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Glomerulonephritis
Glomerulonephritis
MED II-B Group 6 Notes • The anatomy of renal vessels has several important
implications.
Case 1: “Puffy Raffy” • Glomerular disease that interferes with blood flow through
the glomerular capillaries has profound effects on the
1. Recall the anatomic and histologic features of the kidneys. tubules, within both the cortex and the medulla, because all
tubular capillary beds are derived from the efferent
arterioles.
• Each human adult kidney weighs about 150 gm. • The peculiarities of the blood supply to the renal medulla
render them especially vulnerable to ischemia; the medulla
• As the ureter enters the kidney at the hilum, it dilates into a does not have its own arterial blood supply but is dependent
funnel-shaped cavity, the pelvis, from which derive two or on the blood emanating from the glomerular efferent
three main branches, the major calyces; each of these arterioles.
subdivides again into three or four minor calyces.
• The blood in the capillary loops in the medulla has a
• There are about 12 minor calyces in the human kidney. remarkably low level of oxygenation.
• The kidney is richly supplied by blood vessels, and although • The parietal epithelium, situated on Bowman's capsule, lines
both kidneys make up only 0.5% of the total body weight, the urinary space, the cavity in which plasma filtrate first
they receive about 25% of the cardiac output. The cortex is collects.
by far the most richly vascularized part of the kidney,
receiving 90% of the total renal blood supply.
• The glomerular capillary wall is the filtering membrane and
consists of the following structures:
• The main renal artery divides into anterior and posterior
sections at the hilum. A thin layer of fenestrated endothelial cells, each
fenestrum being about 70 to 100 nm in diameter.
Tubules
3
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.
(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.
Systemic SX include headache, malaise, anorexia, and Classic presentations include the following:
flank pain are reported in as many as 50% of cases
o Triad of sinusitis, pulmonary infiltrates, and
5% of children and 20% of adults have proteinuria in nephritis suggesting Wegener granulomatosis
the nephritic change
o Nausea/vomiting, abdominal pain, and purpura
In the 1st week of Sx, 90% of patients will have a observed with Henoch-Schönlein purpura
depressed CH50 and decreased levels of C3 with
normal levels of C4 o Arthralgias associated with systemic lupus
erythematosus (SLE)
A subclinical disease is reported in some series to be
four or five times as common as clinical nephritis, and o Hemoptysis occurring with Goodpasture syndrome
these latter cases are characterized by asymptomatic or idiopathic progressive glomerulonephritis
microscopic hematuria with low level serum
complement levels. 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
(Harrison’s Principles of Medicine 16th Edition) Henoch-Schönlein purpura.
Most often, the patient is a boy, aged 2-14 years, who This description does not include all the physical
suddenly develops puffiness of the eyelids and facial findings that can be associated with the nonnephritic
edema in the setting of a poststreptococcal infection. features of an infectious process (eg, fever), renal
The urine is dark and scanty, and the blood pressure etiology, or systemic etiology, as such a description is
may be elevated. beyond the scope of this article.
Onset of symptoms is usually abrupt. Patients often have a normal physical examination and
blood pressure; most frequently, however, patients
Nonspecific symptoms include weakness, fever, present with a combination of edema, hypertension,
abdominal pain, and malaise. and oliguria.
Onset of nephritis within 1-4 days of streptococcal o Hematuria, either macroscopic (gross) or
infection suggests preexisting renal disease. microscopic, may be noted.
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.
o The patient also commonly has proteinuria and o Serum complement levels are low, compatible
edema, but these are not as severe as those with activation of the complement system and
encountered in the nephrotic syndrome, discussed consumption of complement components.
later.
o The presence of granular immune deposits in the
o The acute nephritic syndrome may occur in such glomeruli demonstrates an immune complex-
multisystem diseases as SLE and microscopic mediated mechanism, and so does the finding of
polyarteritis. electron-dense deposits.
o A small minority of children (perhaps less than 1%) o The acute nephritic syndrome is the clinical
do not improve, become severely oliguric, and correlate of acute glomerular inflammation.
develop a rapidly progressive form of
glomerulonephritis (described later). Some of the
o In its most dramatic form, the acute nephritic
remaining patients may undergo slow progression
syndrome is characterized by sudden onset (i.e.,
to chronic glomerulonephritis with or without
over days to weeks) of acute renal failure and
recurrence of an active nephritic picture.
oliguria (400 mL/day of urine).
o Prolonged and persistent heavy proteinuria and
o Renal blood flow and GFR fall as a result of
abnormal GFR mark patients with an unfavorable
obstruction of the glomerular capillary lumen by
prognosis.
infiltrating inflammatory cells and proliferating
resident glomerular cells.
o In adults, the disease is less benign.
o Renal blood flow and GFR are further
o Although the overall prognosis in epidemics is compromised by intrarenal vasoconstriction and
good, in only about 60% of sporadic cases do the mesangial cell contraction that result from local
patients recover promptly. In the remainder, the imbalances of vasoconstrictor (e.g., leukotrienes,
glomerular lesions fail to resolve quickly, as platelet-activating factor, thromboxanes,
manifested by persistent proteinuria, hematuria, endothelins) and vasodilator substances (e.g.,
and hypertension. nitric oxide, prostacyclin) within the renal
microcirculation.
o In some of these patients, the lesions eventually
clear totally, but others develop chronic
glomerulonephritis.
o Extracellular fluid volume expansion, edema, and
hypertension develop because of impaired GFR
and enhanced tubular reabsorption of salt and
o Some patients will develop a syndrome of rapidly
water. As a result of injury to the glomerular
progressive glomerulonephritis.
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
Nonstreptococcal Acute Glomerulonephritis macroscopic.
(Postinfectious Glomerulonephritis)
o The classic pathologic correlate of the nephritic
syndrome is proliferative glomerulonephritis.
o A similar form of glomerulonephritis occurs o The proliferation of glomerular cells is due initially
sporadically in association with other bacterial to infiltration of the glomerular tuft by neutrophils
infections (e.g., staphylococcal endocarditis, and monocytes and subsequently to true
pneumococcal pneumonia, and proliferation of resident glomerular endothelial and
meningococcemia), viral disease (e.g., hepatitis B, mesangial cells (endocapillary proliferation).
hepatitis C, mumps, human immunodeficiency
virus [HIV] infection, varicella, and infectious o In its most severe form, the nephritic syndrome is
mononucleosis), and parasitic infections (malaria, associated with acute inflammation of most
toxoplasmosis). glomeruli, i.e., acute diffuse proliferative
glomerulonephritis.
o In this setting, granular immunofluorescent
deposits and subepithelial humps characteristic of o When less vigorous, <50% of glomeruli may be
immune complex nephritis are present. involved, i.e., focal proliferative
glomerulonephritis.
(Robbins and Cotran Pathologic Basis of Therapeutics
7th Edition) o In milder forms of nephritic injury, cellular
proliferation may be confined to the mesangium,
Morphology: i.e., mesangioproliferative glomerulonephritis.
8
o RPGN is the clinical correlate of more subacute o Most patients (>70%) with full-blown acute
glomerular inflammation. nephritic syndrome have immune-complex
glomerulonephritis.
o Patients develop renal failure over weeks to
months in association with a nephritic urinary o Pauci-immune glomerulonephritis is less common
sediment, subnephrotic proteinuria and variable in this setting (<30%), and anti-GBM disease is
oliguria, hypervolemia, edema, and hypertension. rare (<1%).
o The classic pathologic correlate of RPGN is o Among patients with RPGN, immune-complex
crescent formation involving most glomeruli glomerulonephritis and pauci-immune
(crescentic glomerulonephritis). glomerulonephritis are equally prevalent (~45%
each), whereas anti- GBM disease again accounts
o In practice, the clinical term rapidly progressive for a minority of cases (<10%).
glomerulonephritis and the pathologic term
crescentic glomerulonephritis are often used o Three serologic markers often predict the
interchangeably. immunofluorescence microscopy findings in
nephritic syndrome and RPGN and may obviate
o In addition to classic crescentic the need for renal biopsy in classic cases.
glomerulonephritis, in which crescents dominate
the glomerular pathology, crescents can also o They are the serum C3 level and titers of anti-GBM
develop concomitantly with proliferative antibody and ANCA.
glomerulonephritis or as a complication of
membranous glomerulopathy and other more
indolent forms of glomerular inflammation.
o As discussed in previous sections, the kidney is
host to immune attack in immune-complex
glomerulonephritis, most cases being initiated
o The acute nephritic syndrome and RPGN are part either by in situ formation of immune complexes
of a spectrum of presentations of immunologically or less commonly by glomerular trapping of
mediated proliferative glomerulonephritis. circulating immune complexes.
STREPTOCOCCAL INFECTION AND INFECTIVE o The serum creatinine is often mildly elevated at
ENDOCARDITIS presentation.
o Patients with overt disease present with gross o The glomerular lesion typically resolves following
hematuria (red or “smoky” urine), headache, and eradication of the cardiac infection.
generalized symptoms such as anorexia, nausea,
vomiting, and malaise. Swelling of the renal
capsule can cause flank or back pain. (Harrison’s Principles of Internal Medicine 16th Edition)
and does not denote a specific etiologic form of These patients cannot usually be helped by
glomerulonephritis. plasmapheresis, and they require treatment for
the underlying disease.
o It is characterized clinically by rapid and
progressive loss of renal function associated with o The third type of RPGN, also called pauci-immune
severe oliguria and (if untreated) death from renal type, is defined by the lack of anti-GBM antibodies
failure within weeks to months. or immune complexes by immunofluorescence and
electron microscopy.
o Regardless of the cause, the classic histologic
picture is characterized by the presence of o Most patients with this type of RPGN have
crescents in most of the glomeruli (crescentic antineutrophil cytoplasmic antibodies (ANCA), of
glomerulonephritis). cytoplasmic (C) or perinuclear (P) patterns, in the
serum, which, as we have seen (Chapter 11), play
o As discussed earlier, these are produced in part by a role in some vasculitides.
proliferation of the parietal epithelial cells lining
Bowman capsule and in part by infiltration of o Hence, in some cases, this type of RPGN is a
monocytes and macrophages. component of a systemic vasculitis such as
Wegener granulomatosis or microscopic
polyarteritis.
o RPGN may be caused by a number of different o More than 90% of such idiopathic cases have c-
diseases, some restricted to the kidney and others ANCA or p-ANCA in the sera.
systemic.
o The presence of circulating ANCAs in both
o Although no single mechanism can explain all idiopathic RPGN and cases of RPGN that occur as a
cases, there is little doubt that in most cases, the component of systemic vasculitis, and the similar
glomerular injury is immunologically mediated. pathologic features in either setting, have led to
the idea that these disorders are pathogenetically
related.
o Thus, a practical classification divides RPGN into
three groups on the basis of immunologic findings
o According to this concept, all cases of RPGN of the
(Table 20-7). In each group, the disease may be
associated with a known disorder, or it may be pauci-immune type are manifestations of small
idiopathic. vessel vasculitis or polyangiitis, which is limited to
glomerular and perhaps peritubular capillaries in
cases of idiopathic crescentic glomerulonephritis.
o The first type of RPGN is best remembered as anti-
GBM antibody-induced disease and hence is
o The clinical distinction between systemic vasculitis
characterized by linear deposits of IgG and, in
many cases, C3 in the GBM, as previously with pauci-immune renal involvement and
described.48 In some of these patients, the anti- idiopathic crescentic glomerulonephritis
GBM antibodies cross-react with pulmonary accordingly has become deemphasized, as these
alveolar basement membranes to produce the entities are viewed as part of a spectrum of
clinical picture of pulmonary hemorrhage vasculitic disease.
associated with renal failure (Goodpasture
syndrome). o ANCAs have proved to be invaluable as a highly
sensitive diagnostic marker for pauci-immune
o Plasmapheresis to remove the pathogenic RPGN, but proof of their role as a direct cause of
circulating antibodies is usually part of the RPGN has been elusive.
treatment, which also includes therapy to
suppress the underlying immune response. o Recent strong evidence of their pathogenic
potential has been obtained by studies in which
antibodies against myeloperoxidase (the target
o The Goodpasture antigen, as was noted earlier, is antigen of most p-ANCAs) are transferred into
a peptide within the noncollagenous portion of the mice.
α3-chain of collagen type IV.
o To summarize, all three types of RPGN may be
o What triggers the formation of these antibodies is associated with a well-defined renal or extrarenal
unclear in most patients. Exposure to viruses or disease, but in many cases (approximately 50%),
hydrocarbon solvents (found in paints and dyes) the disorder is idiopathic. Of the patients with this
has been implicated in some patients, as have syndrome, about one fifth have anti-GBM
various drugs and cancers. antibody-induced disease without lung
involvement; another one fourth have immune
complex-mediated disease RPGN; and the
o There is a high prevalence of certain HLA subtypes remainder are of the pauci-immune type.
and haplotypes (e.g., HLA-DRB1) in affected
patients, a finding consistent with the genetic
predisposition to autoimmunity. o The common denominator in all types of RPGN is
severe glomerular injury.
o The second type of RPGN is the result of immune
complex-mediated disease.
o Recovery of renal function may follow early o Membranous glomerulopathy is a form of chronic
intensive plasmapheresis (plasma exchange) immune complex-mediated disease. In secondary
combined with steroids and cytotoxic agents in membranous glomerulopathy, particular antigens
Goodpasture syndrome. can sometimes be identified in the immune
complexes.
o This therapy appears to reverse both pulmonary
hemorrhage and renal failure. o For example, membranous glomerulopathy in SLE
is associated with deposition of autoantigen-
o Other forms of RPGN also respond well to steroids antibody complexes.
and cytotoxic agents.
o Exogenous (hepatitis B, Treponema antigens) or
o Despite therapy, patients may eventually require endogenous (thyroglobulin) antigens have been
chronic dialysis or transplantation. identified within deposits in some patients.
12
o In time, these spikes thicken to produce domelike o It is rare in childhood and by far the most common
protrusions and eventually close over the immune cause of nephrotic syndrome in the elderly.
deposits, burying them within a markedly
thickened, irregular membrane. o In 25–30% of cases, MGN is secondary to
Immunofluorescence microscopy demonstrates malignancy (solid tumors of the breast, lung,
that the granular deposits contain both colon), infection (hepatitis B, malaria,
immunoglobulins and various amounts of schistosomiasis), or rheumatologic disorders like
complement. lupus or rarely rheumatoid arthritis (Table 277-6).
o As the disease advances, the membrane o Uniform thickening of the basement membrane
thickening progressively encroaches on the along the peripheral capillary loops is seen by light
capillary lumens, and sclerosis of the mesangium microscopy on renal biopsy, this thickening needs
may occur; in the course of time, glomeruli may to be distinguished from that seen in diabetes and
become totally sclerosed. amyloidosis.
o The epithelial cells of the proximal tubules contain o Immunofluorescence demonstrates diffuse
protein reabsorption droplets, and there may be granular deposits of IgG and C3, and electron
considerable mononuclear cell interstitial microscopy typically reveals electron-dense
inflammation. subepithelial deposits.
atrophy or interstitial fibrosis is more predictive of o This relatively benign disorder is the most frequent
progression than is the stage of glomerular cause of nephrotic syndrome in children, but it is
disease. less common in adults.
o Microscopic hematuria is seen in up to 50% of o Although the absence of immune deposits in the
patients. Spontaneous remissions occur in 20–33% glomerulus excludes classic immune complex
of patients and often occur late in the course after mechanisms, several features of the disease point
years of nephrotic syndrome. to an immunologic basis, including (1) the clinical
association with respiratory infections and
prophylactic immunization; (2) the response to
o One-third of patients continue to have relapsing
corticosteroids and/or other immunosuppressive
nephrotic syndrome but maintain normal renal
therapy; (3) the association with other atopic
function, and approximately another third of
disorders (e.g., eczema, rhinitis); (4) the increased
patients develop renal failure or die from the
prevalence of certain HLA haplotypes in patients
complications of nephrotic syndrome. Male
with minimal change disease associated with
gender, older age, hypertension, and the
atopy (suggesting a genetic predisposition); (5)
persistence of proteinuria are associated with
the increased incidence of minimal change disease
worse prognosis.
in patients with Hodgkin disease, in whom defects
in T cell-mediated immunity are well recognized;
o Although thrombotic complications are a feature of and (6) reports of proteinuria-inducing factors in
all nephrotic syndromes, MGN has the highest the plasma or lymphocyte supernatants of
reported incidences of renal vein thrombosis, patients with minimal change disease and focal
pulmonary embolism, and deep vein thrombosis. glomerulosclerosis.
Prophylactic anticoagulation is controversial but
has been recommended for patients with severe o The current leading hypothesis is that minimal
or prolonged proteinuria in the absence of risk
change disease involves some immune
factors for bleeding.
dysfunction, eventually resulting in the elaboration
of a cytokine that damages visceral epithelial cells
o In addition to the treatment of edema, and causes proteinuria.
dyslipidemia, and hypertension, inhibition of the
renin-angiotensin system is recommended. o The ultrastructural changes point to a primary
visceral epithelial cell injury, and studies in animal
o Therapy with immunosuppressive drugs is also models suggest the loss of glomerular polyanions.
recommended for patients with primary MGN and
persistent proteinuria (>3.0 g/24 h). o Thus, defects in the charge barrier may contribute
to the proteinuria.
o The choice of immunosuppressive drugs for
therapy is controversial, but current o The actual route by which protein traverses the
recommendations based on small clinical studies
epithelial cell portion of the capillary wall remains
are to treat with steroids and cyclophosphamide,
an enigma.
chlorambucil, or cyclosporine.
o Possibilities include transcellular passage through
o Experience with mycophenolate mofetil or anti-
the epithelial cells, passage through residual
CD20 antibody is even more limited.
spaces between remaining but damaged foot
processes, or leakage through foci in which the
epithelial cells have become detached from the
basement membrane.
(Harrison’s Principles of Internal Medicine 17th Edition)
o Additional insight into mechanisms by which
epithelial cell injury results in proteinuria in
minimal change disease, focal and segmental
3.1.4Minimal Change 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.
MINIMAL CHANGE DISEASE (LIPOID NEPHROSIS)
o A mutation in the nephrin gene causes a
hereditary form of congenital nephrotic syndrome
(Finnish type) with minimal change glomerular
morphology.
14
o Such mutations and the proteinuria they engender and, less frequently, other lymphomas and
demonstrate that at least some cases of nephrotic leukemias.
syndrome with minimal change disease
morphology can occur in the absence of abnormal
responses of the immune system.
(Robbins and Cotran Pathologic Basis of Disease 7th
Edition)
Morphology
o By electron microscopy, the basement membrane o MCD, sometimes known as nil lesion, causes 70–
appears normal, and no electron-dense material is 90% of nephrotic syndrome in childhood but only
deposited. 10–15% of nephrotic syndrome in adults.
o The principal lesion is in the visceral epithelial o MCD usually presents as a primary renal disease
cells, which show a uniform and diffuse but can be associated with several other
effacement of foot processes, these being conditions, including Hodgkin's disease, allergies,
replaced by a rim of cytoplasm often showing or use of nonsteroidal anti-inflammatory agents;
vacuolization, swelling, and hyperplasia of villi. significant interstitial nephritis often accompanies
cases associated with nonsteroidal use.
o This change, often incorrectly termed "fusion" of
foot processes, actually represents simplification o MCD on renal biopsy shows no obvious glomerular
of the epithelial cell architecture with flattening, lesion by light microscopy and is negative for
retraction, and swelling of foot processes. deposits by immunofluorescent microscopy, or
occasionally shows small amounts of IgM in the
o Foot process effacement is also present in other mesangium.
proteinuric states (e.g., membranous
glomerulopathy, diabetes); it is only when o Electron microscopy, however, consistently
effacement is associated with normal glomeruli by demonstrates an effacement of the foot process
light microscopy that the diagnosis of minimal supporting the epithelial podocytes with
change disease can be made. weakening of slit-pore membranes.
o The visceral epithelial changes are completely o The pathophysiology of this lesion is uncertain.
reversible after corticosteroid therapy,
concomitant with remission of the proteinuria. o Most agree there is a circulating cytokine, perhaps
related to a T cell response that alters capillary
o The cells of the proximal tubules are often laden charge and podocyte integrity.
with lipid and protein, reflecting tubular
reabsorption of lipoproteins passing through o The evidence for cytokine-related immune injury is
diseased glomeruli (thus, the historical term lipoid circumstantial and is suggested by the presence of
nephrosis). preceding allergies, altered cell-mediated
immunity during viral infections, and the high
o Immunofluorescence studies show no frequency of remissions with steroids.
immunoglobulin or complement deposits.
o MCD presents clinically with the abrupt onset of
edema and nephrotic syndrome accompanied by
acellular urinary sediment.
dependent patients relapse as their steroid dose is heroin addiction (heroin nephropathy), sickle
tapered. Frequent relapsers have two or more cell disease, and massive obesity
relapses in the 6 months following taper, and
steroid-resistant patients fail to respond to steroid As a secondary event, reflecting glomerular
therapy. scarring, in cases of focal glomerulonephritis
(e.g., IgA nephropathy)
o Ninety to 95% of children will develop a complete
remission after 8 weeks of steroid therapy, and As a component of the adaptive response to
80–85% of adults will achieve complete remission, loss of renal tissue (renal ablation, described
but only after a longer course of 20–24 weeks. earlier) in advanced stages of other renal
disorders, such as reflux nephropathy,
o Patients with steroid resistance can develop FSGS hypertensive nephropathy, or with unilateral
on repeat biopsy. renal agenesis
Morphology
3.1.5Focal Segmental Glomerulosclerosis
o As the name implies, this lesion is characterized o The lesions initially tend to involve the
by sclerosis of some, but not all, glomeruli (thus, it juxtamedullary glomeruli, although they
is focal); and in the affected glomeruli, only a subsequently become more generalized.
portion of the capillary tuft is involved (thus, it is
segmental).
o In the sclerotic segments, there is collapse of
basement membranes, increase in matrix, and
o Focal segmental glomerulosclerosis is frequently segmental insudation of plasma proteins along the
accompanied clinically by the nephrotic syndrome capillary wall (hyalinosis), which may extend to
or heavy proteinuria. aggregates within glomerular capillaries that
occlude the lumina.
detachment of the epithelial cells with denudation o Nephrin is a key component of the slit diaphragm,
of the underlying GBM. the zipper-like structure between podocyte foot
processes that might control glomerular
o By immunofluorescence microscopy, IgM and C3 permeability.
may be present in the sclerotic areas and/or in the
mesangium. In addition to the focal sclerosis, o Several types of mutations of the NPHS1 gene
there may be pronounced hyalinosis and have been identified, and they give rise to
thickening of afferent arterioles. congenital nephrotic syndrome of the Finnish type.
o With the progression of the disease, increased o Prenatal diagnosis of CNF is now possible based on
numbers of glomeruli become involved, sclerosis analysis of the NPHS1 gene.
spreads within each glomerulus, and there is an
increase in mesangial matrix. o A distinctive pattern of autosomal recessive FSGS
results from mutations in the NPHS2 gene, which
o In time, this leads to total sclerosis of glomeruli, maps to chromosome 1q25-31 and encodes the
with pronounced tubular atrophy and interstitial protein product podocin.
fibrosis.
o Podocin has also been localized to the slit
o A morphologic variant of focal segmental diaphragm.
glomerulosclerosis, called collapsing
glomerulopathy, is characterized by collapse and o Mutations in NPHS2 result in a syndrome of
sclerosis of the entire glomerular tuft in addition to steroid-resistant nephrotic syndrome of childhood
the usual focal segmental glomerulosclerosis onset.
lesions.
o Affected children usually show pathologic features
o A characteristic feature is proliferation and of FSGS but sometimes of minimal change
hypertrophy of glomerular visceral epithelial cells. disease.
o This lesion may be seen in situations in which it is o Podocin mutations may account for up to 30% of
idiopathic, but it is the most characteristic lesion cases of steroid-resistant nephrotic syndrome in
of HIV-associated nephropathy. children.
o In general, children have a better prognosis than o Proteinuria remits in only 20–45% of patients
adults do. receiving a course of steroids over 6–9 months.
o Progression of renal failure occurs at variable o Limited evidence suggests that the use of
rates. cyclosporine in steroid-responsive patients helps
ensure remissions, while other cytotoxic agents
confer little added benefit over steroid therapy.
o About 20% of patients follow an unusually rapid Primary FSGS recurs in 25–40% of patients given
course, with intractable massive proteinuria allografts at end-stage disease, leading to graft
ending in renal failure within 2 years. loss in half of those cases.
o Recurrences are seen in 25% to 50% of patients o The treatment of secondary FSGS typically
receiving allografts. involves treating the underlying cause and
controlling proteinuria. There is no role for steroids
or other immunosuppressive agents in secondary
FSGS.
(Robbins and Cotran Pathologic Basis of Disease 7th
Edition)
medium-sized vessels; most affect vessels smaller o Two main patterns of immunofluorescent staining
than arteries, such as arterioles, venules, and distinguish different ANCA types.
capillaries (designated small vessel vasculitis).
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
Immune Complexes granule constituent.
o The most impressive evidence comes from o An autoimmune process of yet uncertain cause
vasculitis associated with viral infections, and mechanism initiates the formation of ANCA.
particularly hepatitis.
o Proinflammatory cytokines produced during an
o There is a high incidence of hepatitis B antigen infection, by malignancy, or possibly triggered by
(HBsAg) and HBsAg-anti-HBsAg immune drugs induce surface expression of the ANCA
complexes in the serum and, with complement, in target antigens PR-3 and MPO on susceptible cells,
the vascular lesions of some patients with thereby making them accessible to the respective
vasculitis, particularly those with large vessel antibodies.
polyarteritis nodosa and less commonly in those
with membranous or membranoproliferative o Binding of circulating ANCA to these antigens
glomerulonephritis or leukocytoclastic vasculitis. leads to neutrophil degranulation and endothelial
cell injury with subsequent vascular damage.
o Importantly, immunosuppressive treatment results
in a remission of the vasculitis but perpetuates the
hepatitis B virus infection.
Other Mechanisms
o Chronic hepatitis C virus (HCV) infection leads to
glomerulonephritis, in which HCV/RNA and
cryoprecipitates containing anti-HCV antibodies
are detected in glomeruli.
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
Antineutrophil Cytoplasmic Antibodies disease.
o At a still later stage, all that remains is marked o The renal manifestations occur in one-third of
fibrotic thickening of the affected vessel, devoid of patients and include gross or microscopic
significant inflammatory infiltration. Particularly hematuria, proteinuria, and nephrotic syndrome.
characteristic of polyarteritis nodosa is that all
stages of activity may coexist in different vessels o A small number of patients, mostly adults, develop
or even within the same vessel. Thus, whatever a rapidly progressive form of glomerulonephritis
the inflammatory insult, it is apparently recurrent with many crescents.
and strangely haphazard.
o Not all components of the syndrome need to be
present, and individual patients may have
purpura, abdominal pain, or urinary abnormalities
Clinical Course as the dominant feature.
o Because the vascular involvement is widely o This has led to the concept that IgA nephropathy
scattered, the clinical signs and symptoms of this and Henoch-Schönlein purpura are spectra of the
disorder may be varied and puzzling. same disease.68
(Robbins and Cotran Pathologic Basis of Disease 7th (Robbins and Cotran Pathologic Basis of Disease 7th
Edition) Edition)
o Suffice it to say here that the glomerular lesions in o The GBM is clearly thickened, often focally; this is
these three conditions can be histologically similar most evident in the peripheral capillary loops.
and are principally characterized by foci of
glomerular necrosis and crescent formation. o The glomerular capillary wall often shows a
"double-contour" or "tram-track" appearance,
o In the early or mild forms of involvement, there is especially evident in silver or PAS stains.
focal and segmental, sometimes necrotizing,
glomerulonephritis, and most of these patients will o This is caused by "duplication" of the basement
have hematuria with mild decline in GFR. membrane, usually as the result of new basement
membrane synthesis.
o In the more severe cases associated with RPGN,
there is more extensive necrosis, fibrin deposition, o Within the besement membrane there is inclusion
and extensive formation of epithelial (cellular) or interposition of cellular elements, which can be
crescents, which can become organized to form of mesangial, endothelial, or leukocytic origin.
fibrocellular and fibrous crescents if the glomerular
injury evolves into segmental or global scarring
o Such interposition gives rise to the appearance of
(sclerosis).
"split" basement membranes.
Edition)
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.
3.3 Renal Diseases 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
3.3.1Membranoproliferative Glomerulonephritis pathogenesis.
o C3NeF activity also occurs in some patients with a IGA NEPHROPATHY (BERGER DISEASE)
genetically determined disease, partial
lipodystrophy, some of whom develop dense-
deposit disease (type II MPGN).
o This form of glomerulonephritis is characterized by
the presence of prominent IgA deposits in the
mesangial regions, detected by
Clinical Course immunofluorescence microscopy.
o Few remissions occur spontaneously in either o Mild proteinuria is usually present, and the
type, and the disease follows a slowly progressive nephrotic syndrome may occasionally develop.
but unremitting course.
o Rarely, patients may present with rapidly
o Some patients develop numerous crescents and a progressive crescentic glomerulonephritis.
clinical picture of RPGN.
o Whereas IgA nephropathy is typically an isolated
o About 50% develop chronic renal failure within 10 renal disease, similar IgA deposits are present in a
years. systemic disorder of children, Henoch-Schönlein
purpura, to be discussed later, which has many
o Treatments with steroids, immunosuppressive overlapping features with IgA nephropathy.
agents, and antiplatelet drugs have not been
proved to be materially effective. There is a high o In addition, secondary IgA nephropathy occurs in
incidence of recurrence in transplant recipients, patients with liver and intestinal diseases, as
particularly in dense-deposit disease; dense discussed in the section on pathogenesis.
deposits may recur in 90% of such patients,
although renal failure in the allograft is much less
common.
Pathogenesis
Secondary MPGN
23
o IgA, the main immunoglobulin in mucosal o The mesangial widening may be the result of cell
secretions, is at low levels in normal serum, where proliferation, accumulation of matrix, or both.
it is present mostly in monomeric form, the
polymeric forms being catabolized in the liver. o Healing of the focal proliferative lesion may lead to
focal segmental sclerosis.
o In patients with IgA nephropathy, serum polymeric
IgA is increased, and circulating IgA-containing o The characteristic immunofluorescent picture is of
immune complexes are present in some patients. mesangial deposition of IgA often with C3 and
properdin and lesser amounts of IgG or IgM.
o However, it is clear that increased production of
IgA cannot itself cause this disease. 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.
Morphology
4. Identify the different diagnostic modalities for patients with
glomerulonephritis.
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 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 It should be noted, however, that there may be The tubules can be assessed for adjacency to one
some serologic overlap, with as many as 20% of another; separation can be the result of edema, tubular
patients with immune complex or anti-GBM dropout, or collagen deposition resulting from
glomerulonephritis also having at least low levels interstitial fibrosis. Interstitial fibrosis is an ominous
of circulating ANCA. sign of irreversibility and progression to renal failure.
(Harrison’s Principles of Internal Medicine 16th Edition) (Harrison’s Principles of Internal Medicine 17th Edition)
Each region of a renal biopsy is assessed separately. SOME CONTRA-INDICATIONS FOR A RENAL BIOPSY
IMMUNOLOGY Pattern?
Linear
Pattern?
1. Identity of abnormal materials in glomerulus.
Granular
Interpretation ?
2. Where is it?
Where?
Interpretation?
(Dr. Bigornia’s Lecture)
Immune complex deposition
27
5. Identify the different treatment modalities for acute sulbactam, or tazobactam. Other
glomerulonephritis. forms of bacterial resistance include
alteration of bacterial PBPs and
decreased permeability of cell wall
to penicillin.
Adult Dose 500 mg PO q6h
5.1 Antibiotics Therapy <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
Streptococcal Pharyngitis (Including Scarlet Fever) function impairment; bleeding
Contraindication disorder; congestive heart failure;
s cystic fibrosis; GI disease or
antibiotic-associated colitis;
mononucleosis
This is the most common disease produced by S. Probenecid may increase
pyogenes (group A b-hemolytic streptococcus). effectiveness by decreasing
clearance; tetracyclines are
Interactions
Penicillin-resistant isolates have yet to be observed for bacteriostatic, causing decrease in
S. pyogenes. effectiveness of penicillins when
administered concurrently
The preferred oral therapy is with penicillin V, 500 mg C - Fetal risk revealed in studies in
every 6 hours for 10 days. animals but not established or not
Pregnancy
studied in humans; may use if
benefits outweigh risk to fetus
Equally good results are produced by the administration
Precautions Caution in renal impairment
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.
(http://www.emedicine.com/emerg/topic219.htm)
Parenteral therapy is preferred if there are questions of
patient compliance. 5.2 Non-selective β-blocker with Cardioselective α-1 Blocker
Cardiac output is increased because of the positive The pharmacological effects of dobutamine are due to
inotropic and chronotropic effects of the drug in the direct interactions with α and β receptors; its actions do
face of diminished peripheral vascular resistance. not appear to result from release of norepinephrine
from sympathetic nerve endings, nor are they exerted
The cardiac effects of isoproterenol may lead to via dopaminergic receptors.
palpitations, sinus tachycardia, and more serious
arrhythmias; large doses of isoproterenol may cause
myocardial necrosis in animals. Although dobutamine originally was thought to be a
relatively selective β1 receptor agonist, it now is clear
that its pharmacological effects are complex.
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. Dobutamine possesses a center of asymmetry; both
enantiomeric forms are present in the racemic mixture
used clinically.
It prevents or relieves bronchoconstriction.
Alternatively, cardiac a1 receptors may contribute to Alterations in blood pressure or peripheral resistance
the inotropic effect. usually are minor, although some patients may have
marked increases in blood pressure or heart rate.
At equivalent inotropic doses, dobutamine enhances
automaticity of the sinus node to a lesser extent than Clinical evidence of longer-term efficacy remains
does isoproterenol; however, enhancement of uncertain. An infusion of dobutamine in combination
atrioventricular and intraventricular conduction is with echocardiography is useful in the noninvasive
similar for both drugs. assessment of patients with coronary artery disease
(Madu et al., 1994).
In animals, administration of dobutamine at a rate of
2.5 to 15 mg/kg per minute increases cardiac Stressing of the heart with dobutamine may reveal
contractility and cardiac output. cardiac abnormalities in carefully selected patients.
Total peripheral resistance is not greatly affected. Dobutamine has a half-life of about 2 minutes; the
major metabolites are conjugates of dobutamine and 3-
The relatively constant peripheral resistance O-methyldobutamine.
presumably reflects counterbalancing of a1 receptor-
mediated vasoconstriction and b2 receptor-mediated The onset of effect is rapid.
vasodilation (Ruffolo, 1987).
Consequently, a loading dose is not required, and
Heart rate increases only modestly when the rate of steady-state concentrations generally are achieved
administration of dobutamine is maintained at less than within 10 minutes of initiation of the infusion.
20 mg/kg per minute.
The rate of infusion required to increase cardiac output
After administration of b receptor antagonists, infusion typically is between 2.5 and 10 mg/kg per minute,
of dobutamine fails to increase cardiac output, but total although higher infusion rates occasionally are
peripheral resistance increases, confirming that required.
dobutamine has modest direct effects on a adrenergic
receptors in the vasculature. The rate and duration of the infusion are determined by
the clinical and hemodynamic responses of the patient.
Caution in impaired hepatic function; Also, in situ microperfusion of the loop of Henle and in
discontinue therapy if signs of liver vitro microperfusion of the CTAL indicate inhibition of
dysfunction; in elderly patients, transport by low concentrations of furosemide in the
Precautions
lower response rate and higher perfusate.
incidence of toxicity may be
observed Some inhibitors of Na+-K+-2Cl- symport may have
additional effects in the proximal tubule; however, the
significance of these effects is unclear.
(http://www.emedicine.com/emerg/topic219.htm)
It was thought initially that Cl- was transported by a
5.3 Loop Diuretics primary active electrogenic transporter in the luminal
membrane independent of Na+.
Diuretics acting predominantly at sites past the thick K+ channels in the luminal membrane (called ROMK)
ascending limb also have limited efficacy because only provide a conductive pathway for the apical recycling of
a small percentage of the filtered Na+ load reaches this cation, and basolateral Cl- channels (called CLC-Kb)
these more distal sites. provide a basolateral exit mechanism for Cl-.
In contrast, inhibitors of Na+-K+-2Cl-symport in the The luminal membranes of epithelial cells in the thick
thick ascending limb are highly efficacious, and for this ascending limb have a large conductive pathway
reason, they sometimes are called high-ceiling (channels) for K+; therefore, the apical membrane
diuretics. voltage is determined by the equilibrium potential for
K+ (EK) and is hyperpolarized.
The efficacy of inhibitors of Na+-K+-2Cl- symport in the
thick ascending limb of the loop of Henle is due to a In contrast, the basolateral membrane has a large
combination of two factors: (1) Approximately 25% of conductive pathway (channels) for Cl-, so the
the filtered Na+ load normally is reabsorbed by the basolateral membrane voltage is less negative than EK;
thick ascending limb, and (2) nephron segments past i.e., conductance for Cl- depolarizes the basolateral
the thick ascending limb do not possess the membrane.
reabsorptive capacity to rescue the flood of rejectate
exiting the thick ascending limb. 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
Chemistry interstitial space.
Only furosemide (LASIX), bumetanide (BUMEX), As the name implies, inhibitors of Na+-K+-2Cl- symport
ethacrynic acid (EDECRIN), and torsemide (DEMADEX) bind to the Na+-K+-2Cl- symporter in the thick
are available currently in the United States. Furosemide ascending limb and block its function, bringing salt
and bumetanide contain a sulfonamide moiety. transport in this segment of the nephron to a virtual
standstill.
Ethacrynic acid is a phenoxyacetic acid derivative and
torsemide is a sulfonylurea. 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.
Mechanism and Site of Action
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
Inhibitors of Na+-K+-2Cl- symport act primarily in the the dominant driving force for reabsorption of these
thick ascending limb. cations.
Micropuncture of the DCT demonstrates that loop Na+-K+-2Cl- symporters are an important family of
diuretics increase the delivery of solutes out of the loop transport molecules found in many secretory and
of Henle. absorbing epithelia.
31
Abolition of the transepithelial potential difference also Therefore, unlike carbonic anhydrase inhibitors, loop
results in marked increases in the excretion of Ca2+ diuretics do not decrease GFR by activating TGF.
and Mg2+.
Loop diuretics are powerful stimulators of renin release.
Some (e.g., furosemide) but not all (e.g., bumetanide)
sulfonamide-based loop diuretics have weak carbonic This effect is due to interference with NaCl transport by
anhydrase-inhibiting activity. the macula densa and, if volume depletion occurs, to
reflex activation of the sympathetic nervous system
Drugs with carbonic anhydrase-inhibiting activity and to stimulation of the intrarenal baroreceptor
increase the urinary excretion of HCO3 - and mechanism.
phosphate. The mechanism by which inhibition of
carbonic anhydrase increases phosphate excretion is Prostaglandins, particularly prostacyclin, may play an
not known. important role in mediating the renin-release response
to loop diuretics.
All inhibitors of Na+-K+-2Cl- symport increase the
urinary excretion of K+ and titratable acid.
By blocking active NaCl reabsorption in the thick Only in the inner ear, where alterations in the
ascending limb, inhibitors of Na+-K+-2Cl- symport electrolyte composition of endolymph may contribute to
interfere with a critical step in the mechanism that drug-induced ototoxicity, is this effect important
produces a hypertonic medullary interstitium. clinically.
Approximately 65% of furosemide is excreted Loop diuretics can cause ototoxicity that manifests as
unchanged in the urine, and the remainder is tinnitus, hearing impairment, deafness, vertigo, and a
conjugated to glucuronic acid in the kidney. sense of fullness in the ears.
Accordingly, in patients with renal, but not liver, Hearing impairment and deafness are usually, but not
disease, the elimination half-life of furosemide is always, reversible.
prolonged.
Ototoxicity occurs most frequently with rapid
In contrast, bumetanide and torsemide have significant intravenous administration and least frequently with
hepatic metabolism, so the elimination half-lives of oral administration.
these loop diuretics are prolonged by liver, but not
renal, disease. Ethacrynic acid appears to induce ototoxicity more
often than do other loop diuretics and should be used
Although the average oral availability of furosemide is only in patients who cannot tolerate the other loop
approximately 60%, oral availability of furosemide diuretics.
varies from 10% to 100%.
Loop diuretics also can cause hyperuricemia
In contrast, oral availabilities of bumetanide and (occasionally leading to gout) and hyperglycemia
torsemide are reliably high. Heart failure patients have (infrequently precipitating diabetes mellitus) and can
fewer hospitalizations and better quality of life with increase plasma levels of low-density lipoprotein (LDL)
torsemide than with furosemide perhaps because of the cholesterol and triglycerides while decreasing plasma
more reliable absorption of torsemide (Shankar and levels of high-density lipoprotein (HDL) cholesterol.
Brater, 2003).
Other adverse effects include skin rashes,
photosensitivity, paresthesias, bone marrow
As a class, loop diuretics have short elimination half-
depression, and gastrointestinal disturbances.
lives, and prolonged-release preparations are not
available. Consequently, often the dosing interval is too
short to maintain adequate levels of loop diuretics in Contraindications to the use of loop diuretics include
the tubular lumen. Note that torsemide has a longer severe Na+ and volume depletion, hypersensitivity to
t1/2 than other agents available in the United States. sulfonamides (for sulfonamide-based loop diuretics),
and anuria unresponsive to a trial dose of loop diuretic.
As the concentration of loop diuretic in the tubular
lumen declines, nephrons begin to avidly reabsorb Na+, Drug interactions may occur when loop diuretics are
which often nullifies the overall effect of the loop coadministered with (1) aminoglycosides (synergism of
diuretic on total-body Na+. ototoxicity caused by both drugs), (2) anticoagulants
(increased anticoagulant activity), (3) digitalis
glycosides (increased digitalis-induced arrhythmias), (4)
This phenomenon of "postdiuretic Na+ retention" can lithium (increased plasma levels of lithium), (5)
be overcome by restricting dietary Na+ intake or by propranolol (increased plasma levels of propranolol), (6)
more frequent administration of the loop diuretic sulfonylureas (hyperglycemia), (7) cisplatin (increased
(Ellison, 1999). 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
Toxicity, Adverse Effects, Contraindications, Drug diuretic activity of both drugs leading to profound
Interactions diuresis), and (11) amphotericin B (increased potential
for nephrotoxicity and toxicity and intensification of
electrolyte imbalance).
Increased Mg2+ and Ca2+ excretion may result in Diuretics are used widely for the treatment of
hypomagnesemia (a risk factor for cardiac arrhythmias) hypertension and controlled clinical trials
and hypocalcemia (rarely leading to tetany). demonstrating reduced morbidity and mortality have
been conducted with Na+-Cl- symport (thiazides and
Recent evidence suggests that loop diuretics should be thiazidelike diuretics) but not Na+-K+-2Cl- symport
avoided in postmenopausal osteopenic women, in inhibitors.
whom increased Ca2+ excretion may have deleterious
effects on bone metabolism.
33
(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.
35
Phosphoramide mustard is responsible for antitumor myocardial necrosis) may occur after high-dose therapy
effects, while acrolein causes hemorrhagic cystitis often with total doses above 200 mg/kg.
seen during therapy with cyclophosphamide.
The clinical spectrum of activity for cyclophosphamide
As mentioned above, cystitis can be reduced in is very broad.
intensity or prevented by the parenteral
coadministration of mesna. Mesna does not negate the It is an essential component of many effective drug
systemic antitumor activity of the drug. combinations for non-Hodgkin's lymphomas, ovarian
cancers, and solid tumors in children.
For routine clinical use, ample fluid intake is
recommended and vigorous intravenous hydration is Complete remissions and presumed cures have been
required during high-dose treatment. reported when cyclophosphamide was given as a single
agent for Burkitt's lymphoma.
Brisk hematuria in a patient receiving daily oral therapy
should lead to immediate drug discontinuation. It frequently is used in combination with methotrexate
(or doxorubicin) and fluorouracil as adjuvant therapy
Refractory bladder hemorrhage may require after surgery for carcinoma of the breast.
cystectomy for control of bleeding.
Because of its potent immunosuppressive properties,
cyclophosphamide has been used to prevent organ
The syndrome of inappropriate secretion of antidiuretic rejection after transplantation.
hormone has been observed in patients receiving
cyclophosphamide, usually at doses higher than 50
mg/kg. It has activity in nonneoplastic disorders associated
with altered immune reactivity, including Wegener's
granulomatosis, rheumatoid arthritis, and the nephrotic
It is important to be aware of the possibility of water syndrome.
intoxication, since these patients usually are vigorously
hydrated to prevent bladder toxicity.
Caution is advised when the drug is considered for use
in these conditions, not only because of its acute toxic
Pretreatment with CYP inducers such as phenobarbital effects but also because of its potential for inducing
enhances the rate of activation of the sterility, teratogenic effects, and leukemia.
azoxyphosphorenes but does not alter total exposure to
active metabolites over time and does not affect
toxicity or therapeutic activity in humans.
Immunosuppressants
Cyclophosphamide can be used in full doses in patients
with renal dysfunction, as it is eliminated by hepatic
metabolism.
Calcineurin Inhibitors
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. 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
Therapeutic Uses activation.
Recommended doses vary widely, and published Cyclosporine and tacrolimus do not act per se as
protocols for the dosage of cyclophosphamide and immunosuppressive agents.
other chemotherapeutic agents and for the method and
sequence of administration should be consulted. Instead, these drugs bind to an immunophilin
(cyclophilin for cyclosporine or FKBP-12 for tacrolimus),
As a single agent, a daily oral dose of 100 mg/m2 for 14 resulting in subsequent interaction with calcineurin to
days has been recommended as adjuvant therapy for block its phosphatase activity.
breast cancer, and for patients with lymphomas and
chronic lymphocytic leukemia.
Calcineurin-catalyzed dephosphorylation is required for
A higher dosage of 500 mg/m2 intravenously every 2 to movement of a component of the nuclear factor of
4 weeks in combination with other drugs often is activated T lymphocytes (NFAT) into the nucleus.
employed in the treatment of breast cancer and
lymphomas. NFAT, in turn, is required to induce a number of
cytokine genes, including that for interleukin-2 (IL-2), a
The neutrophil nadir of 500 to 1000 cells per mm3 prototypic T-cell growth and differentiation factor.
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 Cyclosporine
g/m2 over a 3- to 5-day period.
Because cyclosporine is lipophilic and highly Since SANDIMMUNE and NEORAL are not bioequivalent,
hydrophobic, it is formulated for clinical administration they cannot be used interchangeably without
using castor oil or other strategies to ensure supervision by a physician and monitoring of drug
solubilization. concentrations in plasma.
This complex binds to calcineurin, inhibiting Ca2+- High- and low-fat meals consumed within 30 minutes of
stimulated dephosphorylation of the cytosolic administration decrease the AUC by approximately 13%
component of NFAT. and the maximum concentration by 33%. This makes it
imperative to individualize dosage regimens for
When cytoplasmic NFAT is dephosphorylated, it outpatients.
translocates to the nucleus and complexes with nuclear
components required for complete T-cell activation, Cyclosporine is distributed extensively outside the
including transactivation of IL-2 and other lymphokine vascular compartment.
genes.
After intravenous dosing, the steady-state volume of
Calcineurin phosphatase activity is inhibited after distribution is reportedly as high as 3 to 5 L/kg in solid-
physical interaction with the cyclosporine/cyclophilin organ transplant recipients.
complex.
Cyclosporine generally is recognized as the agent that Cyclophosphamide is used for etiology-dependent
ushered in the modern era of organ transplantation, treatment of acute glomerulonephritis due to Wegener
increasing the rates of early engraftment, extending granulomatosis.
kidney graft survival, and making cardiac and liver
transplantation possible.
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 • These effects induce T lymphocyte and macrophage
glomerulonephritis best correlates histologically with the infiltrates in the interstitial spaces along with fibrosis and
appearance of tubulointerstitial nephritis rather than with tubular atrophy.
the type of inciting glomerular injury.
• Tubules disappear following direct damage to their
• Loss of renal function due to interstitial damage can be basement membranes, leading to decondensation and
explained hypothetically by several mechanisms. epithelial-mesenchymal transitions forming more interstitial
fibroblasts at the site of injury.
• The simplest explanation is that urine flow is impeded by
tubular obstruction as a result of interstitial inflammation
and fibrosis.
• Transforming growth factor (TGF-), fibroblast growth factor
2, and platelet-derived growth factor (PDGF) are particularly
active in this transition.
• Thus, obstruction of the tubules with debris or by extrinsic
compression results in aglomerular nephrons.
• With persistent nephritis, fibroblasts multiply and lay down
tenascin and a fibronectin scaffold for the polymerization of
• A second mechanism suggests that interstitial changes, new interstitial collagens I/III.
including interstitial edema or fibrosis, alter tubular and
vascular architecture and thereby compromise the normal
• These events form scar tissue through a process called
tubular transport of solutes and water from tubular lumen to
vascular space. fibrogenesis.
• About 0.1% of children and 25% of adults develop chronic • Urinary abnormalities resolve at various times after onset.
kidney failure.
Proteinuria may disappear within the first 2-3 months or
• The prognosis for people with rapidly progressive may decrease slowly over 6 months. Intermittent or
glomerulonephritis depends on the severity of glomerular postural proteinuria has been noted for 1-2 years after
scarring and whether the underlying disease, such as onset.
infection, can be cured.
• 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.
• 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.
(http://www.merck.com/mmhe/sec11/ch144/ch144b.html)
(http://www.emedicine.com/emerg/topic219.htm)