CORE CURRICULUM IN NEPHROLOGY
An Outline of Essential Topics in Glomerular Pathophysiology,
Diagnosis, and Treatment for Nephrology Trainees
Sharon G. Adler, MD, and David J. Salant, MD
Introduction, p. 215
GLOMERULAR STRUCTURE AND FUNCTION
K NOWLEDGE OF the structure and func-
tion of the glomerulus aids in understand-
ing the clinical manifestations of glomerular dis-
eases. Glomerular capillaries are efficient filters
that selectively retard the permeation of macro-
molecular plasma proteins but allow the free
filtration of water (at the rate of 150 to 180
L/day), electrolytes, and other small solutes such
as urea and creatinine. This is attributable to
certain characteristics of glomerular capillaries,
including a high transmembrane pressure gradi-
ent that serves as the driving force for filtration
and a capillary wall that is highly porous to water
and small solutes, but that restricts the passage of
large molecules on the basis of their molecular
size and charge.
Composition of the Capillary Wall
● Fenestrated endothelial cells coated with
podocalyxin, a polyanionic glycoprotein rich
in sialic acid, surround glomerular capillar-
ies; they normally form a nonthrombogenic
surface and express von Willebrand’s factor
and receptors for vascular endothelial growth
factor (VEGF); can be induced to express
leukocyte adhesion molecules;
● Visceral epithelial cells (podocytes) have
prominent foot processes that are attached
to the glomerular basement membrane
(GBM) by ␣3␤1 integrins and dystrogly-
cans and are also coated with podocalyxin.
Adjacent foot processes are separated by
gaps that form the filtration pathway (filtra-
tion slits) and are bridged by a zipper-like
slit-diaphragm. The slit-diaphragms consti-
tute the final barrier to macromolecular per-
meation and contain nephrin, the immuno-
globulin (Ig)-like transmembrane protein that
is mutated in congenital nephrotic syn-
drome. Additional proteins anchor the slit-
American Journal of Kidney Diseases, Vol 42, No 2 (August), 2003: pp 395-418
diaphragms to the podocyte cytoskeleton
and in the plasma membrane. Among these
are podocin, the protein mutated in steroid
resistant nephrotic syndrome, and ␣-actinin,
the protein mutated in a form of hereditary
focal glomerulosclerosis.
● Mesangial cells occupy the axial region
between glomerular capillary loops; they
synthesize the mesangial matrix and share
several features with smooth muscle cells
and macrophages. They also elaborate and
have receptors for inflammatory mediators
and growth factors and contract in response
to vasoactive stimuli, thereby regulating glo-
merular capillary surface area. A small popu-
lation of tissue monocytes/macrophages also
occupies the normal mesangium.
● The GBM comprises a meshwork of ␣3, ␣4,
and ␣5 type IV collagen fibrils that provide
tensile strength embedded in a glycoprotein
matrix of laminin, entactin/nidogen, and
heparan-sulfate proteoglycans. Laminin
serves as the predominant cell attachment
ligand for podocyte and endothelial inte-
grins, and the heparan-sulfate proteoglycans
confer an overall anionic charge.
● The mesangial matrix is made up of ␣1 and
␣2 type IV collagen fibrils, laminin, tenas-
cin, and chondroitin sulfate proteoglycans.
The result of this composition is that the
capillary wall is rich in negatively charged resi-
dues and the permeation of plasma proteins from
capillary lumen to urinary space is restricted on
From the Department of Medicine, Harbor-UCLA Medi-
cal Center, Torrance, CA; and the Department of Medicine,
Evans Biomedical Research Center, Boston University Medi-
cal Center, Boston, MA.
Address reprint requests to Sharon G. Adler, MD, Division
of Nephrology and Hypertension, Harbor-UCLA Medical
Center, 1124 W Carson St, Torrance, CA 90502. E-mail:
sadler@rei.edu
© 2003 by the National Kidney Foundation, Inc.
0272-6386/03/4202-0044$30.00/0
doi:10.1016/S0272-6386(03)00692-9
395
396 ADLER AND SALANT

Table 1. Definition of Clinical Syndromes

Acute Nephritic Syndrome (ANS) Nephrotic Syndrome (NS) Rapidly Progressive Glomerulonephritis (RPGN)

Acute onset of: Insidious onset of:

● Hematuria—macroscopic or ● Proteinuria—severe ● Rapidly progressive renal failure
microscopic (RBC casts) ● Edema—severe (anasarca) ● Hematuria with RBC casts
● Hypertension ● Hypoalbuminemia ● Oliguria—variable
● Oliguria ● Hyperlipidemia ● Hypertension—unusual
● Edema—moderate ● Lipiduria ● Proteinuria—variable
● Proteinuria—mild to moderate ● Hypercoagulability
● Azotemia

the basis of molecular charge as well as molecu- Clinical Syndromes Associated With
lar size. In effect, negatively charged macromol- Glomerular Diseases
ecules encounter narrower “pores” than do posi- ● Isolated hematuria—Microscopic or macro-
tively charged molecules of the same size. Thus scopic (red blood cell [RBC] casts)
albumin, which would be freely filtered on the ● Acute nephritic syndrome
basis of its size (69,000 daltons), is retarded by ● Rapidly progressive glomerulonephritis
virtue of its overall negative charge.
(RPGN)
Determinants of Glomerular Filtration Rate ● Asymptomatic proteinuria

● Transmembrane hydrostatic pressure (⌬P) ● Nephrotic syndrome

● Filtration surface area (S) ● Combinations of above

● Hydraulic conductivity of the capillary wall
(K)
● inversely proportional to “pore” length
(GBM thickness)
● proportional to “pore” density (filtration
slit frequency)
ie, GFR ⫽ ⌬P ⫻ Kf (K ⫻ S).
Thus, glomerular diseases that cause occlu-
sion or obliteration of glomerular capillary loops
or reduce hydraulic conductivity of the glomeru-
lar capillary wall will cause a fall in glomerular
filtration rate (GFR), whereas alterations in size-
and/or charge-selectivity will cause proteinuria.
Definition of Clinical Syndromes
See Table 1.
Clinical-Pathological Correlations
See Table 2.
Diseases Presenting With Proteinuria or
Nephrotic Syndrome
Exclude transient or “benign” causes of pro-
teinuria—eg, exercise-induced, febrile, conges-
tive heart failure, orthostatic (postural) protein-
uria.

Table 2. Clinical-Pathological Correlations

Histology Associated With Histological Lesions Associated Histological Lesions Associated

Hematuric Syndromes With Proteinuric Syndromes With Both Nephritic
(Isolated Hematuria, ANS, or RPGN) (Isolated Proteinuria NS) and Nephrotic Features

● Mesangial proliferative GN (eg, IgA ● Minimal change disease ● Membranoproliferative GN

nephropathy)
● Focal and segmental GN (eg, lupus
nephritis WHO III, infective
endocarditis)
● Diffuse proliferative GN (eg, post-
streptococcal GN, lupus nephritis
WHO IV)
● Crescentic GN (eg, anti-GBM
nephritis, pauci-immune nephritis)
● Focal and segmental ● Fibrillary glomerulopathies
glomerulosclerosis ● Hereditary nephritis (Alport syndrome)
● Collapsing glomerulopathy ● Some cases of mesangial, focal, and
● Membranous nephropathy diffuse proliferative GN
● Diabetic glomerulosclerosis
● Amyloidosis
● Light-chain deposition disease
CORE CURRICULUM
Table 3. Principal Secondary Causes of Nephrotic Syndrome
Diabetic glomerulosclerosis
Dysproteinemias:
● Amyloid nephropathy
● Light-chain-deposition disease
Membranous nephropathy:
● Membranous lupus nephritis
● Hepatitis B
● Gold, penicillamine, NSAIDs
● Occult carcinoma
● De novo in renal transplants
Membranoproliferative GN:
● Bacterial infections (eg, endocarditis)
● Hepatitis C ⫾ mixed cryoglobulinemia
● Non-Hodgkin’s lymphoma
Pathophysiology of Nephrotic Syndrome
● Hypoalbuminemia from urinary loss and
increased tubular catabolism of albumin
● Edema from avid sodium and water reten-
tion by the kidney and decreased plasma
oncotic pressure in systemic capillaries due
to hypoalbuminemia
● Hyperlipidemia from increased hepatic syn-
thesis of lipoproteins
● Hypercoagulability from increased hepatic
synthesis of coagulation factors and loss of
regulatory factors (anti-thrombin III, pro-
tein C and protein S) in the urine
Clinical Consequences of Nephrotic Syndrome
● Predisposition to infection (especially gram
positive) from low serum IgG levels
● Increased risk of thromboembolism and re-
nal vein thrombosis
● Predisposition to hypovolemic shock
● Possible predisposition to atherosclerotic
vascular disease
● Urinary loss of hormone-binding proteins
(eg, thyroid, vitamin D, cortisol)—effects
uncertain
General Principles of Management of
Proteinuria and Nephrotic Syndrome
● Salt restriction
● Angiotensin converting enzyme (ACE) in-
hibitor or angiotensin II receptor blocker
397
Collapsing glomerulopathy:
● HIV-associated nephropathy
Minimal change-like disease:
● Hodgkin’s lymphoma
● Nonsteroidal anti-inflammatory drug
(NSAID) other hypersensitivity reactions
Focal glomerulosclerosis:
● Longstanding nephron loss
●Sickle cell disease
● Reflux nephropathy
● Analgesic nephropathy
● Healed proliferative GN
● Intravenous heroin abuse
Immune-mediated:
● Diffuse proliferative lupus nephritis
● Henoch-Schönlein purpura
Pre-eclamptic toxemia
(ARB) to reduce proteinuria and retard pro-
gression
● Judicious use of diuretics to control edema
and for synergistic action with ACE inhibi-
tors or ARBs
● Lipid lowering agent—Benefit as yet un-
proven in clinical studies, but statins are
safe in nephrotic syndrome with monitoring
of muscle and liver enzymes and use is
prudent given increased rate of coronary
artery disease in nephrotic patients
● Hormone replacement is generally unneces-
sary because free hormone levels are nor-
mal—calcitriol is occasionally indicated if
ionized calcium is reduced
● Patients on extended corticosteroid
therapy—monitor bone density and supple-
ment with calcium carbonate and calcitriol.
Bisphosphonates prevent steroid-induced
bone loss in other settings but their efficacy
and safety in nephrotic syndrome are not
established
Principal Secondary Causes of Nephrotic
Syndrome
Nephrotic syndrome may be due to a primary
(idiopathic) glomerular disease or secondary to one
of several other diseases or toxic agents. Some of
the secondary causes of nephrotic syndrome have
the same clinical and histological features as the
primary renal diseases (see Table 3).
398
REFERENCES
1. Tryggvason K, Wartiovaara J: Molecular basis of glo-
merular permselectivity. Curr Opin Nephrol Hypertens 10:
543-549, 2001
2. Kerjaschki D: Caught flat-footed: Podocyte damage
and the molecular bases of focal glomerulosclerosis. J Clin
Invest 108:1583-1587, 2001
3. Maddux DA, Brenner BM: Glomerular ultrafiltration,
in Brenner BM (ed): Brenner and Rector’s The Kidney (ed
6). Philadelphia, PA, Saunders, 2000, pp 319-374
4. Anderson S, Tank JE, Brenner BM: Renal and sys-
temic manifestations of glomerular disease, in Brenner BM
(ed): Brenner and Rector’s The Kidney (ed 6). Philadelphia,
PA, Saunders, 2000, pp 1871-1900
Minimal Change Disease
Pathogenesis
● Unknown; appears to be a primary disorder
of podocytes; may be linked to T-cell–
mediated immunity
Clinical and Laboratory Features
● Steroid-sensitive nephrotic syndrome
● Main cause of nephrotic syndrome in children
● Renal function and blood pressure (BP)
usually normal
● No known serological abnormalities
Course and Treatment
● ⬎80% respond to corticosteroid or immuno-
suppressive treatment
● Relapse is common (⬎50%)
● Cyclophosphamide or cyclosporin is effec-
tive in steroid-dependent and frequently re-
lapsing cases
● Does not progress to chronic renal failure
Secondary Causes
● Hodgkin’s lymphoma, NSAIDs, other drugs
Histopathology (Am J Kidney Dis Vol. 33, No.
3, March 1999, Atlas)
● Light microscopy (LM): Glomeruli normal
● Immunofluorescence (IF): Negative
● Electron microscopy (EM): Diffuse efface-
ment of podocyte foot processes.
REFERENCES
1. Rifkin IR, Salant DJ: Immune-mediated glomerulopa-
thies, in Humes HD (ed): Kelley’s Textbook of Internal
Medicine (ed 4). Philadelphia, PA, Lippincott Williams and
Wilkins, 2000, pp 1191-1208
2. Ali AA, Wilson E, Moorhead JF, et al: Minimal-
ADLER AND SALANT
change glomerular nephritis. Normal kidneys in an abnor-
mal environment? Transplantation 58:849-852, 1994
3. Nolasco F, Cameron JS, Heywood EF, Hicks J, Ogg C,
Williams DG: Adult-onset minimal change nephrotic syn-
drome: A long-term follow-up. Kidney Int 29:1215-1223,
1986
4. Dember LM, Salant DJ: Minimal change disease, in
Brady HR, Wilcox CS (ed): Therapy in Nephrology and
Hypertension. Philadelphia, PA, Saunders, 2003, pp 207-
221
Focal and Segmental Glomerulosclerosis
(FSGS)
Pathogenesis
● Unknown in idiopathic FSGS; hereditary
cases point to the podocyte as the primary
site of injury; a soluble circulating “perme-
ability-inducing” factor seems to account
for cases that recur after transplantation
● By analogy to experimental models, glomer-
ular hypertension appears to underlie focal
podocyte injury in secondary FSGS
Clinical and Laboratory Features
● Idiopathic FSGS—Common cause of adult
nephrotic syndrome, especially among
Blacks; steroid-resistant NS; may be famil-
ial; often progressive and accompanied by
hypertension; and may recur after renal
transplantation
● Secondary FSGS—Tends to occur after loss
of nephron mass from other diseases, eg,
vesico-ureteric reflux, sickle cell and analge-
sic nephropathies, renal ablation in early
childhood, or “healed” proliferative GN;
also in morbid obesity; often presents as
asymptomatic proteinuria
Course and Treatment
● Idiopathic FSGS—Up to 40% respond to
prolonged treatment with corticosteroids;
studies of cyclosporin and other agents are
ongoing; plasmapheresis is often effective
for recurrent FSGS posttransplant
● Secondary FSGS—Proteinuria often im-
proves with ACE inhibitors or ARBs.
Histopathology (Am J Kidney Dis Vol. 33, No.
4, April 1999, Atlas)
● LM: Because of the focal nature, glomeruli
may appear normal in early disease; later
lesions show segmental areas of sclerosis
CORE CURRICULUM
and hyalinosis of the glomerular tuft, expan-
sion of mesangial matrix, and interstitial
fibrosis with tubular atrophy
● IF: Negative except for IgM and C3 in
sclerotic lesions
● EM: Idiopathic FSGS: diffuse effacement
of foot processes and degeneration of podo-
cytes; secondary FSGS—patchy effacement
of podocyte foot processes
REFERENCES
1. D’Agati V: The many masks of focal segmental glomer-
ulosclerosis. Kidney Int 46:1223-1241, 1994
2. Abbott KC, Sawyers ES, Oliver JD 3rd, et al: Graft
loss due to recurrent focal segmental glomerulosclerosis in
renal transplant recipients in the United States. Am J Kidney
Dis 37:366-73, 2001
3. Savin VJ, Sharma R, Sharma M, et al: Circulating
factor associated with increased glomerular permeability to
albumin in recurrent focal segmental glomerulosclerosis.
N Engl J Med 334:878-883, 1996
4. Cattran DC, Rao P: Long-term outcome in children
and adults with classic focal segmental glomerulosclerosis.
Am J Kidney Dis 32:72-79, 1998
5. Cattran DC, Appel GB, Hebert LA, et al: A random-
ized trial of cyclosporine in patients with steroid-resistant
focal segmental glomerulosclerosis. North America Ne-
phrotic Syndrome Study Group. Kidney Int 56:2220-2226,
1999
Collapsing Glomerulopathy (CG)
Pathogenesis
● Most cases are associated with human immu-
nodeficiency virus (HIV) infection; a simi-
lar lesion in a murine transgenic model of
HIV-associated nephropathy (HIVAN) and
viral detection studies suggest that HIV in-
fects and injures glomerular epithelial cells
despite the lack of known HIV receptors
● The cause of idiopathic CG is unknown, but
its similarity to HIVAN suggests the possi-
bility of other viral infections such as parvo-
virus; there may be an association with
pamidronate therapy
Clinical and Laboratory Features
● Presents with explosive onset of massive
proteinuria, severe hypoalbuminemia, and
rapidly deteriorating renal function; BP may
be normal
● Most prevalent in black patients
● CD4 count is frequently low on presentation
of HIVAN
399
● Clues to diagnosis include large echogenic
kidneys and very broad waxy urinary casts
Course and Treatment
● The majority of patients progress to end-
stage renal failure within 13 months; treat-
ment with steroids and immunosuppres-
sives is generally ineffective, although rare
cases of idiopathic CG may undergo sponta-
neous remission and there are some re-
ported cases of steroid-associated remis-
sion; ACE inhibitors may reduce proteinuria
and slow progression
● The incidence of HIVAN may have de-
clined since introduction of highly active
antiretroviral treatment (HAART) and
HAART plus prednisone may slow the pro-
gression of established HIVAN
Histopathology (Am J Kidney Dis Vol. 36, No.
3, September 2000, Atlas)
● LM: Focal and segmental glomerulosclero-
sis with collapse of the glomerular tufts,
wrinkling of the GBM, and visceral epithe-
lial cell hyperplasia and severe microcystic
changes of the tubules with interstitial fibro-
sis
● IF: Negative except for IgM and C3 in
sclerotic lesions
● EM: Effacement of podocyte foot processes
and degeneration of podocytes; tubulo-
reticular structures in glomerular endothe-
lial cells (especially in HIVAN)
REFERENCES
1. Detwiler RK, Falk RJ, Hogan SL, Jennette JC: Collaps-
ing glomerulopathy: A clinically and pathologically distinct
variant of focal segmental glomerulosclerosis. Kidney Int
45:1416-1424, 1994
2. Laurinavicius A, Hurwitz S, Rennke HG: Collapsing
glomerulopathy in HIV and non-HIV patients: A clinicopatho-
logical and follow-up study. Kidney Int 56:2203-2213, 1999
3. Valeri A, Barisoni L, Appel GB, Seigle R, D’Agati V:
Idiopathic collapsing focal segmental glomerulosclerosis: A
clinicopathologic study. Kidney Int 50:1734-1746, 1996
4. Ross MJ, Klotman PE: Recent progress in HIV-
associated nephropathy. J Am Soc Nephrol 13:2997-3004,
2002
5. Marras D, Bruggeman LA, Gao F, et al: Replication
and compartmentalization of HIV-1 in kidney epithelium of
patients with HIV-associated nephropathy. Nat Med 8:522-
526, 2002
400
Membranous Nephropathy (MN)
Pathogenesis
● Autoimmune disease due to antibodies di-
rected at an unknown podocyte protein; a
rare case of neonatal MN due to allosensiti-
zation of the mother to neutral endopepti-
dase indicates that antigen(s) on the soles of
podocyte foot processes is a likely target in
human MN, as in Heymann nephritis in rats
● By analogy to experimental models, anti-
body-induced assembly of the membrane
attack complex of complement causes podo-
cyte injury and production of new GBM
material around immune deposits shed from
the podocyte cell surface
Clinical and Laboratory Features
● Commonest cause of idiopathic NS in adult
Caucasians (FSGS is more common in Afri-
can Americans)
● Peak incidence 4th to 6th decades; male:
female 2-3:1
● Most present with nephrotic syndrome, the
rest with asymptomatic proteinuria
● Glomerular filtration rate (GFR) and blood
pressure (BP) are often normal on initial
presentation but hypertension develops in
about 30% cases; microscopic hematuria
may be present
● No serological abnormalities
● Some cases present with thromboembolic
complications
Course and Treatment
● Spontaneous remission (40%); progressive
renal failure (30%); persistent proteinuria
with variable renal dysfunction (30%)
● Risk factors for progression: male gender,
severe proteinuria (⬎10 g/24 h), hyperten-
sion, and azotemia, tubulointerstital fibro-
sis, and glomerulosclerosis
● ACE inhibitor or ARB as tolerated to lower
BP to 125/75 and reduce proteinuria, lipid-
lowering agent, and diuretic as tolerated for
control of anasarca
● Cytotoxic agents and prednisone are indi-
cated for progressive cases and those with
symptomatic nephrotic syndrome at risk for
ADLER AND SALANT
progression; other immunosuppressive
agents are under investigation
● May recur or occur de novo posttransplant
Histopathology (Am J Kidney Dis Vol. 31, No.
3, March 1998, Atlas)
● LM: The cortex and glomeruli may be nor-
mal in early MN; later, the GBM is thick-
ened and the capillary wall appears more
rigid than normal; in advanced cases, the
capillary wall is with spikes of GBM extend-
ing between and around subepithelial depos-
its. Advanced glomerular lesions are associ-
ated with tubular atrophy and interstitial
fibrosis
● IF: Granular glomerular capillary wall de-
posits of IgG ⫾ C3 are characteristic even if
light microscopy is normal
● EM: Subepithelial electron dense deposits
along the capillary loops with effacement of
overlying foot processes. With advancing
disease, new GBM material is laid down at
the sides of and around the deposits. Clues
to a secondary form of MN include endothe-
lial cell tubulo-reticular structures (lupus
MN) and mesangial deposits (hepatitis B-
associated, lupus MN)
REFERENCES
1. Cattran DC: Idiopathic membranous glomerulonephri-
tis. Kidney Int 59:1983-1994, 2001
2. Debiec H, Guigonis V, Mougenot B, et al: Antenatal
membranous glomerulonephritis due to anti-neutral endopep-
tidase antibodies. N Engl J Med 346:2053-2060, 2002
3. Schieppati A, Mosconi L, Perna A, et al: Prognosis of
untreated patients with idiopathic membranous nephropathy.
N Engl J Med 329:85-89, 1993
4. Ponticelli C, Zucchelli P, Passerini P, et al: A 10-year
follow-up of a randomized study with methylprednisolone
and chlorambucil in membranous nephropathy. Kidney Int
48:1600-1604, 1995
Dysproteinemias
Amyloid Nephropathy
Pathogenesis
● Glomerular, renal vascular, and interstitial
deposition of beta-pleated sheets of amyloid
fibrils occurs in both primary (AL) and
secondary (AA) forms of amyloidosis
● AL amyloid—Monoclonal Ig light chains
(usually ␭) produced by an abnormal clone
of plasma cells
CORE CURRICULUM
● AA amyloid—Overproduction and proteol-
ysis of serum AA protein, an acute-phase
reactant, in chronic inflammatory states (eg,
rheumatoid arthritis, juvenile rheumatoid ar-
thritis, inflammatory bowel disease, familial
Mediterranean fever [FMF], tuberculosis,
chronic sepsis)
Clinical and Laboratory Features
● Renal manifestations are the same in AL
and AA amyloidosis
● Severe nephrotic syndrome with progres-
sive renal failure
● Multiorgan involvement is common, includ-
ing cardiac, gastrointestinal, cutaneous, au-
tonomic and peripheral nerve disease
● Diagnosis is made by finding Congo red-
positive material in affected tissues includ-
ing abdominal fat pad aspirates (especially
useful in AL amyloidosis)
● Monoclonal light chains are found in the
urine in AL amyloidosis
Course and Treatment
● Five-year survival is ⬍20% even with dialy-
sis; cardiac disease confers the gravest prog-
nosis
● Intensive treatment of AL amyloidosis with
melphalan and prednisone ⫾ autologous
stem cell replacement may induce hemato-
logical remission and halt progression in
some cases
● Treatment of AA amyloidosis is limited to
controlling inflammation or chronic infec-
tion, including colchicine for FMF; experi-
mental therapies are directed at disrupting
fibril formation
Histopathology (Am J Kidney Dis Vol. 32, No.
5, November 1998, Atlas)
● LM: Pale acellular eosinophilic material
infiltrates mesangial areas and peripheral
capillary loops; arterioles, small arteries,
and peritubular interstitium may also be
involved; apple green birefringence of
Congo red-stained sections under polarized
light is diagnostic of amyloid
● EM: Randomly oriented fibrils of 10- to
12-nm diameter replace the mesangium and
GBM
401
REFERENCES
1. Falk RH, Skinner M: The systemic amyloidoses: An
overview. Adv Intern Med 45:107-137, 2000
2. Gertz MA, Lacy MQ, Dispenzieri A: Immunoglobulin
light chain amyloidosis and the kidney. Kidney Int 61:1-9,
2002
3. Ronco PM, Aucouturier P, Moulin B: Renal amyloid-
osis and glomerular diseases with monoclonal immuno-
globuli deposition, in Johnson RJ, Feehally J (eds): Compre-
hensive Clinical Nephrology London, England, Mosby, 2000,
31.1-31.14
4. Dember LM, Sanchorawala V, Seldin DC, et al: Effect
of dose-intensive intravenous melphalan and autologous
blood stem-cell transplantation on AL amyloidosis-associ-
ated renal disease. Ann Intern Med 134:746-753, 2001
Light Chain Deposition Disease (LCDD)
Pathogenesis
● Systemic disease due to tissue deposition of
monoclonal Ig light chains (most often ␬ or
occasionally heavy chains)
● Overt myeloma may be present or develop
over time, but the absence of a monoclonal
spike on serum or urine electrophoresis or
an increase in bone marrow plasma cells is
still consistent with LCDD
● It is unclear why some light chains have a
predilection for tissue deposition rather than
filtration and tubular cast formation as in
myeloma kidney
Clinical and Laboratory Features
● May present with asymptomatic albumin-
uria ⫾ renal insufficiency or with nephrotic
syndrome
● Albuminuria in a patient with myeloma indi-
cates either LCDD or development of amy-
loidosis
● Other organs may be affected as in AL
amyloidosis
Course and Treatment
● Progressive renal failure is the rule
● Treatment as for myeloma with melphalan
and prednisone may prevent deterioration in
renal function in some patients with mild
azotemia but is associated with high morbid-
ity
402
Histopathology (Am J Kidney Dis Vol. 32, No.
6, December 1998, Atlas)
● LM: Nodular glomerulosclerosis indistin-
guishable from diabetic nephropathy; Congo
red stain is negative
● IF: Glomerular capillary wall ⫾ mesangial
staining for a monoclonal ␬ or ␭ light chain
is key to the diagnosis
● EM: Amorphous, granular subendothelial,
mesangial and tubular basement membrane
deposits without fibrils
REFERENCES
1. Lin J, Markowitz GS, Valeri AM, et al: Renal monoclo-
nal immunoglobulin deposition disease: The disease spec-
trum. J Am Soc Nephrol 12:1482-1492, 2001
2. Cogne M, Preud’Homme J-L, Bauwens M, Touchard
G, Aucouturier P: Structure of monoclonal kappa chain of
the VkIV subgroup in the kidney and plasma cells in light
chain deposition disease. J Clin Invest 87:2186-2190, 1991
3. Buxbaum JN, Chuba JV, Hellman GC, Solomon A,
Gallo GR: Monoclonal immunoglobulin deposition disease:
Light chain and light and heavy chain deposition diseases
and their relation to light chain amyloidosis. Clinical fea-
tures, immunopathology, and molecular analysis. Ann Intern
Med 112:455-464, 1990
Fibrillary and Immunotactoid
Glomerulopathies
Pathogenesis
● Fibrillary glomerulopathy (FGN) is due to
the deposition of polyclonal Ig that forms
organized, Congo red-negative fibrils; the
cause is unknown
● Immunotactoid glomerulopathy (ITGN) is
most often due to the deposition of monoclo-
nal Ig that forms Condo red-negative micro-
tubular structures and may be associated
with a monoclonal gammopathy or lympho-
proliferative disease
Clinical and Laboratory Features
● The clinical presentation of FGN and ITGN
is the same with variable amounts of protein-
uria, hematuria, hypertension, and more or
less rapidly progressive renal failure
● Most patients have heavy proteinuria with
nephrotic syndrome in about 60%; some
have a more nephritic presentation
● There are no consistent abnormalities in
serum complement, autoantibodies, anti-
viral titers, or cryoglobulins in either FGN
or ITGN
ADLER AND SALANT
● ITGN may be associated with chronic lym-
phocytic leukemia or non-Hodgkin’s lym-
phoma; IgG or IgM paraproteins of the
same isotype are found in the serum and
renal tissue in most cases of ITGN but not in
FGN
Course and Treatment
● FGN and ITGN cause progressive renal
failure; however, those cases of ITGN with
a lymphoproliferative disease may respond
to chemotherapy
Histopathology (Am J Kidney Dis Vol. 33, No.
2, February 1999, Atlas)
● LM: The morphology is similar in FGN and
ITGN, with mild to severe mesangial prolif-
eration and a membranoproliferative pattern
being most common; crescents are present
in some cases; Congo red stain is negative
● IF: Strongly positive granular mesangial
and capillary wall staining for IgG (espe-
cially IgG4 in FGN); monoclonality is docu-
mented in ITGN by positive staining for ␬
or ␭ light chains
● EM: Randomly arranged fibrils in mesan-
gial, intramembranous, subepithelial, and/or
subendothelial locations; the size of the
fibrils in FGN resemble those in amyloid
but are generally larger (12 to 15 nm);
however, the distinction is made by the
negative Congo red staining. In ITGN the
fibrils assume a microtubular structure
REFERENCES
1. Korbet SM, Schwartz MM, Lewis EJ: Current con-
cepts in renal pathology. The fibrillary glomerulopathies.
Am J Kidney Dis 23:751-765, 1994
2. Bridoux F, Hugue V, Coldefy O, et al: Fibrillary
glomerulonephritis and immunotactoid (microtubular) glo-
merulopathy are associated with distinct immunologic fea-
tures. Kidney Int 62:1764-1775, 2002
Hereditary Nephropathies
Alport Syndrome and Thin Basement Membrane
Disease
Pathogenesis
● Alport syndrome (AS) is X-linked in ap-
proximately 80% of cases; mutations of the
gene for ␣5 type IV collagen (COL4A5)
lead to defective assembly of the GBM in
CORE CURRICULUM
males (including lack of incorporation of a3
and a4 type IV collagen); eventually the
fragile GBM degenerates; female carriers
have thin GBMs
● Homozygous autosomal recessive muta-
tions of the genes for ␣3 (COL4A3) or ␣4
(COL4A4) type IV collagen on chromo-
some 2 cause AS in males and females
equally; mutation of the gene on one allele
causes thin basement membrane disease
● Benign familial hematuria most often is due
to thin basement membrane disease result-
ing from the heterozygous mutation of one
allele of COL4A3 or COL4A4
Clinical and Laboratory Features
● In X-linked AS, microscopic hematuria is
usually present in affected males and female
carriers at or shortly after birth; severe pro-
teinuria ⫾ nephrotic syndrome, hyperten-
sion, and progressive renal failure develop
during adolescence in males but may be
delayed into adulthood; most females retain
normal renal function despite persistent he-
maturia
● The clinical features in autosomal recessive
AS are the same as in X-linked disease,
except that females are equally affected
● Extrarenal manifestations including sensori-
neural hearing loss and/or ocular abnormali-
ties may be present in either X-linked or
autosomal AS; rarely, esophageal leiomyo-
mas are found in X-linked AS
● Diagnosis depends on clinical features, fam-
ily history, screening family members for
hematuria, or classical renal biopsy find-
ings; immunofluorescence of skin biopsy
for ␣5 type IV collagen may be helpful
● Genetic testing is presently in limited use
due to the variability in genetic mutations,
but may be indicated in certain circum-
stances, eg, to exclude the carrier state in an
asymptomatic potential kidney donor
● Most patients with thin basement membrane
disease remain asymptomatic except for mi-
croscopic and occasional episodes of gross
hematuria; however, as with female carriers
of X-linked AS, proteinuria, hypertension,
and renal insufficiency may occur
403
Course and Treatment
● End-stage renal disease (ESRD) usually oc-
curs in males with AS in their late teens to
mid-30s but may be delayed into middle age
● There is no proven benefit of any therapy in
AS, but treatment with an ACE inhibitor or
ARB would seem prudent. A small propor-
tion of patients develop severe anti-GBM
nephritis after renal transplantation due to
allosensitization to the type IV collagen
isoform missing from their own tissues and
present in the allograft; plasmapheresis and
cytotoxic agents are variably effective in
such cases
Histopathology of Alport Syndrome (Am J
Kidney Dis Vol. 35, No. 1, January 2000, Atlas)
● LM: Focal and segmental or global glomer-
ulosclerosis with interstitial fibrosis and
foam cells is present in advanced cases
● IF: No deposits are present; the absence of
GBM staining with antibody to ␣5 type IV
collagen is characteristic of X-linked AS
● EM: Irregular thinning and thickening of
the GBM with a lamellated basket-weave
appearance; podocyte foot processes are fo-
cally effaced
Histopathology of Thin Basement Membrane
Disease (Am J Kidney Dis Vol. 34, No. 6,
December 1999, Atlas)
● LM: Normal glomeruli
● IF: Negative
● EM: Width of the GBM is uniformly re-
duced by comparison with age-matched nor-
mal controls but otherwise appears normal;
the podocytes and endothelial cells are nor-
mal
REFERENCES
1. Kashtan CE: Alport syndrome and thin glomerular
basement membrane disease. J Am Soc Nephrol 9:1736-
1750, 1998
2. Lemmink HH, Nillesen WN, Moschizuki T, et al:
Benign familial hematuria due to mutation of the type IV
collagen ␣4 gene. J Clin Invest 98:1114-1118, 1996
3. Badenas C, Praga M, Tazon B, et al: Mutations in the
COL4A4 and COL4A3 genes cause familial benign hematu-
ria. J Am Soc Nephrol 13:1248-1254, 2002
404
Congenital Nephrotic Syndrome (of the
Finnish Type)
● Autosomal recessive disease presenting with
severe proteinuria and nephrotic syndrome
in utero and at birth due to mutation of
Nephrotic syndrome 1 (NPHS1) on chromo-
some 19
● NPHS1 encodes nephrin, an Ig-like trans-
membrane protein and a major constituent
of the podocyte slit-diaphragm
● Histology shows sclerosis of glomeruli, mi-
crocystic dilatation of tubules and intersti-
tial fibrosis on light microscopy, and podo-
cyte abnormalities and absence of slit-
diaphragms on electron microscopy
● Early nephrectomy, dialysis and renal trans-
plantation may be life saving
● Recurrent nephrotic syndrome develops af-
ter transplantation in some cases and may be
due to allosensitization to nephrin in the
allograft
Steroid-Resistant Nephrotic Syndrome
● Autosomal recessive, steroid-resistant ne-
phrotic syndrome (SRNS) in early child-
hood due to mutation of NPHS2 on chromo-
some 1
● NPHS2 encodes a hairpin-like protein of the
stomatin family called podocin that may
anchor nephrin and the slit-diaphragm in the
plasma membrane
● SRNS presents with proteinuria several
months to years after birth and progresses to
end-stage renal failure
● NPHS2 mutations have been found in appar-
ently idiopathic cases of steroid-resistant
focal glomerulosclerosis
● Histology shows focal and segmental glo-
merulosclerosis with podocyte abnormali-
ties on electron microscopy
Familial Focal Glomerulosclerosis
● Autosomal dominant disease in which sev-
eral members of affected families have
asymptomatic proteinuria, nephrotic syn-
drome, and/or renal insufficiency in adult
life due to mutations of ACTN4 on chromo-
some 19
● Alpha actinin 4 (ACTN4) encodes ␣-acti-
nin-4, a podocyte-specific actin-bundling
protein
ADLER AND SALANT
● Other forms of familial focal glomeruloscle-
rosis exist in which the affected gene has
not been identified
Congenital Syndromes Associated With
Glomerular Abnormalities
● Nail-patella syndrome is an autosomal domi-
nant disease with dysplastic finger nails,
skeletal anomalies, and proteinuric renal
disease due to mutation of LMX1B, a podo-
cyte-specific transcription factor that regu-
lates the coordinated expression of ␣3 and
␣4 type IV collagen and podocin genes and
is characterized by GBM and podocyte ab-
normalities
● Two syndromes are caused by different mu-
tations of the Wilms tumor suppressor gene
1 (WT1):
— Denys-Drash syndrome—Ambiguous or
female genitalia, XY karyotype and dys-
genetic gonads, Wilms tumor, and pro-
teinuria from diffuse mesangial sclerosis
during the first year of life
— Frazier syndrome—Male pseudo-her-
maphroditism with female external geni-
talia, streak gonads and XY karyotype,
gonadoblastoma, and nephrotic syndrome
due to focal and segmental glomerulo-
sclerosis, progressing to end-stage renal
failure in adolescence or early adulthood
REFERENCES
1. Pollak MR: Inherited podocytopathies: FSGS and ne-
phrotic syndrome from a genetic viewpoint. J Am Soc
Nephrol 13:3016-3023, 2002
2. Kaplan JM, Kim SH, North KN, et al: Mutations in
ACTN4, encoding alpha-actinin-4, cause familial focal seg-
mental glomerulosclerosis. Nat Genet 24:251-256, 2000
3. Kestila M, Lenkkeri U, Mannikko M, et al: Position-
ally cloned gene for a novel glomerular protein—neph-
rin—is mutated in congenital nephrotic syndrome. Mol Cell
1:575-582, 1998
4. Boute N, Gribouval O, Roselli S, et al: NPHS2, encod-
ing the glomerular protein podocin, is mutated in autosomal
recessive steroid-resistant nephrotic syndrome. Nat Genet
24:349-354, 2000
Diabetic Nephropathy
Pathogenesis
● Magnitude of pathogenetic features effects
is likely modulated by genetic factors
● Numerous risk genes have been reported,
but these require confirmation
CORE CURRICULUM
● Risk factors include parental hypertension and
diabetes, sibling with diabetic nephropathy,
poor glycemic control, minority ethnicity.
Histopathology (Am J Kidney Dis Vol. 34, No.
5, November 1999, Atlas)
● LM: Diffuse or nodular mesangial expan-
sion with thickened GBMs
● IF: Pseudolinear deposition of albumin and
IgG along GBM; non-specific IgM and
complement may be present in segments of
glomerulosclerosis
● EM: Diffuse or nodular mesangial expan-
sion; thickened GBMs
Clinical and Laboratory Features
● Normoalbuminuria
— After initial presentation, diagnosis, and
stabilization on insulin, Type 1 diabetic
patients are normoalbuminuric
— Type 2 diabetics may not be normoalbu-
minuric on initial diagnosis
● Microalbuminuria
— Earliest manifestation of nephropathy;
predates overt disease
— Defined as 20 to 300 ␮g/min albumin
excretion or a spot albumin/creatinine
ratio of 0.03 to 0.3
— In microalbuminuric Type 1 diabetics,
particularly of long duration (⬎10 years),
significant renal morphological changes
are present
— Affects 25% to 30% of diabetics within 5
to 15 years of diagnosis
— Microalbuminuria occurs at a higher fre-
quency in ethnic minorities
— Progression from microalbuminuria to
overt proteinuria in the pre-ACE inhibi-
tor era was estimated to be approxi-
mately 80% for patients with Type 1
diabetes and approximately 20% for those
with Type 2 diabetes. In recent years,
progression, particularly for those with
Type 1 diabetes has declined to approxi-
mately 40% to 50%
— Microalbuminuria is a cardiovascular
morbidity/mortality risk factor
● Overt Proteinuria
— Defined as ⱖ500 mg proteinura/24 h,
occurs approximately 15 to 20 years af-
ter developing Type 1 diabetes or ⱖ5 to
405
10 years after diagnosis of Type 2 diabe-
tes
— Most have concomitant diabetic retinop-
athy (concordance of retinopathy is
higher for Type 1 than Type 2 diabetics)
— Progression to overt nephropathy occurs
more frequently in ethnic minorities com-
pared to European-Americans
— Urinalysis generally bland, although mi-
croscopic hematuria may be seen in ap-
proximately 15% of patients
— Azotemia follows the onset of overt ne-
phropathy
— Average decline in renal function was
approximately 1 mL/min/mo in the pre-
ACE inhibitor era; now approximately
0.3 mL/min/mo in the best-controlled
patients
— Renal biopsy not usually necessary to
diagnose diabetic nephropathy
— Renal biopsy is rarely indicated in pa-
tients with: renal function declining more
rapidly than anticipated; active urinary
sediment; or in the setting of a history,
physical exam, or serologies suggestive
of an alternative systemic disease or pri-
mary glomerulopathy
Therapy
● Glycemic control prevents/delays progres-
sion from normoalbuminuria to microalbu-
minuria and from microalbuminuria to overt
nephropathy. Goal HbA1c ⱕ7%
● Blood pressure control diminishes the risk
of developing nephropathy and slows pro-
gressive loss of renal function. Goal BP
⬍130/80
● ACE inhibitors/ARBs slow progression from
normoalbuminuria to microalbuminuria
● JNC 7 recommendations for ACE inhibitors
or ARBs along with diuretics to BP ⬍130/80
mm Hg
● High protein diets should be avoided
Course and Prognosis
● Patients with overt nephropathy generally
progress to ESRD
● Major mortality for these patients is cardio-
vascular and cerebrovascular
● Renal transplantation appears to confer a
survival advantage
406
REFERENCES
1. Deckert T, Feldt-Rasmussen B, Borch-Johnsen K,
Jensen T, Kofoed-Enevoldsen A: Albuminuria reflects wide-
spread vascular damage. The Steno hypothesis. Diabetolo-
gia 32:219-226, 1989
2. Steffes MW, Chavers BM, Bilous RW, Mauer SM: The
predictive value of microalbuminuria. Am J Kidney Dis
13:25-28, 1989
3. The effect of intensive treatment of diabetes on the
development and progression of long-term complications in
insulin-dependent diabetes mellitus. The Diabetes Control
and Complications Trial Research Group. N Engl J Med
329:977-86, 1993
4. Lewis EJ, Hunsicker LG, Clarke WR, et al, for the
Collaborative Study Group: Renoprotective effect of the
angiotensin-receptor antagonist irbesartan in patients with
nephropathy due to type 2 diabetes. N Engl J Med 345:851-
860, 2001
5. Brenner BM, Cooper ME, de Zeeuw D, et al, for the
RENAAL Study: Effects of losartan on renal and cardiovas-
cular outcomes in patients with type 2 diabetes and nephrop-
athy. N Engl J Med 345:870-878, 2001
6. Parving H-H, Lehnert H, Brochner-Mortensen J, Go-
mis R, Andersen S, Arner P, for the Irbesartan in Patients
With Type 2 Diabetes and Microalbuminuria Study Group:
The effect of irbesartan on the development of diabetic
nephropathy in patients with type 2 diabetes. N Engl J Med
345:861-870, 2001
7. Adler AI, Stratton IM, Neil HAW, et al: Association of
systolic blood pressure with macrovascular and microvascu-
lar complications of type 2 diabetes (UKPDS 36): Prospec-
tive observational study. BMJ 321:412-419, 2000
8. Wolfe RA, Ashby VB, Milford EL, et al: Comparison
of mortality in all patients on dialysis, patients on dialysis
awaiting transplantation, and recipients of a first cadaveric
transplant. N Engl J Med 341:1725-1730, 1999
INDUCTION OF GLOMERULONEPHRITIS
Immunologically mediated glomerulonephri-
tis results from the generation of glomerular
immune complexes or the dysregulation of T-cell–
mediated immunity in the absence of immune
complexes (“pauci-immune”). Secondary media-
tors then modulate the local inflammatory re-
sponse.
Immune-Complex Mediated
Glomerulonephritis
Immune complexes (IC) are macromolecules
of antigen, antibody, and any fixed complement
components. The antigen can be exogenous (ie,
bacterial, viral, chemical) or endogenous (ie,
deoxyribonucleic acid [DNA], thyroglobulin, tu-
mor antigen, etc). The level and persistence of
immune complexes is dependent upon the source
and amount of antigen, the potency and duration
ADLER AND SALANT
of antibody response, and the level of function of
the mononuclear phagocyte system for clearing
IC from the circulation.
There are two mechanisms for glomerular IC
deposition
(1) Deposition of IC from the circulation
(CIC)
(2) In situ complex formation: Antigen and anti-
body are independently trapped to form an IC
The major clinical examples are membranous
nephropathy and anti-GBM nephritis
Pauci-Immune Glomerulonephritis
● Characterized by the absence of immune
deposits (negative immunofluorescence)
with cellular infiltration of lymphocytes and
monocytes in Bowman’s space (crescent)
● Initiators unknown
● Abnormal immunoregulatory mechanisms
(perhaps genetically defined) permit the dys-
regulation of autoreactive T- and/or B-cell
clones
● Vast majority of these patients have antibod-
ies to neutrophil lysosomal antigens (c-
antineutrophil cytoplasmic antibody
[ANCA] or p-ANCA, see below)
● Clinical examples include: Wegener granu-
lomatosis, microscopic polyangiitis (micro-
scopic polyarteritis nodosa), Churg-Strauss
disease, and idiopathic crescentic glomeru-
lonephritis
Secondary Mediators of Inflammation
Complement
● Complement functions: Cell lysis or injury,
chemotaxis, opsonization, immune complex
solubilization, enhanced vascular permeabil-
ity
● C5b-9 membrane attack complex (MAC)
induces cell membrane lysis and injury;
urinary MAC may reflect degree of glomer-
ular injury, particularly in membranous ne-
phropathy
Cytokines
● Regulate cell proliferation, differentiation,
phenotype, secretion, and/or migration
● Cytokine families include:
— Interleukins
— Colony-stimulating factors
CORE CURRICULUM
— Interferons
— Chemokines
— Growth factors
A description of a few cytokines/growth fac-
tors that are important in the kidney follows:
● Transforming growth factor-␤
— Master regulator of matrix synthesis and
degradation; promotes fibrosis
— Regulates cell proliferation and differen-
tiation, wound healing, angiogenesis
— Pathogenetically implicated in most ex-
perimental forms of glomerulonephritis
— Increased in human diabetic nephropa-
thy
● Platelet-derived growth factor
— Increases mitogenesis, chemotaxis, mes-
angial cell contraction
— Implicated in the pathogenesis of IgA
nephropathy, diabetic nephropathy
● Insulin-like growth factor-1/growth hor-
mone
— Implicated in the pathogenesis of renal
hypertrophy and glomerulosclerosis
● Adhesion molecules/integrins/selectins
— Regulate cell-cell and cell-matrix interac-
tions
— Coordinates (in concert with cytokines
and chemokines) the development of im-
mune and inflammatory reactions
— Facilitates signaling from inside the cell
to the outside matrix and from outside
the cell to the nucleus via the cytoskel-
eton
Reactive Oxygen Species
● Potential injurious agents—primarily O⫺,
H2O2, OH⫺, HOCl
— Detoxification: enzymes (superoxide dis-
mutase, catalase); O2 scavengers
Signal Transduction Molecules
● Exogenous molecules such as cytokines,
chemokines, growth factors, and hypergly-
cemia induce activation of intracellular sig-
naling molecules within cells
● Signaling pathways such as the mitogen-
activated protein kinases and the protein
kinase C pathway mediate actions of the
extracellular signals by inducing the forma-
tion of nuclear transcription factors, which
bind to regions on genes and activate them
407
● These mediate change in experimental mod-
els of glomerular disease
REFERENCES
1. Rifkin IR, Salant DJ: Immune-mediated glomerulopa-
thies, in Humes HD (ed): Kelley’s Textbook of Internal
Medicine (ed 4). Philadelphia, PA, Lippincott, Williams and
Wilkins, 2000, p 1191-1208
2. Couser WG: Pathogenesis of glomerular damage in
glomerulonephritis. Nephrol Dial Transplant 13:10-15, 1998
(suppl 1)
3. Cybulsky AV: Growth factor pathways in proliferative
glomerulonephritis. Curr Opin Nephrol Hypertens 9:217-
223, 2000
4. Gwinner W, Grone HJ: Role of reactive oxygen spe-
cies in glomerulonephritis. Nephrol Dial Transplant 15:1127-
1132, 2000
DISORDERS ASSOCIATED WITH NEPHRITIS
Membranoproliferative Glomerulonephritis
(MPGN)
Pathogenesis
Three distinct entities defined by histopathol-
ogy.
● Type I: The most common form; immune-
complex mediated
● Type II (dense deposit disease): Less com-
mon; in animal models and some families,
there is a deficiency or absence of comple-
ment Factor H
● Type III: Rare; immune-complex mediated
Pathology
● Type I: Mesangial hypercellularity with sub-
endothelial and mesangial immune complex
deposits, capillary wall mesangial interposi-
tion, and monocyte infiltration. IF shows
granular mesangial and capillary wall IgG,
C3 ⫾ IgM (Am J Kidney Dis Vol. 31, No. 1,
January 1998, Atlas)
● Type II: Deposition of electron dense mate-
rial within capillary wall; complement C3c
is present (Am J Kidney Dis Vol. 31, No. 2,
February 1998, Atlas)
● Type III: Subepithelial and subendothelial
deposits associated with GBM disruption
and lamina densa layering
● All 3 types have double-contoured GBM
Clinical Associations
● Histological features of Type 1 MPGN may
be seen in patients (particularly adults) with
408
underlying neoplasms, infections, and colla-
gen-vascular diseases
● Partial lipodystrophy associated with Type
2, less commonly other types
This Section Focuses on the Primary Forms of
MPGN
● May present as...
— Asymptomatic with microhematuria or
nonnephrotic proteinuria
— Nephrotic syndrome
— Acute nephritic syndrome
— Crescentic rapidly progressive glomeru-
lonephritis
● Hypertension and diminished GFR may be
present at diagnosis
● ⱖ80% of patients with Type 1 MPGN have
underlying hepatitis C; less commonly, hepa-
titis B
● Cryoglobulinemic vasculitis (Am J Kidney
Dis Vol. 32, No. 6, December 1998, Atlas)
may complicate hepatitis C-associated
MPGN and present with low C3 and/or C4,
rheumatoid factor, positive ANA (approxi-
mately 20%), arthritis, and skin leukocyto-
clastic vasculitis
● Low C3 is found in approximately 70% to
90% of patients
— In idiopathic MPGN, C3 nephritic factor
stabilizes C3 convertase
— In some families, complement factor H
deficiency induces continued C3 activa-
tion
● Usually sporadic, but some hereditary, par-
ticularly Types II and III
● Slow progression to end-stage renal disease
(ESRD) in Types I and II, more frequently
than Type III
● Spontaneous remission occurs rarely
● All may recur in renal allografts, particu-
larly with a live-related donor
Therapy
● No consensus. All of the following have
been used:
— Used singly or in combination: glucocor-
ticoids, dipyridamole, warfarin, and/or
aspirin with or without cyclophospha-
mide
ADLER AND SALANT
— Steroids/immunosuppressives may en-
hance viral replication in hepatitis-asso-
ciated MPGN; may be necessary with
complicating cryoglobulinemic vasculi-
tis
— Cyclosporine, mycophenolate mofetil,
and intravenous (IV) Igs used anecdot-
ally
— ACE inhibitor/ARB for their antiprotein-
uric effects
— Pegylated interferon and ribavirin have
not been studied systematically for ef-
fects on nephritis
— Ribavirin is contraindicated with GFR
⬍50%
REFERENCES
1. Andresdottir MB, Assmann KJ, Hoitsma AJ, Koene
RA, Wetzels JF: Recurrence of type I membranoprolifera-
tive glomerulonephritis after renal transplantation: Analysis
of the incidence, risk factors, and impact on graft survival.
Transplantation 63:1628-1633, 1997
2. Johnson RJ, Gretch DR, Yamabe H, et al: Membrano-
proliferative glomerulonephritis associated with hepatitis C
virus infection. N Engl J Med 328:465-470, 1993
3. D’Amico G, Ferrario F: Cryoglobulinemic glomerulo-
nephritis: A MPGN induced by hepatitis C virus. Am J
Kidney Dis 25:361-369, 1995
IgA Nephropathy (Berger’s Disease)
Pathogenesis
● Mesangial deposition of undergalactosy-
lated polyclonal IgA1
● Origin of IgA1 controversial, but may de-
rive from bone marrow or mucosa
● Posited to be due to binding of IgA to
mesangial cell Fc receptors, resulting in
mesangial cell growth factor, cytokine, and
chemokine elaboration inducing mesangial
proliferation, infiltrating monocytes, and ma-
trix expansion
Clinical Associations
● Primary idiopathic form
● Secondary forms: Henoch-Schönlein pur-
pura, alcoholic cirrhosis, gluten enteropa-
thy, HLA-B27 arthritides, IgA monoclonal
gammopathies, dermatitis herpetiformis,
psoriasis
● Some familial forms
CORE CURRICULUM
Histopathology (Am J Kidney Dis Vol. 31, No.
1, January 1998, Atlas)
● LM: global or segmental mesangial hyper-
cellularity; mesangial deposits may be seen
with trichrome stain
● IF: microscopy: mesangial IgA and C3.
Co-deposition of mesangial IgG or IgM
frequent. Deposits may occasionally extend
to involve the GBM
● EM: mesangial deposits often with cluster-
ing at the paramesangial basement mem-
brane.
Clinical and Laboratory Features
● Most common primary glomerulonephritis
in the world
● Varied clinical presentation
— Asymptomatic; microscopic hematuria;
intermittent gross hematuria; synpharyn-
gitic hematuria; nephrotic (⬍15%) or
nonnephrotic proteinuria; acute glomeru-
lonephritis; rapidly progressive glomeru-
lonephritis
● Often associated with hypertension
● Approximately 50% of patients have in-
creased serum IgA levels
Course and Prognosis
● 20-year renal survival approximately 50%
to 70%
● Risk factors for progression: heavy protein-
uria, diminished GFR at onset, older age at
onset, uncontrolled hypertension, crescents,
tubulointerstitial fibrosis/atrophy, familial
forms
● Prognostic value of gross hematuria is con-
troversial
● Certain genotypes may be associated with
progression
● Recurrent IgA deposits in renal allografts
rarely induce clinical disease
Therapy: Controversial; Varies Substantially
According to Local Practices
● ACE inhibitor/ARB for their antiproteinuric
effects. GFR benefit mostly inferential
● Eicosapentaenoic acid/docasahexaenoic acid
slowed progression in some but not all stud-
ies
● Steroids, steroids plus short-term cyclophos-
409
phamide followed by azathioprine, and com-
binations of steroids, cytotoxics, coumadin,
and dipyridamole beneficial in some but not
all studies
● Mycophenolate mofetil under study in ran-
domized trials
REFERENCES
1. Donadio JV, Grande JP: IgA nephropathy. N Engl
J Med 347:738-748, 2002
2. Pozzi C, Bolasco PG, Fogazzi GB, et al: Corticoste-
roids in IgA nephropathy: A randomized controlled trial.
Lancet 353:883-887, 1999
3. Ballardie FW, Roberts IS: Controlled prospective trial
of prednisolone and cytotoxics in progressive IgA nephropa-
thy. J Am Soc Nephrol 13:142-148, 2002
Henoch-Schönlein Purpura Nephritis (HSP)
Pathogenesis
● Similar to IgA nephropathy (above), but
with widespread systemic involvement, par-
ticularly in the kidneys, skin and gastrointes-
tinal tract
Histopathology: Highly Variable
● LM:
—Minimal changes (2%)
— Mild mesangial hypercellularity, few leu-
kocytes (10% to 32%)
— Focal/segmental mesangial hypercellular-
ity, more WBCs (20% to 45%)
— Diffuse mesangial hypercellularity, up to
50% crescents (15%)
● IF: Granular mesangial IgA with C3, fibrino-
gen, both light chains, lesser amounts of
IgG/IgM
● EM: Mesangial electron dense deposits; oc-
casional involvement of capillary loops; vari-
able foot process effacement; occasional
GBM thinning, thickening, and lamellation
Clinical and Laboratory Features
● Classical clinical triad is purpura, abdomi-
nal pain, and hematuria
● Affects children predominantly; M:F ratio
2:1 in children
● More prevalent in winter
● Approximately 1 in 3 patients experience a
precipitant event
● Spectrum of symptoms from mild to severe
petechial rash, gastrointestinal, renal, neuro-
410
logic, urologic, pulmonary, and rheumato-
logic disease
● Predominance of renal involvement in adults,
skin in children
● Susceptibility may be genetic; uncommon
in those of African descent
● May recur in renal allografts, particularly
living-related kidneys
Course
● Average renal disease duration approxi-
mately 1 month
● Extrarenal involvement often lasts ⬎1 month
● Overall good renal outcome; complete recov-
ery in approximately 90% adults
● Protracted courses and relapse may occur
● Prognosis poorer in acute nephritic syn-
drome or proteinuria ⬎1 g/d
● Persistent proteinuria should be treated with
ACE inhibitors and/or ARBs
Therapy
● Symptomatic for mild cases
● For severe nephritis, treatment is controver-
sial and is based on experience from small
series and case reports. All of the following
have been tried:
— Steroids as monotherapy
— Multidrug therapy with various combina-
tions of steroids, cyclophosphamide, di-
pyridamole, heparin, and/or warfarin
— IV Ig
REFERENCE
1. Rai A, Nast CC, Adler S: Henoch-Schönlein purpura
nephritis. J Am Soc Neph 10:2637-2644, 1999
Lupus Nephritis
Pathogenesis
● Loss of self-tolerance, followed by autoanti-
body production
● Leads to immune complex deposition
● The latter induces activation of complement
and elaboration of chemokines and cyto-
kines, resulting in leukocyte chemotaxis,
mesangial hypercellularity and matrix ex-
pansion, occasionally fibrinoid necrosis
and/or crescentic GN, and glomerulosclero-
sis
ADLER AND SALANT
Histopathology (Am J Kidney Dis Vol. 32, No.
1, July 1998 [WHO II and V]; Am J Kidney Dis
Vol. 31, No. 6, June 1998 [WHO III and IV],
Atlas)
● World Health Organization (WHO) classifi-
cation of 1982 (currently undergoing revi-
sion): I—Normal; II—Mesangial prolifera-
tion with immune complexes limited to
mesangium; III—Focal proliferative
(FPGN); IV—Diffuse proliferative (DPGN);
V—Membranous; VI—Sclerosing
● Activity/chronicity indices score severity of
inflammation/sclerosis
● Immune deposits often characterized by
“full-house” IF, with IgG, IgA, IgM, C1q,
C3, fibrin, ␬ and ␭ light chains
● Electron microscopy shows dense deposits
(II—mesangial; III and IV—mesangial, sub-
endothelial, occasional subepithelial;
V—subepithelial) and frequently endothe-
lial tubuloreticular structures
● “Non-WHO” lesions may also occur:
— Combinations of WHO lesions
— Superimposed acute tubular necrosis or
acute interstitial nephritis
— Thrombotic microangiopathy
Clinical and Laboratory Features
● Nonnephrotic or nephrotic range protein-
uria, usually with hematuria, often with some
pyuria
● Red cell casts may be present, especially in
patients with FPGN and DPGN with or
without crescents, so-called “telescopic
urine”
— Renal presentation occasionally pre-
cedes systemic lupus erythematosus
(SLE) diagnosis
● Hypertension (⬎50%)
● Hypocomplementemia (particularly direct
pathway components C2, C3, C4) approxi-
mately 90% in DPGN/FPGN
● Systemic: Arthralgias, nondeforming arthri-
tis, malar or discoid rash, photosensitivity,
oral ulcers, alopecia, myalgias, serositis,
cerebritis, myocarditis
Course and Prognosis
● Good prognosis for patients with mesangial
proliferation only
CORE CURRICULUM
● Progression to renal failure is more com-
mon in FPGN and DPGN
— Improved prognosis for DPGN; progres-
sion to ESRD in 5 years now approxi-
mately 10% reflecting success of current
therapies
● Membranous SLE prognosis is similar to
idiopathic membranous
● Conversion from less to more proliferation
occurs in approximately 35% of patients
● Risk factors for progression, apart from
WHO class, include African-American race,
hematocrit ⬍25%, elevated serum creati-
nine, and heavy proteinuria at presentation
● SLE activity usually becomes quiescent at
ESRD, but exceptions occur
● Clinically significant lupus nephritis rarely
recurs in renal allografts
Therapy: Highly Controversial
● General principles
— Most aggressive therapy is directed to-
ward treating DPGN because of its seri-
ous prognosis if inadequately treated
— The more sclerosis and tubulointerstitial
fibrosis on biopsy the greater the likeli-
hood of progression
● Treatment of mesangial proliferation
— Treat extrarenal manifestations only
● Treatment of FPGN/DPGN
— Current regimens of prednisone, methyl-
prednisolone pulsing, and IV cyclophos-
phamide improved prognosis
— Optimal duration of treatment course
controversial
— Concerns regarding toxicity, including
sepsis, hemorrhagic cystitis, bladder can-
cer, and ovarian failure spurred assess-
ment of alternative regimens
— Continued interest in the use of azathio-
prine to induce and/or consolidate remis-
sion
— Recent reports suggest results with myco-
phenolate mofetil equivalent to cyclo-
phosphamide to induce or consolidate
remission
— Fewer side-effects with mycopheno-
late mofetil
— Long-term renal survival is currently
unknown with mycophenolate mofetil
— Still very controversial
411
— Azathioprine may be best choice during
pregnancy
— Plasmapheresis has no proven benefit
— Total lymphoid irradiation, IV Ig, and
stem cell infusions have been used as
salvage therapy in selected patients
— New immunomodulatory agents are un-
der investigation
● Treatment of membranous lupus nephritis
— ACE inhibitor/ARB initially to minimize
proteinuria
— Steroids for extrarenal manifestations
— If proteinuria remains nephrotic and/or se-
rum creatinine is rising, consider cyclospor-
ine or IV cyclophosphamide and steroids
— Preliminary studies from NIH suggest
benefit with these beyond steroids alone
— Relapse after achievement of complete re-
mission is common, occurring in 45% of
patients at a median time of 36 months,
emphasizing the need for continued fol-
low-up
REFERENCES
1. Balow JE, Austin HA III: Progress in the treatment of
lupus nephritis. Curr Opin Nephrol Hypertens 9:107-115,
2000
2. Zimmerman R, Radhakrishnan J, Valeri A, et al: Ad-
vances in the treatment of lupus nephritis. Annu Rev Med
52:63-78, 2001
3. Chan TM, Tang CS, Wong RW, et al: Efficacy of
mycophenolate mofetil in patients with diffuse proliferative
lupus nephritis. N Engl J Med 343:1156-1162, 2000
4. Illei GG, Takada K, Parkin D, et al: Renal flares in
patients with severe proliferative lupus nephritis treated with
pulse immunosuppressive therapy: Long-term followup of a
cohort of 145 patients participating in randomized con-
trolled studies. Arthr Rheum 46:995-1002, 2002
5. Houssiau FA, Vasconcelos C, D’Cruz D, et al: Immu-
nosuppressive therapy in lupus nephritis: The Euro-Lupus
Trial, a randomized trial of low-dose versus high-dose
intravenous cyclophosphamide. Arthr Rheum 46:2121-
2131, 2002
6. Gescuk BD, Davis JC Jr: Novel therapeutic agents for
systemic lupus erythematosus. Curr Opin Rheumatol 14:515-
521, 2002
ANCA-Associated/ANCA-Generated
Glomerulonephritis (Pauci-Immune)
Pathogenesis
● Infection, drug exposure, or other inflamma-
tory processes activate polymorphonuclear
leukocytes and endothelial cells, leading to:
— Local generation of cytokines
412
— Translocation of ANCA lysosomal anti-
gens proteinase-3 (PR3) or myeloperoxi-
dase (MPO) to the cell membrane
— Specific anti-PR3 or anti-MPO antibod-
ies bind and further activate target neutro-
phils to secrete damaging reactive oxy-
gen species and other mediators of
inflammation
● Crescentic glomerulonephritis and systemic
vasculitis can be transferred by infusion of
MPO ANCA antibody or by activated
splenocytes synthesizing anti-MPO ANCA
antibody, supporting a pathogenetic role for
MPO ANCA
Laboratory Diagnosis
Tests are performed by indirect immunofluo-
rescence (IIF) for the pattern of antigen expres-
sion or by enzyme-linked immunosorbent assay
(ELISA) for specific antigen identification
● Indirect IF: Ethanol-permeabilized WBCs
are incubated with patients’ sera and then
with fluorescein-conjugated antihuman IgG.
A cytoplasmic pattern (cANCA) indicates
that the target antigen is PR3. A perinuclear
pattern (pANCA) usually indicates that the
antigen is MPO. Other antigens can also
uncommonly confer a perinuclear pattern
● ELISA: Identifies the antigen to which the
ANCA antibody is directed in a positive IIF
test
Wegener Granulomatosis
Histopathology (Am J Kidney Dis 32:344-349,
1998, Atlas)
● LM: Granulomatous vasculitis of medium
sized to small arterioles and venules. Renal
biopsy may disclose any of the following:
normal; mesangial proliferative glomerulo-
nephritis; segmental necrotizing glomerulo-
nephritis; crescents
● IF: Pauci-immune glomerulonephritis; fi-
brin may be present in crescents; tubulointer-
stitial granulomas
● EM: No immune deposits are seen
Laboratory Diagnosis
● cANCA is specific and sensitive for diagnos-
ing untreated patients
● Some patients (approximately 20% to 30%)
ADLER AND SALANT
have pANCA and a few may be ANCA
negative, particularly in the setting of partial
or full treatment
● Titers may be useful to follow therapeutic
response or predict relapse (controversial)
Clinical Presentation
● Presenting symptoms most often involve
upper respiratory tract including rhinorrhea,
sinusitis, nasopharyngeal mucosal ulcer-
ation
● Lung involvement in ⬎80% of patients,
most often cough, dyspnea, hemoptysis; tran-
sient infiltrates or nodular densities may be
seen on chest x-ray (CXR)
● Renal involvement characterized by protein-
uria, hematuria, red cell casts
● Approximately 10% of patients have
azotemia on presentation
● Other signs/symptoms: fever, weight loss,
malaise, arthralgias, nondeforming arthritis,
mononeuritis multiplex, skin papules,
vesicles, purpura
Treatment
● Oral cyclophosphamide dramatically im-
proved survival in uncontrolled trials
● High incidence of bladder cancer the decade
following prolonged treatment with daily
oral cyclophosphamide
● IV cyclophosphamide advocated to dimin-
ish side effects
● Oral and IV cyclophosphamide protocols
are roughly equivalent in remission induc-
tion efficacy, but oral may be marginally
better than IV in preventing relapse
● Steroids useful adjunctive therapy, particu-
larly in patients with severe renal or pulmo-
nary disease, skin or cerebral vasculitis, eye
involvement, or pericarditis
● In situations with severe pulmonary hemor-
rhage and fulminant renal disease, pulse
methylprednisolone and/or plasmapheresis
may confer additional benefit
● Studies of short course cyclophosphamide
followed by azathioprine claim equivalent
short-term efficacy compared to more inten-
sive cyclophosphamide-based regimens;
long-term efficacy and relapse rates not yet
known
● Sulfamethoxazole/trimethaprim may dimin-
CORE CURRICULUM
ish relapse rates, particularly respiratory,
but drug intolerance is common
● In refractory patients, the following have
been tried with limited success: mycopheno-
late mofetil, IV Ig, anti–tumor necrosis fac-
tor (TNF) drugs (etanercept; infliximab);
antithymocyte globulin, deoxyspergalin, le-
flunomide
Course and Prognosis
● ⬎80% to 90% 1-year mortality if left un-
treated
● Relapse occurs in 25% to 50% of patients
followed up for 3 to 5 years
Microscopic Polyangiitis (Polyarteritis)
Histopathology (Am J Kidney Dis 32:344-349,
1998, Atlas)
Vasculitis of small to medium sized arteries
and venules, without granulomatous changes typi-
cal of Wegener granulomatosis. Glomeruli with
pauci-immune glomerulonephritis
Laboratory Diagnosis
Both pANCA and cANCA positivity is seen,
with a slight preponderance of pANCA.
Clinical Presentation
● Similar to Wegener granulomatosis, but with
less emphasis on pulmonary and upper respi-
ratory tract involvement, although alveolar
capillaritis without granulomatous change
causing hemoptysis can occur
● The following medications have been asso-
ciated with the development of microscopic
polyangiitis: propylthiouracil, hydralazine,
penicillamine, and silica
Treatment and Course
Similar to Wegener granulomatosis
Churg-Strauss Vasculitis
Histopathology
Similar to other ANCA-positive vasculitides,
but characteristic feature is eosinophilic pulmo-
nary infiltrates
Laboratory Diagnosis
Usually pANCA (MPO) positive
413
Clinical Presentation
● Eosinophilia and necrotizing vasculitis in
the presence of asthma
● Vasculitis can affect lung, skin, peripheral
nerves, muscles, intestine, and kidneys, al-
though glomerulonephritis is usually (but
not always) mild
● Associated with leukotriene antagonist
therapy, but causation not proven
Treatment and Course
● Glomerular involvement usually mild; se-
vere crescentic glomerulonephritis is rare
● Progression to ESRD is uncommon
● Therapy is similar to other forms of vasculi-
tis and is dependent upon the severity of
organ involvement in the major systems
involved
Idiopathic Crescentic Glomerulonephritis
Histopathology
Pauci-immune crescentic glomerulonephritis
Laboratory Diagnosis
Both pANCA and cANCA positivity is seen,
mostly pANCA
Clinical Presentation
● Renal-limited glomerular capillaritis, char-
acterized by gross or microscopic hematu-
ria, nonnephrotic proteinuria, red cell uri-
nary casts, and rapidly rising serum
creatinine
● Extra-renal signs/symptoms absent except
nonspecific constitutional symptoms
Treatment and Course
Similar to Wegener granulomatosis
REFERENCES
1. Savage COS: ANCA-associated renal vasculitis. Kid-
ney Int 60:1614-1627, 2001
2. Xiao H, Heeringa P, Hu P, et al: Antineutrophil cytoplas-
mic autoantibodies specific for myeloperoxidase cause glo-
merulonephritis and vasculitis in mice. J Clin Invest 110:955-
963, 2002
Goodpasture Syndrome (Anti-GBM
Nephritis)
Pathogenesis
Inflammatory sequelae due to antibodies to an
epitope on the noncollagenous domain of the ␣3
414
chain of Type IV collagen. Expression of the
antigen is restricted predominantly to glomerular
and alveolar basement membranes.
Clinical Associations
● Pulmonary hemorrhage exacerbated by vola-
tile hydrocarbon exposure, smoking, influ-
enza
● Rarely occurs superimposed on nail-patella
syndrome or membranous nephropathy
● Anti-GBM antibodies may deposit in renal
allografts of patients with Alport syndrome
Histopathology (Am J Kidney Dis Vol. 32, No.
2, August 1998, Atlas)
● LM: Glomerulonephritis without tuft hyper-
cellularity, crescents frequent
● IF: Continuous linear IgG and C3 along
GBM. Rarely other Igs
● EM: No deposits
Clinical and Laboratory Features
● Once thought to occur primarily in young
adult males; now M:F sexual predilection
closer to 55:45
● Presentations
— Pulmonary symptoms (cough, dyspnea,
rales, hemoptysis) precede or are coinci-
dent with renal symptoms ⱖ70% of cases
— Azotemia in 50% to 70% of cases at
initial presentation
— Arthritis/arthralgia common
— Anemia is out of proportion to degree of
azotemia and presents with iron defi-
ciency characteristics due to pulmonary
hemorrhage
— Hypertension uncommon (⬍20%)
— U/A shows hematuria, red cell casts, non-
nephrotic proteinuria
— Serology usually negative/normal except
for the anti-GBM antibody
— Antibody titer does not correlate with
severity of illness
— Approximately 20% to 30% of patients
are also pANCA positive
Therapy
● Remissions have been achieved with plasma-
pheresis, glucocorticoids, and cytotoxic
agents in patients with serum creatinine ⬍5
mg/dL (⬍442 ␮mol/L)
ADLER AND SALANT
● Renal recovery less likely with oligoanuria
and serum creatinine ⬎6 mg/dL (⬎530
␮mol/L)
Course
● Majority of untreated patients progress to
ESRD, although rare spontaneous remis-
sions reported
● Smoking and volatile hydrocarbon expo-
sure exacerbates pulmonary hemorrhage and
may precipitate recurrence
● Recurrence in renal allografts is rare if anti-
body titers are negative
REFERENCES
1. Salama AD, Levy JB, Lightstone L, Pusey CD: Good-
pasture’s disease. Lancet 358:917-920, 2001
2. Kalluri R: Goodpasture syndrome. Kidney Int 55:1120-
1122, 1999
Infection-Associated Glomerulonephritis
Post-Streptococcal Glomerulonephritis
(PSGN)
Pathogenesis
● Due to an immune response to infection
with nephritogenic Group A (rarely Groups
C or G) ␤-hemolytic streptococcus
● Deposited antibodies may be directed at
streptococcal antigens and/or intrinsic glo-
merular epitopes such as extracellular ma-
trix
● Local activation of the complement cas-
cade, interleukin-6 (IL-6), intercellular adhe-
sion molecule-1 (ICAM-1), and the plasmin-
plasminogen system contribute to local
inflammation
Histopathology (Am J Kidney Dis Vol. 31, No.
5, May 1998, Atlas)
● LM: Glomerular tufts are enlarged, hyper-
cellular, with leukocytes in glomerular cap-
illaries; rarely crescents. Hypercellularity
may be global or segmental
● IF: Large, irregular subepithelial, and some
mesangial and/or subendothelial deposits,
usually with IgG, IgM, and complement.
Deposition of C3 may precede Ig. Three
patterns of deposits reported:
— Starry sky describes presence of fine
granular capillary wall and mesangial
CORE CURRICULUM
deposits. Has been associated with chro-
nicity
— Mesangial describes a mesangial-pre-
dominant pattern of immune deposits
— Garland describes predominantly capil-
lary wall deposits
● EM: Subepithelial “hump” shaped depos-
its; some mesangial and subendothelial de-
posits
Clinical and Laboratory Manifestations
● Typically a preceding throat or skin infec-
tion with a latent period of approximately 1
to 3 weeks or 3 to 6 weeks, respectively, for
the appearance of renal symptoms
● Infection often inapparent when glomerulo-
nephritic symptoms present
● Occurs epidemically and sporadically
● Most frequent in school-age children with
M:F ratio 2:1
● Presentation
— Gross hematuria (50%)
— Nephrotic/nonnephrotic proteinuria
(96%)
— Edema (85%)
— Hypertension (60%)
— Lethargy, confusion, seizures (20%)
— Oligoanuria (35%)
— Azotemia (74%)
— Pulmonary symptoms (23%)
— Gastrointestinal complaints (29%)
— Ascites (particularly in children) (26%)
● Hypocomplementemia (low C3 but normal
C4 demonstrating alternate complement
pathway activation), present in almost all
patients, usually resolves within 2 months
● Low level cryoglobulinemia is frequent
● Anti-streptolysin O titers are usually el-
evated with a preceding throat infection.
Antihyaluronidase and anti-DNAse B titers
are more common with preceding skin infec-
tions
Therapy
● No specific therapy; treatment of underlying
infection as appropriate
● Gentle diuresis may be required for comfort
● Hypertension should be aggressively treated,
especially in children, in whom hyperten-
sive seizures may occur
● Supportive dialysis as necessary
415
Course and Prognosis
● Complete resolution of hematuria/protein-
uria may take months to years
● Renal prognosis favorable in children ex-
cept with severe acute disease
● Up to 40% of adults develop chronic
azotemia
REFERENCE
1. Nordstrand A, Norgren M, Holm SE: Pathogenic
mechanism of acute post-streptococcal glomerulonephritis.
Scand J Infect Dis 31:523-537, 1999
Acute and Subacute Bacterial Endocarditis
(ABE, SBE)
Pathogenesis
Immune-complex mediated
Histopathology
● LM: ABE—Glomerular hypercellularity
with or without segmental necrosis; SBE—
Focal segmental proliferation, often with
fibrinoid necrosis or capillary thrombi; rarely
crescents
● IF: IgG, IgM, and complement deposits in
mesangium and GBM
● EM: ABE—Dense deposits in the mesan-
gium and GBM; SBE—Mostly mesangial
deposits, with relative sparing of GBM
Clinical and Laboratory Features
● In industrialized nations, mostly seen in
patients with prosthetic heart valves or in IV
drug abusers
● In developing nations, mostly seen in pa-
tients with a history of rheumatic heart dis-
ease
● May also complicate aortic sclerosis/mitral
valve prolapse
Presentation
● Fever, myalgias, malaise, arthralgias, ane-
mia, purpura
● Gross or microscopic hematuria
● Usually nonnephrotic proteinuria
● Often azotemia, but rapid progression is
uncommon
● Fewer extrarenal clinical manifestations in
right-sided endocarditis, but renal involve-
ment more common
● Hypocomplementemia (low C3 and C4),
416
normochromic normocytic anemia, leukocy-
tosis, elevated sedimentation rate, and el-
evated C-reactive protein are characteristic
● Low-level cryoglobulinemia is frequent
Therapy
● Supportive care in conjunction with treat-
ment of the underlying infection
● In patients with crescentic glomerulonephri-
tis, anecdotal reports suggest benefit from
steroids, immunosuppression, and/or plas-
mapheresis after or in conjunction with anti-
biotics
Course and Prognosis
● Overall prognosis determined by therapy
for the valvular disease
● Most renal disease resolves within weeks
with antibiotic treatment
● In patients with severe renal disease on
presentation, there may be residual protein-
uria, hypertension, and/or azotemia
Other Infection-Related Syndromes
● Chronic visceral abscess
● Shunt nephritis
● Pneumonia
REFERENCE
1. Adler SG, Cohen AH: Glomerulonephritis with bacte-
rial endocarditis, ventriculovascular shunts, and visceral
infections, in Schrier RW, Gottschalk CW (eds): Diseases of
the Kidney, Vol 2 (ed 5). Boston, MA, Little, Brown and
Company, 1993, pp 1681-1688
Thrombotic Microangiopathies (TMA)
Thrombotic Thrombocytopenic Purpura
(TTP)
Pathogenesis
● Diminished activity of von Willebrand fac-
tor (vWF) cleaving protein, due to either an
inherited mutation or to the presence of an
Ig interfering with the function of the vWF
cleaving protein, results in abnormal amount/
and or size of vWF
● Unusually large vWF binds to extracellular
matrix and platelets, induces platelet activa-
tion and aggregation, and leads to intravas-
cular platelet thrombi, organ ischemia, and
necrosis
● Defective vWF cleavage typifies active TTP
ADLER AND SALANT
and distinguishes it from other causes of
hemolysis, thrombosis, or thrombocytope-
nia
● vWF cleaving protein is a zinc metallopro-
teinase named “a disintegrin and metallopro-
tease with thrombospondin type 1 repeat”
(ADAMTS)
● Patients with familial and recurrent TTP
have ADAMTS13 mutations
Histopathology (Am J Kidney Dis Vol. 34, No.
3, September 1999, Atlas)
● LM: Glomerular capillary and sometimes
arteriolar fibrin thrombi
● IF: Fibrin in capillaries and arterioles; no
immune complexes
● EM: Endothelial cell swelling, capillary and
arteriolar fibrin, and lamina rara externa
expansion due to fibrin deposition
Clinical and Laboratory Features
● Presentation
— Classic pentad of fever, microangio-
pathic hemolytic anemia, thrombocytope-
nic purpura, renal disease, central ner-
vous system symptoms
— Occurs as acquired acute disease or in a
chronic relapsing form
— Continued hemolysis best followed by
serum LDH levels
● Clinical associations
— Medications: quinine, mitomycin-C, cy-
clophilin inhibitors, ticlopidine
— Collagen-vascular disorders: SLE, sclero-
derma
— Malignancy
— Infections: HIV
Therapy
● Plasma infusion provides missing enzyme
activity
● Plasma exchange removes any circulating
vWF cleaving protein inhibitor and facili-
tates infusion of large amounts of fresh
frozen plasma (FFP) (average course of FFP
is approximately 21 L)
● Steroids may be useful adjunctive therapy
● Supportive dialysis therapy as needed
● Rituximab used with some success in a few
refractory patients
CORE CURRICULUM
● Splenectomy and platelet inhibitors are not
of proven value
● Platelet infusions are contraindicated
Course and Prognosis
● Untreated, mortality approaches 90%
● 60% to 90% patient survival with plasma
infusion ⫾ plasma exchange
● Most who go into remission have excellent
long-term prognoses
● A subset develop chronic TTP and require
long-term treatment
Hemolytic-Uremic Syndrome (HUS)
Pathogenesis
● Biochemical and genetic data regarding de-
fective vWF cleaving protein and AD-
AMTS 13 in TTP (above) challenge the
assumption that HUS and TTP represent
different clinical expressions of a single
disease process
● In HUS with a diarrheal prodrome
(D⫹HUS), it is postulated that Shiga-like
toxin binds to colonic epithelium and in-
duces elaboration of chemokines and cyto-
kines, causing polymorphonuclear (PMN)
influx and abrogation of barrier function,
permitting Shiga-like toxin to enter the cir-
culation free or bound to PMNs
● Toxin binds to glomerular/renal arteriolar
and proximal tubular epithelial cell recep-
tors, resulting in local inflammation, endo-
thelial injury, thrombosis, and acute renal
failure
Histopathology
All TMAs are histologically identical (see
TTP)
Clinical and Laboratory Features
Classic triad of microangiopathic hemolytic
anemia, thrombocytopenia, and renal disease,
with peak incidence in summer
● D⫹HUS induced by organisms producing a
Shiga-like toxin (predominantly Esche-
richia coli O157:H7) or other enteric infec-
tions (Shigella, Salmonella, Campylobacter,
Yersinia)
— Epidemics associated with ingestion of
undercooked hamburger
417
● May also occur in a nondiarrheal form (D-
HUS)
— Inherited form (complement factor H mu-
tation)
— Medications: calcineurin inhibitors, rapa-
mycin, mitomycin-C, ciprofloxacin, oral
contraceptives, gencytobine
— Other infections: S penumoniae
— Pregnancy
— Neoplasms
— Collagen-vascular disease
— Systemic vasculitis
— Bone marrow transplantation
● Leukocytosis and fever common
● Diarrhea ranges from watery to hemor-
rhagic
● Other manifestations: fluid/electrolyte distur-
bances, hypertension, cerebral edema/sei-
zures, congestive heart failure, pulmonary
edema, arrhythmias
Therapy
● Supportive
● Of questionable or no value: anticoagulants,
fibrinolytics, IV Ig, plasma infusion, plasma-
pheresis, antiplatelet agents
Course and Prognosis
● Poor outcome associated with marked leuko-
cytosis, older age at onset, D-HUS, preg-
nancy, Shigella or pneumococcal infection,
anuria, persistent proteinuria, hypertension,
cortical necrosis
Antiphospholipid Syndrome
Pathogenesis
Induced by antibodies to phospholipid moi-
eties and/or to the phospholipid binding protein
␤2-gylcoprotein 1, resulting in TMA
Histopathology
All TMAs are histologically identical (see
TTP)
Clinical and Laboratory Features
● Diagnosis requires ⱖ1 clinical and ⱖ1 labo-
ratory manifestation
● Obstetrical: frequent first trimester spontane-
ous abortions; fetal death; prematurity
● Also may involve arterial/venous, central
418
nervous system, kidney, gastrointestinal
tract, lung, skin, skeletal, cerebrovascular,
and cardiovascular systems
● Diagnostic laboratory studies involve a dem-
onstration of antibodies to phospholipid moi-
eties and includes any of the following:
prolonged prothrombin time or partial throm-
boplastin time, abnormal Russel viper venom
test, anticardiolipin antibody, antiphospho-
lipid antibody, or false positive VDRL test
● Antibody to the phospholipid binding pro-
tein ␤2-glycoprotein 1 is frequent, but not
yet included in the diagnostic classification
● Thrombocytopenia is frequent
● May occur as a primary syndrome or associ-
ated with SLE
● May occur in a “catastrophic” form (pres-
ence of 3 organ systems)
● Renal presentations
● Acute renal failure
● Hypertension: mild to malignant
● Cortical necrosis
● Thrombotic microangiopathy
● Progressive chronic renal insufficiency to
failure
● Thrombosed renal allografts
Therapy
● Anticoagulation for the primary syndrome
and those with SLE (INR ⬎3)
● Avoid prothrombotic drugs (calcineurin an-
tagonists, oral contraceptives, hydralazine,
procainamide, chlorpromazine)
● ASA in women with prior pregnancy com-
plications
ADLER AND SALANT
● Hydroxychloroquine/chloroquine in SLE
● Role in prevention of thrombosis is con-
troversial
● Pregnancy management
● Addition of steroids, plasmapheresis, IVIg
implemented as salvage therapy in patients
with severe and/or multiple organ involve-
ment
Course and Prognosis
● Long-term anticoagulation required
● Mortality of “catastrophic” syndrome ap-
proximately 50%
REFERENCES
1. Tsai H-M: Von Willebrand factor, ADAMTS13, and
thrombotic thrombocytopenic purpura. J Mol Med 80:639-
647, 2002
2. Rock GA, Shumack KH, Buskard NA, et al, and the
Canadian Apheresis Group: Comparison of plasma ex-
change with plasma infusion in the treatment of thrombotic
thrombocytopenic purpura. N Engl J Med 325:393-397,
1991
3. Tsai H-M, Lian C-Y: Antibodies to von Willebrand
factor cleaving protease in acute thrombocytopenic purpura.
N Engl J Med 339:1585-1594, 1998
4. Remuzzi G, Galbusera M, Noris M, et al, and the
Italian Registry of recurrent and familial HUS/TTP: von
Willebrand factor cleaving protease (ADAMST13) is defi-
cient in recurrent and familial thrombotic thrombocytopenic
purpura and hemolytic uremic syndrome. Blood 100:778-
785, 2002
5. King AJ: Acute inflammation in the pathogenesis of
hemolytic-uremic syndrome. Kidney Int 61:1553-1564, 2002
6. Andreoli SP, Trachtman H, Acheson DWK, Siegler
RL, Obrig TG: Hemolytic uremic syndrome: Epidemiology,
pathophysiology, and therapy. Pediatr Nephrol 17:293-298,
2002
7. Moake JL: Mechanisms of disease: Thrombotic mi-
croangiopathies. N Engl J Med 347:589-600, 2002