introduced into western medicine in 1924, although it
had been used in China for thousands of years.
 The next major advance was the development in the
1940s of isoproterenol, a b receptor-selective agonist;
this provided a drug for asthma that lacked a receptor
activity.
 The recent development of b2-selective agonists has
resulted in drugs with even more valuable
characteristics, including adequate oral bioavailability,
lack of a adrenergic activity, and diminished likelihood
of some adverse cardiovascular effects.
 β-receptor agonists may be used to stimulate the rate
and force of cardiac contraction.
 The chronotropic effect is useful in the emergency
treatment of arrhythmias such as torsades de pointes,
bradycardia, or heart block (see Chapter 34), whereas
the inotropic effect is useful when it is desirable to
augment myocardial contractility.
 The therapeutic uses of b receptor agonists are
discussed later in the chapter.

Isoproterenol
 Isoproterenol (isopropylarterenol, isopropyl
norepinephrine, isoprenaline, isopropyl noradrenaline,
d,l-b-[3,4-dihydroxyphenyl]-a-isopropylaminoethanol)
(Table 10-1) is a potent, nonselective b receptor agonist
with very low affinity for a receptors.
 Consequently, isoproterenol has powerful effects on all
b receptors and almost no action at a receptors.
Pharmacological Actions
 The major cardiovascular effects of isoproterenol
(compared with epinephrine and norepinephrine) are
illustrated in Figure 10-3.
 Intravenous infusion of isoproterenol lowers peripheral
vascular resistance, primarily in skeletal muscle but
also in renal and mesenteric vascular beds.
 Diastolic pressure falls.
 Systolic blood pressure may remain unchanged or rise,
although mean arterial pressure typically falls.
 Cardiac output is increased because of the positive
inotropic and chronotropic effects of the drug in the
face of diminished peripheral vascular resistance.
 The cardiac effects of isoproterenol may lead to
palpitations, sinus tachycardia, and more serious
arrhythmias; large doses of isoproterenol may cause
myocardial necrosis in animals.
 Isoproterenol relaxes almost all varieties of smooth
muscle when the tone is high, but this action is most
pronounced on bronchial and GI smooth muscle.
 It prevents or relieves bronchoconstriction.
 Its effect in asthma may be due in part to an additional
action to inhibit antigen-induced release of histamine
and other mediators of inflammation; this action is
shared by b2 receptor-selective stimulants.
Absorption, Fate, and Excretion
 Isoproterenol is readily absorbed when given
parenterally or as an aerosol.
 It is metabolized primarily in the liver and other tissues
by COMT.
 Isoproterenol is a relatively poor substrate for MAO and
is not taken up by sympathetic neurons to the same
extent as are epinephrine and norepinephrine.
 The duration of action of isoproterenol therefore may
be longer than that of epinephrine, but it still is brief.
Toxicity and Adverse Effects
28
 Palpitations, tachycardia, headache, and flushing are
common.
 Cardiac ischemia and arrhythmias may occur,
particularly in patients with underlying coronary artery
disease.
Therapeutic Uses
 Isoproterenol (ISUPREL, others) may be used in
emergencies to stimulate heart rate in patients with
bradycardia or heart block, particularly in anticipation
of inserting an artificial cardiac pacemaker or in
patients with the ventricular arrhythmia torsades de
pointes.
 In disorders such as asthma and shock, isoproterenol
largely has been replaced by other sympathomimetic
drugs (see below and Chapter 27).
Dobutamine
 Dobutamine resembles dopamine structurally but
possesses a bulky aromatic substituent on the amino
group (Table 10-1).
 The pharmacological effects of dobutamine are due to
direct interactions with α and β receptors; its actions do
not appear to result from release of norepinephrine
from sympathetic nerve endings, nor are they exerted
via dopaminergic receptors.
 Although dobutamine originally was thought to be a
relatively selective β1 receptor agonist, it now is clear
that its pharmacological effects are complex.
 Dobutamine possesses a center of asymmetry; both
enantiomeric forms are present in the racemic mixture
used clinically.
 The (-) isomer of dobutamine is a potent agonist at a1
receptors and is capable of causing marked pressor
responses.
 In contrast, (+)-dobutamine is a potent a1 receptor
antagonist, which can block the effects of (-)-
dobutamine. The effects of these two isomers are
mediated via b receptors.
 The (+) isomer is a more potent b receptor agonist than
the (-) isomer (approximately tenfold). Both isomers
appear to be full agonists.
Cardiovascular Effects
 Cardiovascular effects of racemic dobutamine represent
a composite of the distinct pharmacological properties
of the (-) and (+) stereoisomers.
 Dobutamine has relatively more prominent inotropic
than chronotropic effects on the heart compared to
isoproterenol.
 Although not completely understood, this useful
selectivity may arise because peripheral resistance is
relatively unchanged.
 29

 Alternatively, cardiac a1 receptors may contribute to
the inotropic effect.
 At equivalent inotropic doses, dobutamine enhances
automaticity of the sinus node to a lesser extent than
does isoproterenol; however, enhancement of
atrioventricular and intraventricular conduction is
similar for both drugs.
 In animals, administration of dobutamine at a rate of
2.5 to 15 mg/kg per minute increases cardiac
contractility and cardiac output.
 Alterations in blood pressure or peripheral resistance
usually are minor, although some patients may have
marked increases in blood pressure or heart rate.
 Clinical evidence of longer-term efficacy remains
uncertain. An infusion of dobutamine in combination
with echocardiography is useful in the noninvasive
assessment of patients with coronary artery disease
(Madu et al., 1994).
 Stressing of the heart with dobutamine may reveal
cardiac abnormalities in carefully selected patients.

 Total peripheral resistance is not greatly affected.
 The relatively constant peripheral resistance
presumably reflects counterbalancing of a1 receptor-
mediated vasoconstriction and b2 receptor-mediated
vasodilation (Ruffolo, 1987).
 Heart rate increases only modestly when the rate of
administration of dobutamine is maintained at less than
20 mg/kg per minute.
 After administration of b receptor antagonists, infusion
of dobutamine fails to increase cardiac output, but total
peripheral resistance increases, confirming that
dobutamine has modest direct effects on a adrenergic
receptors in the vasculature.
 Dobutamine has a half-life of about 2 minutes; the
major metabolites are conjugates of dobutamine and 3-
O-methyldobutamine.
 The onset of effect is rapid.
 Consequently, a loading dose is not required, and
steady-state concentrations generally are achieved
within 10 minutes of initiation of the infusion.
 The rate of infusion required to increase cardiac output
typically is between 2.5 and 10 mg/kg per minute,
although higher infusion rates occasionally are
required.
 The rate and duration of the infusion are determined by
the clinical and hemodynamic responses of the patient.

(Goodman and Gilman’s The Pharmacological Basis of

Therapeutics 11th Edition)

Adverse Effects  Labetalol is used for hypertensive encephalopathy and

malignant hypertension.

Drug Name Labetalol (Normodyne)

 In some patients, blood pressure and heart rate Has nonselective beta-antagonist
increase significantly during dobutamine and cardioselective alpha1-
administration; this may require reduction of the rate of antagonist effects. Beta-blocking
infusion. effects predominate, particularly
when used IV.
Description
 Patients with a history of hypertension may exhibit such Low lipid solubility means
an exaggerated pressor response more frequently. bioavailability is reduced by first
pass metabolism and enhanced by
coadministration of food. Drug is not
 Since dobutamine facilitates atrioventricular removed by hemodialysis.
conduction, patients with atrial fibrillation are at risk of 20 mg (0.25 mg/kg for 80-kg
marked increases in ventricular response rates; digoxin patient) IV microdrip labetalol
or other measures may be required to prevent this from hydrochloride injection slowly over 2
occurring. Some patients may develop ventricular min; desired BP may be achieved
ectopic activity. with continued injections of 40-80
Adult Dose
mg at 10-min intervals or until 300
 As with any inotropic agent, dobutamine potentially mg has been administered prn; to
may increase the size of a myocardial infarct by reduce possibility of postural
increasing myocardial oxygen demand. hypotension, patients should remain
supine for 3 h after administration
 This risk must be balanced against the patient's overall Not established
clinical status. Pediatric Dose Suggested dose: 0.4-1 mg/kg/h IV;
not to exceed 3 mg/kg/h
 The efficacy of dobutamine over a period of more than Documented hypersensitivity;
a few days is uncertain; there is evidence for the cardiogenic shock; atrioventricular
development of tolerance. Contraindication block; uncompensated congestive
s heart failure; pulmonary edema;
bradycardia; reactive airway
disease; severe bradycardia
Decreases effect of diuretics and
Therapeutic Uses increases toxicity of methotrexate,
lithium, and salicylates; may
diminish reflex tachycardia, resulting
from nitroglycerin use, without
Interactions
 Dobutamine (DOBUTREX, others) is indicated for the interfering with hypotensive effects;
short-term treatment of cardiac decompensation that cimetidine may increase labetalol
may occur after cardiac surgery or in patients with blood levels; glutethimide may
congestive heart failure or acute myocardial infarction. decrease labetalol effects by
Dobutamine increases cardiac output and stroke inducing microsomal enzymes
volume in such patients, usually without a marked B - Fetal risk not confirmed in
increase in heart rate. Pregnancy studies in humans but has been
shown in some studies in animals

Caution in impaired hepatic function;
discontinue therapy if signs of liver
dysfunction; in elderly patients,
Precautions
lower response rate and higher
incidence of toxicity may be
observed
(http://www.emedicine.com/emerg/topic219.htm)
5.3 Loop Diuretics
INHIBITORS OF NA+-K+-2CL- SYMPORT (LOOP DIURETICS,
HIGH-CEILING DIURETICS)
 Drugs in this group of diuretics inhibit the activity of the
Na+-K+-2Cl- symporter in the thick ascending limb of
the loop of Henle; hence these diuretics also are
referred to as loop diuretics.
 Although the proximal tubule reabsorbs approximately
65% of the filtered Na+, diuretics acting only in the
proximal tubule have limited efficacy because the thick
ascending limb has a great reabsorptive capacity and
reabsorbs most of the rejectate from the proximal
tubule.
 Diuretics acting predominantly at sites past the thick
ascending limb also have limited efficacy because only
a small percentage of the filtered Na+ load reaches
these more distal sites.
 In contrast, inhibitors of Na+-K+-2Cl-symport in the
thick ascending limb are highly efficacious, and for this
reason, they sometimes are called high-ceiling
diuretics.
 The efficacy of inhibitors of Na+-K+-2Cl- symport in the
thick ascending limb of the loop of Henle is due to a
combination of two factors: (1) Approximately 25% of
the filtered Na+ load normally is reabsorbed by the
thick ascending limb, and (2) nephron segments past
the thick ascending limb do not possess the
reabsorptive capacity to rescue the flood of rejectate
exiting the thick ascending limb.
Chemistry
 Inhibitors of Na+-K+-2Cl- symport are a chemically
diverse group.
 Only furosemide (LASIX), bumetanide (BUMEX),
ethacrynic acid (EDECRIN), and torsemide (DEMADEX)
are available currently in the United States. Furosemide
and bumetanide contain a sulfonamide moiety.
 Ethacrynic acid is a phenoxyacetic acid derivative and
torsemide is a sulfonylurea.
Mechanism and Site of Action
 Inhibitors of Na+-K+-2Cl- symport act primarily in the
thick ascending limb.
 Micropuncture of the DCT demonstrates that loop
diuretics increase the delivery of solutes out of the loop
of Henle.
30
 Also, in situ microperfusion of the loop of Henle and in
vitro microperfusion of the CTAL indicate inhibition of
transport by low concentrations of furosemide in the
perfusate.
 Some inhibitors of Na+-K+-2Cl- symport may have
additional effects in the proximal tubule; however, the
significance of these effects is unclear.
 It was thought initially that Cl- was transported by a
primary active electrogenic transporter in the luminal
membrane independent of Na+.
 Discovery of furosemide-sensitive Na+-K+-2Cl- symport
in other tissues prompted a more careful investigation
of the Na+ dependence of Cl- transport in the isolated
perfused rabbit CTAL.
 Scrupulous removal of Na+ from the luminal perfusate
demonstrated the dependence of Cl- transport on Na+.
 It is now well accepted that flux of Na+, K+, and Cl-
from the lumen into the epithelial cells in the thick
ascending limb is mediated by a Na+-K+-2Cl-
symporter.
 This symporter captures the free energy in the Na+
electrochemical gradient established by the basolateral
Na+ pump and provides for "uphill" transport of K+ and
Cl- into the cell.
 K+ channels in the luminal membrane (called ROMK)
provide a conductive pathway for the apical recycling of
this cation, and basolateral Cl- channels (called CLC-Kb)
provide a basolateral exit mechanism for Cl-.
 The luminal membranes of epithelial cells in the thick
ascending limb have a large conductive pathway
(channels) for K+; therefore, the apical membrane
voltage is determined by the equilibrium potential for
K+ (EK) and is hyperpolarized.
 In contrast, the basolateral membrane has a large
conductive pathway (channels) for Cl-, so the
basolateral membrane voltage is less negative than EK;
i.e., conductance for Cl- depolarizes the basolateral
membrane.
 Hyperpolarization of the luminal membrane and
depolarization of the basolateral membrane result in a
transepithelial potential difference of approximately 10
mV, with the lumen positive with respect to the
interstitial space.
 This lumen-positive potential difference repels cations
(Na+, Ca2+, and Mg2+) and thereby provides an
important driving force for the paracellular flux of these
cations into the interstitial space.
 As the name implies, inhibitors of Na+-K+-2Cl- symport
bind to the Na+-K+-2Cl- symporter in the thick
ascending limb and block its function, bringing salt
transport in this segment of the nephron to a virtual
standstill.
 The molecular mechanism by which this class of drugs
blocks the Na+-K+-2Cl- symporter is unknown, but
evidence suggests that these drugs attach to the Cl--
binding site.
 Inhibitors of Na+-K+-2Cl- symport also inhibit Ca2+ and
Mg2+ reabsorption in the thick ascending limb by
abolishing the transepithelial potential difference that is
the dominant driving force for reabsorption of these
cations.
 Na+-K+-2Cl- symporters are an important family of
transport molecules found in many secretory and
absorbing epithelia.

Effects on Urinary Excretion
 Owing to blockade of the Na+-K+-2Cl- symporter, loop
diuretics increase in the urinary excretion of Na+ and
Cl- profoundly (i.e., up to 25% of the filtered load of
Na+).
 Abolition of the transepithelial potential difference also
results in marked increases in the excretion of Ca2+
and Mg2+.
 Some (e.g., furosemide) but not all (e.g., bumetanide)
sulfonamide-based loop diuretics have weak carbonic
anhydrase-inhibiting activity.
 Drugs with carbonic anhydrase-inhibiting activity
increase the urinary excretion of HCO3 - and
phosphate. The mechanism by which inhibition of
carbonic anhydrase increases phosphate excretion is
not known.
 All inhibitors of Na+-K+-2Cl- symport increase the
urinary excretion of K+ and titratable acid.
 This effect is due in part to increased delivery of Na+ to
the distal tubule.
 The mechanism by which increased distal delivery of
Na+ enhances excretion of K+ and H+ is discussed in
the section on inhibitors of Na+ channels.
 Other mechanisms contributing to enhanced K+ and
H+ excretion include flow-dependent enhancement of
ion secretion by the collecting duct, nonosmotic
vasopressin release, and activation of the renin-
angiotensin-aldosterone axis.
 Acutely, loop diuretics increase the excretion of uric
acid, whereas chronic administration of these drugs
results in reduced excretion of uric acid.
 The chronic effects of loop diuretics on uric acid
excretion may be due to enhanced transport in the
proximal tubule secondary to volume depletion, leading
to increased uric acid reabsorption, or to competition
between the diuretic and uric acid for the organic acid
secretory mechanism in the proximal tubule, leading to
reduced uric acid secretion.
 By blocking active NaCl reabsorption in the thick
ascending limb, inhibitors of Na+-K+-2Cl- symport
interfere with a critical step in the mechanism that
produces a hypertonic medullary interstitium.
 Therefore, loop diuretics block the kidney's ability to
concentrate urine during hydropenia.
 Also, since the thick ascending limb is part of the
diluting segment, inhibitors of Na+-K+-2Cl- symport
markedly impair the kidney's ability to excrete a dilute
urine during water diuresis.
Effects on Renal Hemodynamics
 If volume depletion is prevented by replacing fluid
losses, inhibitors of Na+-K+-2Cl- symport generally
increase total RBF and redistribute RBF to the
midcortex.
 However, the effects on RBF are variable.
31
 The mechanism of the increase in RBF is not known but
may involve prostaglandins.
 Nonsteroidal antiinflammatory drugs (NSAIDs)
attenuate the diuretic response to loop diuretics in part
by preventing prostaglandin-mediated increases in RBF.
 Loop diuretics block TGF by inhibiting salt transport into
the macula densa so that the macula densa no longer
can detect NaCl concentrations in the tubular fluid.
 Therefore, unlike carbonic anhydrase inhibitors, loop
diuretics do not decrease GFR by activating TGF.
 Loop diuretics are powerful stimulators of renin release.
 This effect is due to interference with NaCl transport by
the macula densa and, if volume depletion occurs, to
reflex activation of the sympathetic nervous system
and to stimulation of the intrarenal baroreceptor
mechanism.
 Prostaglandins, particularly prostacyclin, may play an
important role in mediating the renin-release response
to loop diuretics.
Other Actions
 Loop diuretics may cause direct vascular effects.
 Loop diuretics, particularly furosemide, acutely increase
systemic venous capacitance and thereby decrease left
ventricular filling pressure.
 This effect, which may be mediated by prostaglandins
and requires intact kidneys, benefits patients with
pulmonary edema even before diuresis ensues.
 Furosemide and ethacrynic acid can inhibit Na+,K+-
ATPase, glycolysis, mitochondrial respiration, the
microsomal Ca2+ pump, adenylyl cyclase,
phosphodiesterase, and prostaglandin dehydrogenase;
however, these effects do not have therapeutic
implications.
 In vitro, high doses of inhibitors of Na+-K+-2Cl- symport
can inhibit electrolyte transport in many tissues.
 Only in the inner ear, where alterations in the
electrolyte composition of endolymph may contribute to
drug-induced ototoxicity, is this effect important
clinically.
Absorption and Elimination
 Because furosemide, bumetanide, ethacrynic acid, and
torsemide are bound extensively to plasma proteins,
delivery of these drugs to the tubules by filtration is
limited.
 However, they are secreted efficiently by the organic
acid transport system in the proximal tubule and
thereby gain access to their binding sites on the Na+-
K+-2Cl- symport in the luminal membrane of the thick
ascending limb.
 Probenecid shifts the plasma concentration-response
curve to furosemide to the right by competitively
inhibiting furosemide secretion by the organic acid
transport system.

 Approximately 65% of furosemide is excreted
unchanged in the urine, and the remainder is
conjugated to glucuronic acid in the kidney.
 Accordingly, in patients with renal, but not liver,
disease, the elimination half-life of furosemide is
prolonged.
 In contrast, bumetanide and torsemide have significant
hepatic metabolism, so the elimination half-lives of
these loop diuretics are prolonged by liver, but not
renal, disease.
 Although the average oral availability of furosemide is
approximately 60%, oral availability of furosemide
varies from 10% to 100%.
 In contrast, oral availabilities of bumetanide and
torsemide are reliably high. Heart failure patients have
fewer hospitalizations and better quality of life with
torsemide than with furosemide perhaps because of the
more reliable absorption of torsemide (Shankar and
Brater, 2003).
 As a class, loop diuretics have short elimination half-
lives, and prolonged-release preparations are not
available. Consequently, often the dosing interval is too
short to maintain adequate levels of loop diuretics in
the tubular lumen. Note that torsemide has a longer
t1/2 than other agents available in the United States.
 As the concentration of loop diuretic in the tubular
lumen declines, nephrons begin to avidly reabsorb Na+,
which often nullifies the overall effect of the loop
diuretic on total-body Na+.
 This phenomenon of "postdiuretic Na+ retention" can
be overcome by restricting dietary Na+ intake or by
more frequent administration of the loop diuretic
(Ellison, 1999).
Toxicity, Adverse Effects, Contraindications, Drug
Interactions
 Adverse effects unrelated to the diuretic efficacy are
rare, and most adverse effects are due to abnormalities
of fluid and electrolyte balance.
 Overzealous use of loop diuretics can cause serious
depletion of total-body Na+.
 This may be manifest as hyponatremia and/or
extracellular fluid volume depletion associated with
hypotension, reduced GFR, circulatory collapse,
thromboembolic episodes, and in patients with liver
disease, hepatic encephalopathy.
 Increased delivery of Na+ to the distal tubule,
particularly when combined with activation of the renin-
angiotensin system, leads to increased urinary
excretion of K+ and H+, causing a hypochloremic
alkalosis.
 If dietary K+ intake is not sufficient, hypokalemia may
develop, and this may induce cardiac arrhythmias,
particularly in patients taking cardiac glycosides.
 Increased Mg2+ and Ca2+ excretion may result in
hypomagnesemia (a risk factor for cardiac arrhythmias)
and hypocalcemia (rarely leading to tetany).
 Recent evidence suggests that loop diuretics should be
avoided in postmenopausal osteopenic women, in
whom increased Ca2+ excretion may have deleterious
effects on bone metabolism.
32
 Loop diuretics can cause ototoxicity that manifests as
tinnitus, hearing impairment, deafness, vertigo, and a
sense of fullness in the ears.
 Hearing impairment and deafness are usually, but not
always, reversible.
 Ototoxicity occurs most frequently with rapid
intravenous administration and least frequently with
oral administration.
 Ethacrynic acid appears to induce ototoxicity more
often than do other loop diuretics and should be used
only in patients who cannot tolerate the other loop
diuretics.
 Loop diuretics also can cause hyperuricemia
(occasionally leading to gout) and hyperglycemia
(infrequently precipitating diabetes mellitus) and can
increase plasma levels of low-density lipoprotein (LDL)
cholesterol and triglycerides while decreasing plasma
levels of high-density lipoprotein (HDL) cholesterol.
 Other adverse effects include skin rashes,
photosensitivity, paresthesias, bone marrow
depression, and gastrointestinal disturbances.
 Contraindications to the use of loop diuretics include
severe Na+ and volume depletion, hypersensitivity to
sulfonamides (for sulfonamide-based loop diuretics),
and anuria unresponsive to a trial dose of loop diuretic.
 Drug interactions may occur when loop diuretics are
coadministered with (1) aminoglycosides (synergism of
ototoxicity caused by both drugs), (2) anticoagulants
(increased anticoagulant activity), (3) digitalis
glycosides (increased digitalis-induced arrhythmias), (4)
lithium (increased plasma levels of lithium), (5)
propranolol (increased plasma levels of propranolol), (6)
sulfonylureas (hyperglycemia), (7) cisplatin (increased
risk of diuretic-induced ototoxicity), (8) NSAIDs (blunted
diuretic response and salicylate toxicity when given
with high doses of salicylates), (9) probenecid (blunted
diuretic response), (10) thiazide diuretics (synergism of
diuretic activity of both drugs leading to profound
diuresis), and (11) amphotericin B (increased potential
for nephrotoxicity and toxicity and intensification of
electrolyte imbalance).
Therapeutic Uses
 A major use of loop diuretics is in the treatment of
acute pulmonary edema.
 A rapid increase in venous capacitance in conjunction
with a brisk natriuresis reduces left ventricular filling
pressures and thereby rapidly relieves pulmonary
edema. Loop diuretics also are used widely for the
treatment of chronic congestive heart failure when
diminution of extracellular fluid volume is desirable to
minimize venous and pulmonary congestion.
 In this regard, a meta-analysis of randomized clinical
trials demonstrates that diuretics cause a significant
reduction in mortality and the risk of worsening heart
failure, as well as an improvement in exercise capacity.
 Diuretics are used widely for the treatment of
hypertension and controlled clinical trials
demonstrating reduced morbidity and mortality have
been conducted with Na+-Cl- symport (thiazides and
thiazidelike diuretics) but not Na+-K+-2Cl- symport
inhibitors.

 Nonetheless, Na+-K+-2Cl- symport inhibitors appear to
lower blood pressure as effectively as Na+-Cl- symport
inhibitors while causing smaller perturbations in the
lipid profile.
 However, the short elimination half-lives of loop
diuretics render them less useful for hypertension than
thiazide-type diuretics.
 The edema of nephrotic syndrome often is refractory to
other classes of diuretics, and loop diuretics often are
the only drugs capable of reducing the massive edema
associated with this renal disease.
 Loop diuretics also are employed in the treatment of
edema and ascites of liver cirrhosis; however, care
must be taken not to induce encephalopathy or
hepatorenal syndrome. In patients with a drug
overdose, loop diuretics can be used to induce a forced
diuresis to facilitate more rapid renal elimination of the
offending drug.
 Loop diuretics, combined with isotonic saline
administration to prevent volume depletion, are used to
treat hypercalcemia.
 Loop diuretics interfere with the kidney's capacity to
produce a concentrated urine.
 Consequently, loop diuretics combined with hypertonic
saline are useful for the treatment of life-threatening
hyponatremia.
5.4 Corticosteroids
 Loop diuretics also are used to treat edema associated
with chronic renal insufficiency.
 However, animal studies have demonstrated that loop
diuretics increase PGC by activating the renin-
angiotensin system, an effect that could accelerate
renal injury.
 Most patients with ARF receive a trial dose of a loop
diuretic in an attempt to convert oliguric ARF to
nonoliguric ARF.
 However, there is no evidence that loop diuretics
prevent ATN or improve outcome in patients with ARF.
(Goodman and Gilman’s The Pharmacological Basis of
Therapeutics 11th Edition)
 Loop diuretics are used for hypertensive
encephalopathy with CNS signs and circulatory
congestion or pulmonary edema.
 Furosemide is DOC for this indication.
Drug Name Furosemide (Lasix)
Description Inhibits resorption of sodium and water
in ascending limb of loop of Henle by
interfering with Na+/K+/Cl- channel.
An antihypercalcemic effect is
mediated by an increased excretion of
calcium.
Plasma volume, blood pressure, and
cardiac output are reduced.
Calcium excretion is increased.
Absorption of oral furosemide is
reduced with renal disease or
nephrotic syndrome as a result of
edematous bowel.
Parenteral administration may be
indicated in patients with
compromised kidneys; metabolized by
hepatic biotransformation and renal
33
excretion; onset of action is 20-60 min
PO and 5 min IV. Children with
nephrotic syndrome may require
higher dosing beyond the scope of ED
care.
20-80 mg PO/IV once initially, followed
by once qd, or once qod after titrating
Adult Dose
for optimum efficacy, or by dividing
daily dose bid/tid
Initially: 2 mg/kg PO/IV once; titrate
Pediatric Dose
with additional 1-2 mg/kg q6h.
Documented hypersensitivity; hepatic
coma; anuria; renal function
Contraindicatio
impairment; diabetes mellitus; gout;
ns
MI; pancreatitis; state of severe
electrolyte depletion.
Metformin decreases furosemide
concentrations; furosemide interferes
with hypoglycemic effect of
antidiabetic agents and antagonizes
muscle-relaxing effect of tubocurarine;
auditory toxicity appears to be
increased with coadministration of
Interactions
aminoglycosides and furosemide
(hearing loss of varying degrees may
occur); anticoagulant activity of
warfarin may be enhanced when taken
concurrently; increased plasma lithium
levels and toxicity are possible when
taken concurrently.
(http://www.emedicine.com/emerg/topic219.htm)
General Mechanisms for Corticosteroid Effects
 Corticosteroids interact with specific receptor proteins
in target tissues to regulate the expression of
corticosteroid-responsive genes, thereby changing the
levels and array of proteins synthesized by the various
target tissues.
 As a consequence of the time required to modulate
gene expression and protein synthesis, most effects of
corticosteroids are not immediate but become apparent
after several hours.
 This fact is of clinical significance, because a delay
generally is seen before beneficial effects of
corticosteroid therapy become manifest.
 Although corticosteroids predominantly act to increase
expression of target genes, there are well-documented
examples in which glucocorticoids decrease
transcription of target genes.
 The receptors for corticosteroids are members of the
nuclear receptor family of transcription factors that
transduce the effects of a diverse array of small,
hydrophobic ligands, including the steroid hormones,
thyroid hormone, vitamin D, and retinoids.
 These receptors share two highly conserved domains: a
region of approximately 70 amino acids forming two
zinc-binding domains, called zinc fingers, that are
essential for the interaction of the receptor with specific
DNA sequences, and a region at the carboxyl terminus
that interacts with ligand (the ligand-binding domain).
 Although complete loss of glucocorticoid receptor (GR)
function apparently is lethal, mutations leading to
partial loss of GR function have been identified in rare
patients with generalized glucocorticoid resistance.
 These patients harbor mutations in the GR that impair
glucocorticoid binding and decrease transcriptional
activation.
 As a consequence of these mutations, cortisol levels
that normally mediate feedback inhibition fail to
suppress the HPA axis completely.
 In this setting of partial loss of GR function, the HPA
axis resets to a higher level to provide compensatory
increases in ACTH and cortisol secretion.
 34

 Because the GR defect is partial, adequate monitor patients for hypokalemia

compensation for the end-organ insensitivity can result when taking medication
from the elevated cortisol level, but the excess concurrently with diuretics
 ACTH secretion also stimulates the production of C - Fetal risk revealed in studies in
mineralocorticoids and adrenal androgens. animals but not established or not
Pregnancy
 Because the mineralocorticoid receptor (MR) and the studied in humans; may use if
androgen receptor are intact, these subjects present benefits outweigh risk to fetus
with manifestations of mineralocorticoid excess Adverse effects include allergy,
(hypertension and hypokalemic alkalosis) and/or of cataracts, Cushing syndrome,
increased androgen levels (acne, hirsutism, male severe acne, GI irritation, and
pattern baldness, menstrual irregularities, anovulation, pancreatitis
and infertility). In children, the excess adrenal Hyperglycemia, edema,
androgens can cause precocious sexual development. Precautions osteonecrosis, peptic ulcer disease,
hypokalemia, osteoporosis,
euphoria, psychosis, growth
suppression, myopathy, and
infections are possible
complications of glucocorticoid use
Glucocorticoids

(http://www.emedicine.com/emerg/topic219.htm)

 Patients with nephrotic syndrome secondary to minimal 5.5 Antineoplastics and Immunosuppressants
change disease generally respond well to steroid
therapy, and glucocorticoids clearly are the first-line
treatment in both adults and children. Initial daily doses
of prednisone are 1 to 2 mg/kg for 6 weeks, followed by
Antineoplastic Agents (Cyclophosphamide)
a gradual tapering of the dose over 6 to 8 weeks,
although some nephrologists advocate alternate-day
therapy.
 Objective evidence of response, such as diminished
proteinuria, is seen within 2 to 3 weeks in 85% of Pharmacological and Cytotoxic Actions
patients, and more than 95% of patients will have
remission within 3 months.
 Cessation of steroid therapy frequently is complicated
by disease relapse, as manifested by recurrent  The general cytotoxic action of this drug is similar to
proteinuria. that of other alkylating agents.
 Patients who relapse repeatedly are termed steroid-
resistant and often are treated with other
 The drug is not a vesicant, and produces no local
immunosuppressive drugs such as azathioprine or
irritation.
cyclophosphamide.
 Patients with renal disease secondary to systemic lupus
erythematosus also are generally given a therapeutic
trial of glucocorticoids.
 Studies with other forms of renal disease, such as Absorption, Fate, and Excretion
membranous and membranoproliferative
glomerulonephritis and focal sclerosis, have provided
conflicting data on the role of glucocorticoids.
 In clinical practice, patients with these disorders often  Cyclophosphamide is well absorbed orally.
are given a therapeutic trial of glucocorticoids with
careful monitoring of laboratory indices of response. In
the case of membranous glomerulonephritis, many  The drug is activated by CYP2B to 4-
nephrologists recommend a trial of alternate-day hydroxycyclophosphamide, which is in a steady state
glucocorticoids for 8 to 10 weeks (e.g., prednisone, 120 with the acyclic tautomer aldophosphamide.
mg every other day), followed by a 1- to 2-month
period of tapering.
 A closely related oxazaphosphorine, ifosfamide, is
 Ethylprednisolone is used for nonstreptococcal hydroxylated by CYP3A4.
etiologies of acute glomerulonephritis, particularly in
lupus nephritis and in idiopathic progressive  This difference may account for the somewhat slower
glomerulonephritis. activation of ifosfamide in vivo, and the interpatient
variability in toxicity of both molecules.
(Goodman and Gilman’s The Pharmacological Basis of
Therapeutics 11th Edition)  The rate of metabolic activation of cyclophosphamide
exhibits significant interpatient variability and increases
Drug Name Methylprednisolone (Medrol) with successive doses in high-dose regimens, but
Has anti-inflammatory effect and is appears to be saturable above infusion rates of 4 g/90
immunosuppressive. minutes and concentrations of parent compound above
Description
Metabolized by hepatic 150 uM.
transformation and renal excretion.
Pulse therapy of 30 mg/kg IV over  4-Hydroxycyclophosphamide may be oxidized further
Adult Dose
minimum of 30 min by aldehyde oxidase, either in liver or in tumor tissue,
Pediatric Dose Administer as in adults and perhaps by other enzymes, yielding the inactive
Contraindication Documented hypersensitivity; viral, metabolites carboxyphosphamide and 4-
s fungal, or tubercular skin infections ketocyclophosphamide, and ifosfamide is inactivated in
Interactions Coadministration with digoxin may an analogous reaction.
increase digitalis toxicity secondary
to hypokalemia; estrogens may  The active cyclophosphamide metabolites such as 4-
increase levels of hydroxycyclophosphamide and its tautomer,
methylprednisolone; phenobarbital, aldophosphamide, are carried in the circulation to
phenytoin, and rifampin may tumor cells where aldophosphamide cleaves
decrease levels of spontaneously, generating stoichiometric amounts of
methylprednisolone (adjust dose); phosphoramide mustard and acrolein.

 Phosphoramide mustard is responsible for antitumor
effects, while acrolein causes hemorrhagic cystitis often
seen during therapy with cyclophosphamide.
 As mentioned above, cystitis can be reduced in
intensity or prevented by the parenteral
coadministration of mesna. Mesna does not negate the
systemic antitumor activity of the drug.
 For routine clinical use, ample fluid intake is
recommended and vigorous intravenous hydration is
required during high-dose treatment.
 Brisk hematuria in a patient receiving daily oral therapy
should lead to immediate drug discontinuation.
 Refractory bladder hemorrhage may require
cystectomy for control of bleeding.
 The syndrome of inappropriate secretion of antidiuretic
hormone has been observed in patients receiving
cyclophosphamide, usually at doses higher than 50
mg/kg.
 It is important to be aware of the possibility of water
intoxication, since these patients usually are vigorously
hydrated to prevent bladder toxicity.
 Pretreatment with CYP inducers such as phenobarbital
enhances the rate of activation of the
azoxyphosphorenes but does not alter total exposure to
active metabolites over time and does not affect
toxicity or therapeutic activity in humans.
 Cyclophosphamide can be used in full doses in patients
with renal dysfunction, as it is eliminated by hepatic
metabolism.
 Urinary and fecal recovery of unchanged
cyclophosphamide is minimal after intravenous
administration. Maximal concentrations in plasma are
achieved 1 hour after oral administration, and the half-
life of parent drug in plasma is about 7 hours.
Therapeutic Uses
 Cyclophosphamide (CYTOXAN, NEOSAR, others) is
administered orally or intravenously.
 Recommended doses vary widely, and published
protocols for the dosage of cyclophosphamide and
other chemotherapeutic agents and for the method and
sequence of administration should be consulted.
 As a single agent, a daily oral dose of 100 mg/m2 for 14
days has been recommended as adjuvant therapy for
breast cancer, and for patients with lymphomas and
chronic lymphocytic leukemia.
 A higher dosage of 500 mg/m2 intravenously every 2 to
4 weeks in combination with other drugs often is
employed in the treatment of breast cancer and
lymphomas.
 The neutrophil nadir of 500 to 1000 cells per mm3
generally serves as a guide to dosage adjustments in
prolonged therapy. In regimens associated with bone
marrow or peripheral stem cell rescue,
cyclophosphamide may be given in total doses of 5 to 7
g/m2 over a 3- to 5-day period.
 Gastrointestinal ulceration, cystitis (counteracted by
mesna and diuresis), and less commonly pulmonary,
renal, hepatic, and cardiac toxicities (a hemorrhagic
35
myocardial necrosis) may occur after high-dose therapy
with total doses above 200 mg/kg.
 The clinical spectrum of activity for cyclophosphamide
is very broad.
 It is an essential component of many effective drug
combinations for non-Hodgkin's lymphomas, ovarian
cancers, and solid tumors in children.
 Complete remissions and presumed cures have been
reported when cyclophosphamide was given as a single
agent for Burkitt's lymphoma.
 It frequently is used in combination with methotrexate
(or doxorubicin) and fluorouracil as adjuvant therapy
after surgery for carcinoma of the breast.
 Because of its potent immunosuppressive properties,
cyclophosphamide has been used to prevent organ
rejection after transplantation.
 It has activity in nonneoplastic disorders associated
with altered immune reactivity, including Wegener's
granulomatosis, rheumatoid arthritis, and the nephrotic
syndrome.
 Caution is advised when the drug is considered for use
in these conditions, not only because of its acute toxic
effects but also because of its potential for inducing
sterility, teratogenic effects, and leukemia.
Immunosuppressants
Calcineurin Inhibitors
 Perhaps the most effective immunosuppressive drugs in
routine use are the calcineurin inhibitors, cyclosporine
and tacrolimus, which target intracellular signaling
pathways induced as a consequence of T-cell-receptor
activation.
 Although they are structurally unrelated and bind to
distinct, albeit related molecular targets, they inhibit
normal T-cell signal transduction essentially by the
same mechanism.
 Cyclosporine and tacrolimus do not act per se as
immunosuppressive agents.
 Instead, these drugs bind to an immunophilin
(cyclophilin for cyclosporine or FKBP-12 for tacrolimus),
resulting in subsequent interaction with calcineurin to
block its phosphatase activity.
 Calcineurin-catalyzed dephosphorylation is required for
movement of a component of the nuclear factor of
activated T lymphocytes (NFAT) into the nucleus.
 NFAT, in turn, is required to induce a number of
cytokine genes, including that for interleukin-2 (IL-2), a
prototypic T-cell growth and differentiation factor.
Cyclosporine
Chemistry

 Cyclosporine (cyclosporin A), a cyclic polypeptide
consisting of 11 amino acids, is produced by the fungus
species Beauveria nivea.
 Of note, all amide nitrogens are either hydrogen
bonded or methylated, the single D-amino acid is at
position 8, the methyl amide between residues 9 and
10 is in the cis configuration, and all other methyl
amide moieties are in the trans form.
 Because cyclosporine is lipophilic and highly
hydrophobic, it is formulated for clinical administration
using castor oil or other strategies to ensure
solubilization.
Mechanism of Action
 Cyclosporine suppresses some humoral immunity, but
is more effective against T-cell-dependent immune
mechanisms such as those underlying transplant
rejection and some forms of autoimmunity.
 It preferentially inhibits antigen-triggered signal
transduction in T lymphocytes, blunting expression of
many lymphokines including IL-2, and the expression of
antiapoptotic proteins.
 Cyclosporine forms a complex with cyclophilin, a
cytoplasmic receptor protein present in target cells.
 This complex binds to calcineurin, inhibiting Ca2+-
stimulated dephosphorylation of the cytosolic
component of NFAT.
 When cytoplasmic NFAT is dephosphorylated, it
translocates to the nucleus and complexes with nuclear
components required for complete T-cell activation,
including transactivation of IL-2 and other lymphokine
genes.
 Calcineurin phosphatase activity is inhibited after
physical interaction with the cyclosporine/cyclophilin
complex.
 This prevents NFAT dephosphorylation such that NFAT
does not enter the nucleus, gene transcription is not
activated, and the T lymphocyte fails to respond to
specific antigenic stimulation.
 Cyclosporine also increases expression of transforming
growth factor-b (TGF-b), a potent inhibitor of IL-2-
stimulated T-cell proliferation and generation of
cytotoxic T lymphocytes (CTL).
Disposition and Pharmacokinetics
 Cyclosporine can be administered intravenously or
orally.
 The intravenous preparation (SANDIMMUNE Injection) is
provided as a solution in an ethanol-polyoxyethylated
castor oil vehicle that must be further diluted in 0.9%
sodium chloride solution or 5% dextrose solution before
injection.
 The oral dosage forms include soft gelatin capsules and
oral solutions.
36
Cyclosporine supplied in the original soft gelatin
capsule (SANDIMMUNE) is absorbed slowly with 20% to
50% bioavailability.
 A modified microemulsion formulation (NEORAL) is
available.
 It has more uniform and slightly increased
bioavailability compared to SANDIMMUNE and is
provided as 25-mg and 100-mg soft gelatin capsules
and a 100-mg/ml oral solution.
 Since SANDIMMUNE and NEORAL are not bioequivalent,
they cannot be used interchangeably without
supervision by a physician and monitoring of drug
concentrations in plasma.
 Comparison of blood concentrations in published
literature and in clinical practice must be performed
with a detailed knowledge of the assay system
employed.
 Generic preparations of both NEORAL and
SANDIMMUNE are available that are bioequivalent by
FDA criteria.
 The generic preparations for NEORAL have been shown
to be bioequivalent in normal volunteers, and, in some
studies, also in transplant recipients.
 After oral administration of cyclosporine (as NEORAL),
the time to peak blood concentrations is 1.5 to 2 hours.
 Administration with food delays and decreases
absorption.
 High- and low-fat meals consumed within 30 minutes of
administration decrease the AUC by approximately 13%
and the maximum concentration by 33%. This makes it
imperative to individualize dosage regimens for
outpatients.
 Cyclosporine is distributed extensively outside the
vascular compartment.
 After intravenous dosing, the steady-state volume of
distribution is reportedly as high as 3 to 5 L/kg in solid-
organ transplant recipients.
 Only 0.1% of cyclosporine is excreted unchanged in
urine.
 Cyclosporine is extensively metabolized in the liver by
CYP3A and to a lesser degree by the gastrointestinal
tract and kidneys (Fahr, 1993).
 At least 25 metabolites have been identified in human
bile, feces, blood, and urine.
 Although the cyclic peptide structure of cyclosporine is
relatively resistant to metabolism, the side chains are
extensively metabolized.
 All of the metabolites have reduced biological activity
and toxicity compared to the parent drug.
 Cyclosporine and its metabolites are excreted
principally through the bile into the feces, with only
about 6% being excreted in the urine.
 Cyclosporine also is excreted in human milk.
 In the presence of hepatic dysfunction, dosage
adjustments are required. No adjustments generally are
necessary for dialysis or renal failure patients.
 37

Therapeutic Uses  Cyclosporine, as opposed to tacrolimus, is more likely

to produce elevations in LDL cholesterol.

 Clinical indications for cyclosporine are kidney, liver,

(Goodman and Gilman’s The Pharmacological Basis of
heart, and other organ transplantation; rheumatoid Therapeutics 11th Edition)
arthritis; and psoriasis.

 Cyclosporine generally is recognized as the agent that
ushered in the modern era of organ transplantation,
increasing the rates of early engraftment, extending
kidney graft survival, and making cardiac and liver
transplantation possible.
 Cyclophosphamide is used for etiology-dependent
treatment of acute glomerulonephritis due to Wegener
granulomatosis.

 Cyclosporine usually is combined with other agents,

especially glucocorticoids and either azathioprine or Cyclophosphamide (Cytoxan,
mycophenolate mofetil, and most recently, sirolimus. Drug Name
Neosar, Procytox)
Acts as alkylating agent that cross-
 The dose of cyclosporine varies, depending on the links strands of DNA and RNA.
organ transplanted and the other drugs used in the Other actions include inhibition of
specific treatment protocol(s). Description protein synthesis,
immunosuppression, and
cholinesterase inhibition. Not within
 The initial dose generally is not given before the
the scope of ED care.
transplant because of the concern about nephrotoxicity.
For long-term therapy, the
following doses are used:
 Especially for renal transplant patients, therapeutic 400-1800 mg/m2 (30-40 mg/kg) IV
algorithms have been developed to delay cyclosporine Adult Dose in divided doses over 2-5 d; may
introduction until a threshold renal function has been repeat at 2- to 4-wk intervals;
attained. alternatively, 10-15 mg/kg IV q7-
10d or 3-5 mg/kg twice weekly
 The amount of the initial dose and reduction to Long-term therapy: Administer as
Pediatric Dose
maintenance dosing is sufficiently variable that no in adults
specific recommendation is provided here. Documented hypersensitivity;
Contraindication
severely depressed bone marrow
s
 Dosage is guided by signs of rejection (too low a dose), function
renal or other toxicity (too high a dose), and close Allopurinol may increase risk of
monitoring of blood levels. Great care must be taken to bleeding or infection and enhance
differentiate renal toxicity from rejection in kidney myelosuppressive effects; may
transplant patients. potentiate doxorubicin-induced
cardiotoxicity; may reduce digoxin
serum levels and antimicrobial
 Ultrasound-guided allograft biopsy is the best way to
effects of quinolones
assess the reason for renal dysfunction.
Chloramphenicol may increase
half-life while decreasing
 Because adverse reactions have been ascribed more Interactions metabolite concentrations; may
frequently to the intravenous formulation, this route of increase effect of anticoagulants;
administration is discontinued as soon as the patient is coadministration with high doses of
able to take the drug orally. phenobarbital may increase rate of
metabolism and leukopenic
activity; thiazide diuretics may
prolong cyclophosphamide-induced
Toxicity leukopenia and neuromuscular
blockade by inhibiting
cholinesterase activity
D - Fetal risk shown in humans; use
Pregnancy only if benefits outweigh risk to
 The principal adverse reactions to cyclosporine therapy fetus
are renal dysfunction, tremor, hirsutism, hypertension, Regularly examine hematologic
hyperlipidemia, and gum hyperplasia. profile (particularly neutrophils and
platelets) to monitor for
 Hyperuricemia may lead to worsening of gout, Precautions hematopoietic suppression;
increased P-glycoprotein activity, and regularly examine urine for RBCs,
hypercholesterolemia. which may precede hemorrhagic
cystitis
 Nephrotoxicity occurs in the majority of patients treated
and is the major indication for cessation or modification
of therapy. (http://www.emedicine.com/emerg/topic219.htm)

 Hypertension occurs in approximately 50% of renal 6. Identify the complications of glomerulonephritis.

transplant and almost all cardiac transplant patients.

 Combined use of calcineurin inhibitors and

glucocorticoids is particularly diabetogenic, although Progression of Glomerular Disease
this apparently is more problematic in patients treated
with tacrolimus (see below).

 Especially at risk are obese patients, African-American • Persistent glomerulonephritis that worsens renal function is
or Hispanic recipients, or those with family history of always accompanied by interstitial nephritis, renal fibrosis,
type II diabetes or obesity. and tubular atrophy.
 38

• What is not so obvious, however, is that renal failure in
glomerulonephritis best correlates histologically with the
appearance of tubulointerstitial nephritis rather than with
the type of inciting glomerular injury.
• Loss of renal function due to interstitial damage can be
explained hypothetically by several mechanisms.
• The simplest explanation is that urine flow is impeded by
tubular obstruction as a result of interstitial inflammation
and fibrosis.
• Thus, obstruction of the tubules with debris or by extrinsic
compression results in aglomerular nephrons.
• A second mechanism suggests that interstitial changes,
including interstitial edema or fibrosis, alter tubular and
vascular architecture and thereby compromise the normal
tubular transport of solutes and water from tubular lumen to
vascular space.
• These effects induce T lymphocyte and macrophage
infiltrates in the interstitial spaces along with fibrosis and
tubular atrophy.
• Tubules disappear following direct damage to their
basement membranes, leading to decondensation and
epithelial-mesenchymal transitions forming more interstitial
fibroblasts at the site of injury.
• Transforming growth factor (TGF-), fibroblast growth factor
2, and platelet-derived growth factor (PDGF) are particularly
active in this transition.
• With persistent nephritis, fibroblasts multiply and lay down
tenascin and a fibronectin scaffold for the polymerization of
new interstitial collagens I/III.
• These events form scar tissue through a process called
fibrogenesis.

• In experimental studies, bone morphogenetic protein 7 and

• This failure increases the solute and water content of the
tubule fluid, resulting in isothenuria and polyuria. hematopoietic growth factor can reverse early fibrogenesis
and preserve tubular architecture.

• Adaptive mechanisms related to tubuloglomerular feedback

also fail, resulting in a reduction of renin output from the • When fibroblasts outdistance their survival factors, they
apoptose, and the permanent renal scar becomes acellular,
juxtaglomerular apparatus of glomeruli trapped by interstitial
inflammation. leading to irreversible renal failure.

• Consequently, the local vasoconstrictive influence of

angiotensin II on the glomerular arterioles decreases, and
filtration drops owing to a generalized decrease in arteriolar (Harrison's Principles of Internal Medicine 17th Edition)
tone.

• A third mechanism involves changes in vascular resistance

due to damage of peritubular capillaries. Complications

• The cross-sectional volume of these capillaries is decreased

in areas of interstitial inflammation, edema, or fibrosis.
• These structural alterations in vascular resistance affect
renal function through two mechanisms.
• First, tubular cells are very metabolically active, and, as a
result, decreased perfusion could lead to ischemic injury.
• Second, impairment of glomerular arteriolar outflow leads to
increased intraglomerular hypertension in less involved
glomeruli; this selective intraglomerular hypertension
aggravates and extends mesangial sclerosis and
glomerulosclerosis to less-involved glomeruli.
• Regardless of the exact mechanism, early acute
tubulointerstitial nephritis suggests potentially recoverable
renal function, while the development of chronic interstitial
fibrosis prognosticates a permanent loss.
• Persistent damage to glomerular capillaries spreads to the
tubulointerstitium in association with proteinuria.
• Progression to sclerosis is rare in the typical patient;
however, in 0.5-2% of patients with acute
glomerulonephritis, the course progresses toward renal
failure, resulting in kidney death in a short period.
• Abnormal urinalysis (ie, microhematuria) may persist for
years.
• Marked decline in glomerular filtration rate is rare.
• Other complications, resulting in relevant end-organ damage
in the central nervous and cardiopulmonary systems, can
develop in patients who present with severe hypertension,
encephalopathy, and pulmonary edema.
• Those complications include the following:
 Hypertensive retinopathy
 Hypertensive encephalopathy

• There is an untested hypothesis that efferent arterioles

leading from inflamed glomeruli carry forward inflammatory  Rapidly progressive glomerulonephritis
mediators, which induces downstream interstitial nephritis,
resulting in fibrosis.  Chronic renal failure

• Glomerular filtrate from injured glomerular capillaries (http://www.emedicine.com/emerg/topic219.htm)

adherent to Bowman's capsule may also be misdirected to
the periglomerular interstitium. 7. Identify the prognosis of acute glomerulonephritis.

• Most nephrologists believe, however, that proteinuric

glomerular filtrate forming tubular fluid is the primary route
to downstream tubulointerstitial injury, although none of
Prognosis (Acute Glomerulonephritis)
these hypotheses are mutually exclusive.

• The simplest explanation for the effect of proteinuria on the

development of interstitial nephritis is that increasingly
severe proteinuria, carrying activated cytokines and • Acute poststreptococcal glomerulonephritis resolves
lipoproteins producing reactive oxygen species, triggers a completely in most cases, especially in children.
downstream inflammatory cascade in and around epithelial
cells lining the tubular nephron.
 39

• About 0.1% of children and 25% of adults develop chronic
kidney failure.
• The prognosis for people with rapidly progressive
glomerulonephritis depends on the severity of glomerular
scarring and whether the underlying disease, such as
infection, can be cured.
• Urinary abnormalities resolve at various times after onset.
 Proteinuria may disappear within the first 2-3 months or
may decrease slowly over 6 months. Intermittent or
postural proteinuria has been noted for 1-2 years after
onset.

• In about 75% of the people who are treated early (within

 Microscopic hematuria usually disappears after 6
weeks to a few months), kidney function is preserved and months, but its presence for as long as 1 year should
not cause undue concern, and even more prolonged
dialysis is not needed.
hematuria (1-3 y) has been observed.

• However, because the early symptoms can be subtle and

vague, many people who have rapidly progressive  Consider the possibility of chronic renal disease when
glomerulonephritis are not aware of the underlying disease both hematuria and proteinuria persist longer than 12
and do not seek medical care until kidney failure develops. months.

• If treatment occurs late, the person is more likely to develop • The ultimate prognosis in individuals with PSAGN depends
chronic kidney failure. largely on the severity of the initial insult.

• The prognosis also depends on the cause, the person's age,

and any other diseases the person might have. When the  In a few hospitalized patients, the initial injury is so
cause is unknown or the person is older, the prognosis is severe that either persistent renal failure or progressive
worse. renal failure ensues.

• In some children and adults who do not recover completely  Clinical manifestations of the disease rarely recur after
from acute glomerulonephritis, other types of kidney the first 3 months, and second episodes of AGN are
disorders develop, such as asymptomatic proteinuria and rare.
hematuria syndrome or nephrotic syndrome.

• Other people with acute glomerulonephritis, especially older

adults, often develop chronic glomerulonephritis. (http://www.emedicine.com/ped/topic27.htm)

(http://www.merck.com/mmhe/sec11/ch144/ch144b.html)

Prognosis (Acute Post-Streptococcal Glomerulonephritis)

• In poststreptococcal nephritis, the long-term prognosis

generally is good. More than 98% of individuals are
asymptomatic after 5 years, with chronic renal failure
reported 1-3% of the time.
• The prognosis for nonstreptococcal postinfectious
glomerulonephritis depends on the underlying agent, which
must be identified and addressed.
• Generally, the prognosis is worse in patients with heavy
proteinuria, severe hypertension, and significant elevations
of creatinine level.
• Other causes of acute glomerulonephritis have outcomes
varying from complete recovery to complete renal failure.
Prognosis depends on the underlying disease and the overall
health of the patient.
• Occurrence of cardiopulmonary or neurologic complications
worsens the prognosis.

(http://www.emedicine.com/emerg/topic219.htm)

Prognosis (Acute Post-Streptococcal Glomerulonephritis)

• Epidemic PSAGN appears to end in virtually complete

resolution and healing in all patients, and the prognosis is
favorable for most children with sporadic PSAGN.

 Edema usually resolves within 5-10 days, and BP

usually returns to normal after 2-3 weeks, even though
persistence of elevated pressures for as many as 6
weeks is compatible with complete resolution.

 Gross hematuria usually disappears within 1-3 weeks

but may be exacerbated by physical activity.

 C3 concentration returns to normal in more than 95% of

patients by the end of 8-10 weeks.