An Outline of Essential Topics in Glomerular Pathophysiology ...

An Outline of Essential Topics in Glomerular Pathophysiology ... An Outline of Essential Topics in Glomerular Pathophysiology ...

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CORE CURRICULUM IN NEPHROLOGY An Outline of Essential Topics in Glomerular Pathophysiology, Diagnosis, and Treatment for Nephrology Trainees Introduction, p. 215 GLOMERULAR STRUCTURE AND FUNCTION KNOWLEDGE OF the structure and function of the glomerulus aids in understanding the clinical manifestations of glomerular diseases. Glomerular capillaries are efficient filters that selectively retard the permeation of macromolecular 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 gradient 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 capillaries; 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 31 integrins and dystroglycans and are also coated with podocalyxin. Adjacent foot processes are separated by gaps that form the filtration pathway (filtration slits) and are bridged by a zipper-like slit-diaphragm. The slit-diaphragms constitute the final barrier to macromolecular permeation and contain nephrin, the immunoglobulin (Ig)-like transmembrane protein that is mutated in congenital nephrotic syndrome. Additional proteins anchor the slit- Sharon G. Adler, MD, and David J. Salant, MD 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 glomerular capillary surface area. A small population 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 integrins, 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, tenascin, and chondroitin sulfate proteoglycans. The result of this composition is that the capillary wall is rich in negatively charged residues and the permeation of plasma proteins from capillary lumen to urinary space is restricted on From the Department of Medicine, Harbor-UCLA Medical Center, Torrance, CA; and the Department of Medicine, Evans Biomedical Research Center, Boston University Medical 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 American Journal of Kidney Diseases, Vol 42, No 2 (August), 2003: pp 395-418 395

CORE CURRICULUM IN NEPHROLOGY

An Outline of Essential Topics in Glomerular Pathophysiology,

Diagnosis, and Treatment for Nephrology Trainees

Introduction, p. 215

GLOMERULAR STRUCTURE AND FUNCTION

KNOWLEDGE OF the structure and function

of the glomerulus aids in understanding

the clinical manifestations of glomerular diseases.

Glomerular capillaries are efficient filters

that selectively retard the permeation of macromolecular

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 gradient

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 capillaries;

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 31 integrins and dystroglycans

and are also coated with podocalyxin.

Adjacent foot processes are separated by

gaps that form the filtration pathway (filtration

slits) and are bridged by a zipper-like

slit-diaphragm. The slit-diaphragms constitute

the final barrier to macromolecular permeation

and contain nephrin, the immunoglobulin

(Ig)-like transmembrane protein that

is mutated in congenital nephrotic syndrome.

Additional proteins anchor the slit-

Sharon G. Adler, MD, and David J. Salant, MD

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 glomerular

capillary surface area. A small population

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 integrins,

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, tenascin,

and chondroitin sulfate proteoglycans.

The result of this composition is that the

capillary wall is rich in negatively charged residues

and the permeation of plasma proteins from

capillary lumen to urinary space is restricted on

From the Department of Medicine, Harbor-UCLA Medical

Center, Torrance, CA; and the Department of Medicine,

Evans Biomedical Research Center, Boston University Medical

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

0272-6386/03/4202-0044$30.00/0

doi:10.1016/S0272-6386(03)00692-9

American Journal of Kidney Diseases, Vol 42, No 2 (August), 2003: pp 395-418 395

396

the basis of molecular charge as well as molecular

size. In effect, negatively charged macromolecules

encounter narrower “pores” than do positively

charged molecules of the same size. Thus

albumin, which would be freely filtered on the

basis of its size (69,000 daltons), is retarded by

virtue of its overall negative charge.

Determinants of Glomerular Filtration Rate

● Transmembrane hydrostatic pressure (P)

● Filtration surface area (S)

● Hydraulic conductivity of the capillary wall

(K)

● inversely proportional to “pore” length

(GBM thickness)

● proportional to “pore” density (filtration

slit frequency)

ie, GFR P K f (K S).

Thus, glomerular diseases that cause occlusion

or obliteration of glomerular capillary loops

or reduce hydraulic conductivity of the glomerular

capillary wall will cause a fall in glomerular

filtration rate (GFR), whereas alterations in sizeand/or

charge-selectivity will cause proteinuria.

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

● Azotemia

● Hypercoagulability

Histology Associated With

Hematuric Syndromes

(Isolated Hematuria, ANS, or RPGN)

● Mesangial proliferative GN (eg, IgA

nephropathy)

● Focal and segmental GN (eg, lupus

nephritis WHO III, infective

endocarditis)

● Diffuse proliferative GN (eg, poststreptococcal

GN, lupus nephritis

WHO IV)

● Crescentic GN (eg, anti-GBM

nephritis, pauci-immune nephritis)

Table 2. Clinical-Pathological Correlations

Histological Lesions Associated

With Proteinuric Syndromes

(Isolated Proteinuria NS)

● Minimal change disease

● Focal and segmental

glomerulosclerosis

● Collapsing glomerulopathy

● Membranous nephropathy

● Diabetic glomerulosclerosis

● Amyloidosis

● Light-chain deposition disease

Clinical Syndromes Associated With

Glomerular Diseases

● Isolated hematuria—Microscopic or macroscopic

(red blood cell [RBC] casts)

● Acute nephritic syndrome

● Rapidly progressive glomerulonephritis

(RPGN)

● Asymptomatic proteinuria

● Nephrotic syndrome

● Combinations of above

Definition of Clinical Syndromes

See Table 1.

Clinical-Pathological Correlations

See Table 2.

ADLER AND SALANT

Diseases Presenting With Proteinuria or

Nephrotic Syndrome

Exclude transient or “benign” causes of proteinuria—eg,

exercise-induced, febrile, congestive

heart failure, orthostatic (postural) proteinuria.

Histological Lesions Associated

With Both Nephritic

and Nephrotic Features

● Membranoproliferative GN

● Fibrillary glomerulopathies

● Hereditary nephritis (Alport syndrome)

● Some cases of mesangial, focal, and

diffuse proliferative GN

CORE CURRICULUM 397

Diabetic glomerulosclerosis

Pathophysiology of Nephrotic Syndrome

● Hypoalbuminemia from urinary loss and

increased tubular catabolism of albumin

● Edema from avid sodium and water retention

by the kidney and decreased plasma

oncotic pressure in systemic capillaries due

to hypoalbuminemia

● Hyperlipidemia from increased hepatic synthesis

of lipoproteins

● Hypercoagulability from increased hepatic

synthesis of coagulation factors and loss of

regulatory factors (anti-thrombin III, protein

C and protein S) in the urine

Clinical Consequences of Nephrotic Syndrome

Table 3. Principal Secondary Causes of Nephrotic Syndrome

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

● Predisposition to infection (especially gram

positive) from low serum IgG levels

● Increased risk of thromboembolism and renal

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) inhibitor

or angiotensin II receptor blocker

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 progression

● Judicious use of diuretics to control edema

and for synergistic action with ACE inhibitors

or ARBs

● Lipid lowering agent—Benefit as yet unproven

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 unnecessary

because free hormone levels are normal—calcitriol

is occasionally indicated if

ionized calcium is reduced

● Patients on extended corticosteroid

therapy—monitor bone density and supplement

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 glomerular

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 systemic

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 immunosuppressive

treatment

● Relapse is common (50%)

● Cyclophosphamide or cyclosporin is effective

in steroid-dependent and frequently relapsing

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 effacement

of podocyte foot processes.

REFERENCES

1. Rifkin IR, Salant DJ: Immune-mediated glomerulopathies,

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-

change glomerular nephritis. Normal kidneys in an abnormal

environment? Transplantation 58:849-852, 1994

3. Nolasco F, Cameron JS, Heywood EF, Hicks J, Ogg C,

Williams DG: Adult-onset minimal change nephrotic syndrome:

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 “permeability-inducing”

factor seems to account

for cases that recur after transplantation

● By analogy to experimental models, glomerular

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 familial;

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 analgesic

nephropathies, renal ablation in early

childhood, or “healed” proliferative GN;

also in morbid obesity; often presents as

asymptomatic proteinuria

Course and Treatment

ADLER AND SALANT

● 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 improves

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 399

and hyalinosis of the glomerular tuft, expansion

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 podocytes;

secondary FSGS—patchy effacement

of podocyte foot processes

REFERENCES

1. D’Agati V: The many masks of focal segmental glomerulosclerosis.

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 randomized

trial of cyclosporine in patients with steroid-resistant

focal segmental glomerulosclerosis. North America Nephrotic

Syndrome Study Group. Kidney Int 56:2220-2226,

1999

Collapsing Glomerulopathy (CG)

Pathogenesis

● Most cases are associated with human immunodeficiency

virus (HIV) infection; a similar

lesion in a murine transgenic model of

HIV-associated nephropathy (HIVAN) and

viral detection studies suggest that HIV infects

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 possibility

of other viral infections such as parvovirus;

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

● Clues to diagnosis include large echogenic

kidneys and very broad waxy urinary casts

Course and Treatment

● The majority of patients progress to endstage

renal failure within 13 months; treatment

with steroids and immunosuppressives

is generally ineffective, although rare

cases of idiopathic CG may undergo spontaneous

remission and there are some reported

cases of steroid-associated remission;

ACE inhibitors may reduce proteinuria

and slow progression

● The incidence of HIVAN may have declined

since introduction of highly active

antiretroviral treatment (HAART) and

HAART plus prednisone may slow the progression

of established HIVAN

Histopathology (Am J Kidney Dis Vol. 36, No.

3, September 2000, Atlas)

● LM: Focal and segmental glomerulosclerosis

with collapse of the glomerular tufts,

wrinkling of the GBM, and visceral epithelial

cell hyperplasia and severe microcystic

changes of the tubules with interstitial fibrosis

● IF: Negative except for IgM and C3 in

sclerotic lesions

● EM: Effacement of podocyte foot processes

and degeneration of podocytes; tubuloreticular

structures in glomerular endothelial

cells (especially in HIVAN)

REFERENCES

1. Detwiler RK, Falk RJ, Hogan SL, Jennette JC: Collapsing

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 clinicopathological

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 HIVassociated

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 directed

at an unknown podocyte protein; a

rare case of neonatal MN due to allosensitization

of the mother to neutral endopeptidase

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, antibody-induced

assembly of the membrane

attack complex of complement causes podocyte

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 African

Americans)

● Peak incidence 4 th to 6 th 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), hypertension,

and azotemia, tubulointerstital fibrosis,

and glomerulosclerosis

● ACE inhibitor or ARB as tolerated to lower

BP to 125/75 and reduce proteinuria, lipidlowering

agent, and diuretic as tolerated for

control of anasarca

● Cytotoxic agents and prednisone are indicated

for progressive cases and those with

symptomatic nephrotic syndrome at risk for

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 normal

in early MN; later, the GBM is thickened

and the capillary wall appears more

rigid than normal; in advanced cases, the

capillary wall is with spikes of GBM extending

between and around subepithelial deposits.

Advanced glomerular lesions are associated

with tubular atrophy and interstitial

fibrosis

● IF: Granular glomerular capillary wall deposits

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 endothelial

cell tubulo-reticular structures (lupus

MN) and mesangial deposits (hepatitis Bassociated,

lupus MN)

REFERENCES

1. Cattran DC: Idiopathic membranous glomerulonephritis.

Kidney Int 59:1983-1994, 2001

2. Debiec H, Guigonis V, Mougenot B, et al: Antenatal

membranous glomerulonephritis due to anti-neutral endopeptidase

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

ADLER AND SALANT

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 401

● AA amyloid—Overproduction and proteolysis

of serum AA protein, an acute-phase

reactant, in chronic inflammatory states (eg,

rheumatoid arthritis, juvenile rheumatoid arthritis,

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 progressive

renal failure

● Multiorgan involvement is common, including

cardiac, gastrointestinal, cutaneous, autonomic

and peripheral nerve disease

● Diagnosis is made by finding Congo redpositive

material in affected tissues including

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 dialysis;

cardiac disease confers the gravest prognosis

● Intensive treatment of AL amyloidosis with

melphalan and prednisone autologous

stem cell replacement may induce hematological

remission and halt progression in

some cases

● Treatment of AA amyloidosis is limited to

controlling inflammation or chronic infection,

including colchicine for FMF; experimental

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

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 amyloidosis

and glomerular diseases with monoclonal immunoglobuli

deposition, in Johnson RJ, Feehally J (eds): Comprehensive

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-associated

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 albuminuria

renal insufficiency or with nephrotic

syndrome

● Albuminuria in a patient with myeloma indicates

either LCDD or development of amyloidosis

● 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 morbidity

402

Histopathology (Am J Kidney Dis Vol. 32, No.

6, December 1998, Atlas)

● LM: Nodular glomerulosclerosis indistinguishable

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 monoclonal

immunoglobulin deposition disease: The disease spectrum.

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 features,

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 monoclonal

Ig that forms Condo red-negative microtubular

structures and may be associated

with a monoclonal gammopathy or lymphoproliferative

disease

Clinical and Laboratory Features

● The clinical presentation of FGN and ITGN

is the same with variable amounts of proteinuria,

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, antiviral

titers, or cryoglobulins in either FGN

or ITGN

● ITGN may be associated with chronic lymphocytic

leukemia or non-Hodgkin’s lymphoma;

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 proliferation

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 (especially

IgG4 in FGN); monoclonality is documented

in ITGN by positive staining for

or light chains

● EM: Randomly arranged fibrils in mesangial,

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 concepts

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) glomerulopathy

are associated with distinct immunologic features.

Kidney Int 62:1764-1775, 2002

Hereditary Nephropathies

ADLER AND SALANT

Alport Syndrome and Thin Basement Membrane

Disease

Pathogenesis

● Alport syndrome (AS) is X-linked in approximately

80% of cases; mutations of the

gene for 5 type IV collagen (COL4A5)

lead to defective assembly of the GBM in

CORE CURRICULUM 403

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 mutations

of the genes for 3 (COL4A3) or 4

(COL4A4) type IV collagen on chromosome

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 resulting

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 proteinuria

nephrotic syndrome, hypertension,

and progressive renal failure develop

during adolescence in males but may be

delayed into adulthood; most females retain

normal renal function despite persistent hematuria

● The clinical features in autosomal recessive

AS are the same as in X-linked disease,

except that females are equally affected

● Extrarenal manifestations including sensorineural

hearing loss and/or ocular abnormalities

may be present in either X-linked or

autosomal AS; rarely, esophageal leiomyomas

are found in X-linked AS

● Diagnosis depends on clinical features, family

history, screening family members for

hematuria, or classical renal biopsy findings;

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 circumstances,

eg, to exclude the carrier state in an

asymptomatic potential kidney donor

● Most patients with thin basement membrane

disease remain asymptomatic except for microscopic

and occasional episodes of gross

hematuria; however, as with female carriers

of X-linked AS, proteinuria, hypertension,

and renal insufficiency may occur

Course and Treatment

● End-stage renal disease (ESRD) usually occurs

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 proportion

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 glomerulosclerosis

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 focally

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 reduced

by comparison with age-matched normal

controls but otherwise appears normal;

the podocytes and endothelial cells are normal

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 hematuria.

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 chromosome

19

● NPHS1 encodes nephrin, an Ig-like transmembrane

protein and a major constituent

of the podocyte slit-diaphragm

● Histology shows sclerosis of glomeruli, microcystic

dilatation of tubules and interstitial

fibrosis on light microscopy, and podocyte

abnormalities and absence of slitdiaphragms

on electron microscopy

● Early nephrectomy, dialysis and renal transplantation

may be life saving

● Recurrent nephrotic syndrome develops after

transplantation in some cases and may be

due to allosensitization to nephrin in the

allograft

Steroid-Resistant Nephrotic Syndrome

● Autosomal recessive, steroid-resistant nephrotic

syndrome (SRNS) in early childhood

due to mutation of NPHS2 on chromosome

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 apparently

idiopathic cases of steroid-resistant

focal glomerulosclerosis

● Histology shows focal and segmental glomerulosclerosis

with podocyte abnormalities

on electron microscopy

Familial Focal Glomerulosclerosis

● Autosomal dominant disease in which several

members of affected families have

asymptomatic proteinuria, nephrotic syndrome,

and/or renal insufficiency in adult

life due to mutations of ACTN4 on chromosome

19

● Alpha actinin 4 (ACTN4) encodes -actinin-4,

a podocyte-specific actin-bundling

protein

● Other forms of familial focal glomerulosclerosis

exist in which the affected gene has

not been identified

Congenital Syndromes Associated With

Glomerular Abnormalities

● Nail-patella syndrome is an autosomal dominant

disease with dysplastic finger nails,

skeletal anomalies, and proteinuric renal

disease due to mutation of LMX1B, a podocyte-specific

transcription factor that regulates

the coordinated expression of 3 and

4 type IV collagen and podocin genes and

is characterized by GBM and podocyte abnormalities

● Two syndromes are caused by different mutations

of the Wilms tumor suppressor gene

1 (WT1):

— Denys-Drash syndrome—Ambiguous or

female genitalia, XY karyotype and dysgenetic

gonads, Wilms tumor, and proteinuria

from diffuse mesangial sclerosis

during the first year of life

— Frazier syndrome—Male pseudo-hermaphroditism

with female external genitalia,

streak gonads and XY karyotype,

gonadoblastoma, and nephrotic syndrome

due to focal and segmental glomerulosclerosis,

progressing to end-stage renal

failure in adolescence or early adulthood

REFERENCES

1. Pollak MR: Inherited podocytopathies: FSGS and nephrotic

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 segmental

glomerulosclerosis. Nat Genet 24:251-256, 2000

3. Kestila M, Lenkkeri U, Mannikko M, et al: Positionally

cloned gene for a novel glomerular protein—nephrin—is

mutated in congenital nephrotic syndrome. Mol Cell

1:575-582, 1998

4. Boute N, Gribouval O, Roselli S, et al: NPHS2, encoding

the glomerular protein podocin, is mutated in autosomal

recessive steroid-resistant nephrotic syndrome. Nat Genet

24:349-354, 2000

Diabetic Nephropathy

Pathogenesis

ADLER AND SALANT

● Magnitude of pathogenetic features effects

is likely modulated by genetic factors

● Numerous risk genes have been reported,

but these require confirmation

CORE CURRICULUM 405

● 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 expansion

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 expansion;

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 normoalbuminuric

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 frequency

in ethnic minorities

— Progression from microalbuminuria to

overt proteinuria in the pre-ACE inhibitor

era was estimated to be approximately

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 approximately

40% to 50%

— Microalbuminuria is a cardiovascular

morbidity/mortality risk factor

● Overt Proteinuria

— Defined as 500 mg proteinura/24 h,

occurs approximately 15 to 20 years after

developing Type 1 diabetes or 5 to

10 years after diagnosis of Type 2 diabetes

— Most have concomitant diabetic retinopathy

(concordance of retinopathy is

higher for Type 1 than Type 2 diabetics)

— Progression to overt nephropathy occurs

more frequently in ethnic minorities compared

to European-Americans

— Urinalysis generally bland, although microscopic

hematuria may be seen in approximately

15% of patients

— Azotemia follows the onset of overt nephropathy

— 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 patients

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 primary

glomerulopathy

Therapy

● Glycemic control prevents/delays progression

from normoalbuminuria to microalbuminuria

and from microalbuminuria to overt

nephropathy. Goal HbA1c 7%

● Blood pressure control diminishes the risk

of developing nephropathy and slows progressive

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 cardiovascular

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 widespread

vascular damage. The Steno hypothesis. Diabetologia

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 cardiovascular

outcomes in patients with type 2 diabetes and nephropathy.

N Engl J Med 345:870-878, 2001

6. Parving H-H, Lehnert H, Brochner-Mortensen J, Gomis

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 microvascular

complications of type 2 diabetes (UKPDS 36): Prospective

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 glomerulonephritis

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 mediators

then modulate the local inflammatory response.

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, tumor

antigen, etc). The level and persistence of

immune complexes is dependent upon the source

and amount of antigen, the potency and duration

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 antibody

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 dysregulation

of autoreactive T- and/or B-cell

clones

● Vast majority of these patients have antibodies

to neutrophil lysosomal antigens (cantineutrophil

cytoplasmic antibody

[ANCA] or p-ANCA, see below)

● Clinical examples include: Wegener granulomatosis,

microscopic polyangiitis (microscopic

polyarteritis nodosa), Churg-Strauss

disease, and idiopathic crescentic glomerulonephritis

Secondary Mediators of Inflammation

Complement

● Complement functions: Cell lysis or injury,

chemotaxis, opsonization, immune complex

solubilization, enhanced vascular permeability

● C5b-9 membrane attack complex (MAC)

induces cell membrane lysis and injury;

urinary MAC may reflect degree of glomerular

injury, particularly in membranous nephropathy

Cytokines

ADLER AND SALANT

● Regulate cell proliferation, differentiation,

phenotype, secretion, and/or migration

● Cytokine families include:

— Interleukins

— Colony-stimulating factors

CORE CURRICULUM 407

— Interferons

— Chemokines

— Growth factors

A description of a few cytokines/growth factors

that are important in the kidney follows:

● Transforming growth factor-

— Master regulator of matrix synthesis and

degradation; promotes fibrosis

— Regulates cell proliferation and differentiation,

wound healing, angiogenesis

— Pathogenetically implicated in most experimental

forms of glomerulonephritis

— Increased in human diabetic nephropathy

● Platelet-derived growth factor

— Increases mitogenesis, chemotaxis, mesangial

cell contraction

— Implicated in the pathogenesis of IgA

nephropathy, diabetic nephropathy

● Insulin-like growth factor-1/growth hormone

— Implicated in the pathogenesis of renal

hypertrophy and glomerulosclerosis

● Adhesion molecules/integrins/selectins

— Regulate cell-cell and cell-matrix interactions

— Coordinates (in concert with cytokines

and chemokines) the development of immune

and inflammatory reactions

— Facilitates signaling from inside the cell

to the outside matrix and from outside

the cell to the nucleus via the cytoskeleton

Reactive Oxygen Species

● Potential injurious agents—primarily O ,

H2O2,OH ,HOCl

— Detoxification: enzymes (superoxide dismutase,

catalase); O2 scavengers

Signal Transduction Molecules

● Exogenous molecules such as cytokines,

chemokines, growth factors, and hyperglycemia

induce activation of intracellular signaling

molecules within cells

● Signaling pathways such as the mitogenactivated

protein kinases and the protein

kinase C pathway mediate actions of the

extracellular signals by inducing the formation

of nuclear transcription factors, which

bind to regions on genes and activate them

● These mediate change in experimental models

of glomerular disease

REFERENCES

1. Rifkin IR, Salant DJ: Immune-mediated glomerulopathies,

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 species

in glomerulonephritis. Nephrol Dial Transplant 15:1127-

1132, 2000

DISORDERS ASSOCIATED WITH NEPHRITIS

Membranoproliferative Glomerulonephritis

(MPGN)

Pathogenesis

Three distinct entities defined by histopathology.

● Type I: The most common form; immunecomplex

mediated

● Type II (dense deposit disease): Less common;

in animal models and some families,

there is a deficiency or absence of complement

Factor H

● Type III: Rare; immune-complex mediated

Pathology

● Type I: Mesangial hypercellularity with subendothelial

and mesangial immune complex

deposits, capillary wall mesangial interposition,

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 material

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 collagen-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 glomerulonephritis

● Hypertension and diminished GFR may be

present at diagnosis

● 80% of patients with Type 1 MPGN have

underlying hepatitis C; less commonly, hepatitis

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 (approximately

20%), arthritis, and skin leukocytoclastic

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 activation

● Usually sporadic, but some hereditary, particularly

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, particularly

with a live-related donor

Therapy

● No consensus. All of the following have

been used:

— Used singly or in combination: glucocorticoids,

dipyridamole, warfarin, and/or

aspirin with or without cyclophosphamide

— Steroids/immunosuppressives may enhance

viral replication in hepatitis-associated

MPGN; may be necessary with

complicating cryoglobulinemic vasculitis

— Cyclosporine, mycophenolate mofetil,

and intravenous (IV) Igs used anecdotally

— ACE inhibitor/ARB for their antiproteinuric

effects

— Pegylated interferon and ribavirin have

not been studied systematically for effects

on nephritis

— Ribavirin is contraindicated with GFR

50%

REFERENCES

1. Andresdottir MB, Assmann KJ, Hoitsma AJ, Koene

RA, Wetzels JF: Recurrence of type I membranoproliferative

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: Membranoproliferative

glomerulonephritis associated with hepatitis C

virus infection. N Engl J Med 328:465-470, 1993

3. D’Amico G, Ferrario F: Cryoglobulinemic glomerulonephritis:

A MPGN induced by hepatitis C virus. Am J

Kidney Dis 25:361-369, 1995

IgA Nephropathy (Berger’s Disease)

Pathogenesis

● Mesangial deposition of undergalactosylated

polyclonal IgA1

● Origin of IgA1 controversial, but may derive

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 matrix

expansion

Clinical Associations

ADLER AND SALANT

● Primary idiopathic form

● Secondary forms: Henoch-Schönlein purpura,

alcoholic cirrhosis, gluten enteropathy,

HLA-B27 arthritides, IgA monoclonal

gammopathies, dermatitis herpetiformis,

psoriasis

● Some familial forms

CORE CURRICULUM 409

Histopathology (Am J Kidney Dis Vol. 31, No.

1, January 1998, Atlas)

● LM: global or segmental mesangial hypercellularity;

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 clustering

at the paramesangial basement membrane.

Clinical and Laboratory Features

● Most common primary glomerulonephritis

in the world

● Varied clinical presentation

— Asymptomatic; microscopic hematuria;

intermittent gross hematuria; synpharyngitic

hematuria; nephrotic (15%) or

nonnephrotic proteinuria; acute glomerulonephritis;

rapidly progressive glomerulonephritis

● Often associated with hypertension

● Approximately 50% of patients have increased

serum IgA levels

Course and Prognosis

● 20-year renal survival approximately 50%

to 70%

● Risk factors for progression: heavy proteinuria,

diminished GFR at onset, older age at

onset, uncontrolled hypertension, crescents,

tubulointerstitial fibrosis/atrophy, familial

forms

● Prognostic value of gross hematuria is controversial

● 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 studies

● Steroids, steroids plus short-term cyclophos-

phamide followed by azathioprine, and combinations

of steroids, cytotoxics, coumadin,

and dipyridamole beneficial in some but not

all studies

● Mycophenolate mofetil under study in randomized

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: Corticosteroids

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 nephropathy.

J Am Soc Nephrol 13:142-148, 2002

Henoch-Schönlein Purpura Nephritis (HSP)

Pathogenesis

● Similar to IgA nephropathy (above), but

with widespread systemic involvement, particularly

in the kidneys, skin and gastrointestinal

tract

Histopathology: Highly Variable

● LM:

—Minimal changes (2%)

— Mild mesangial hypercellularity, few leukocytes

(10% to 32%)

— Focal/segmental mesangial hypercellularity,

more WBCs (20% to 45%)

— Diffuse mesangial hypercellularity, up to

50% crescents (15%)

● IF: Granular mesangial IgA with C3, fibrinogen,

both light chains, lesser amounts of

IgG/IgM

● EM: Mesangial electron dense deposits; occasional

involvement of capillary loops; variable

foot process effacement; occasional

GBM thinning, thickening, and lamellation

Clinical and Laboratory Features

● Classical clinical triad is purpura, abdominal

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 rheumatologic

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 approximately

1 month

● Extrarenal involvement often lasts 1 month

● Overall good renal outcome; complete recovery

in approximately 90% adults

● Protracted courses and relapse may occur

● Prognosis poorer in acute nephritic syndrome

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 controversial

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 combinations

of steroids, cyclophosphamide, dipyridamole,

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 autoantibody

production

● Leads to immune complex deposition

● The latter induces activation of complement

and elaboration of chemokines and cytokines,

resulting in leukocyte chemotaxis,

mesangial hypercellularity and matrix expansion,

occasionally fibrinoid necrosis

and/or crescentic GN, and glomerulosclerosis

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) classification

of 1982 (currently undergoing revision):

I—Normal; II—Mesangial proliferation

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, subendothelial,

occasional subepithelial;

V—subepithelial) and frequently endothelial

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

ADLER AND SALANT

● Nonnephrotic or nephrotic range proteinuria,

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 precedes

systemic lupus erythematosus

(SLE) diagnosis

● Hypertension (50%)

● Hypocomplementemia (particularly direct

pathway components C2, C3, C4) approximately

90% in DPGN/FPGN

● Systemic: Arthralgias, nondeforming arthritis,

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 411

● Progression to renal failure is more common

in FPGN and DPGN

— Improved prognosis for DPGN; progression

to ESRD in 5 years now approximately

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 creatinine,

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 toward

treating DPGN because of its serious

prognosis if inadequately treated

— The more sclerosis and tubulointerstitial

fibrosis on biopsy the greater the likelihood

of progression

● Treatment of mesangial proliferation

— Treat extrarenal manifestations only

● Treatment of FPGN/DPGN

— Current regimens of prednisone, methylprednisolone

pulsing, and IV cyclophosphamide

improved prognosis

— Optimal duration of treatment course

controversial

— Concerns regarding toxicity, including

sepsis, hemorrhagic cystitis, bladder cancer,

and ovarian failure spurred assessment

of alternative regimens

— Continued interest in the use of azathioprine

to induce and/or consolidate remission

— Recent reports suggest results with mycophenolate

mofetil equivalent to cyclophosphamide

to induce or consolidate

remission

— Fewer side-effects with mycophenolate

mofetil

— Long-term renal survival is currently

unknown with mycophenolate mofetil

— Still very controversial

— 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 under

investigation

● Treatment of membranous lupus nephritis

— ACE inhibitor/ARB initially to minimize

proteinuria

— Steroids for extrarenal manifestations

— If proteinuria remains nephrotic and/or serum

creatinine is rising, consider cyclosporine

or IV cyclophosphamide and steroids

— Preliminary studies from NIH suggest

benefit with these beyond steroids alone

— Relapse after achievement of complete remission

is common, occurring in 45% of

patients at a median time of 36 months,

emphasizing the need for continued follow-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: Advances

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 controlled

studies. Arthr Rheum 46:995-1002, 2002

5. Houssiau FA, Vasconcelos C, D’Cruz D, et al: Immunosuppressive

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 inflammatory

processes activate polymorphonuclear

leukocytes and endothelial cells, leading to:

— Local generation of cytokines

412

— Translocation of ANCA lysosomal antigens

proteinase-3 (PR3) or myeloperoxidase

(MPO) to the cell membrane

— Specific anti-PR3 or anti-MPO antibodies

bind and further activate target neutrophils

to secrete damaging reactive oxygen

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 immunofluorescence

(IIF) for the pattern of antigen expression

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 glomerulonephritis;

segmental necrotizing glomerulonephritis;

crescents

● IF: Pauci-immune glomerulonephritis; fibrin

may be present in crescents; tubulointerstitial

granulomas

● EM: No immune deposits are seen

Laboratory Diagnosis

● cANCA is specific and sensitive for diagnosing

untreated patients

● Some patients (approximately 20% to 30%)

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 ulceration

● Lung involvement in 80% of patients,

most often cough, dyspnea, hemoptysis; transient

infiltrates or nodular densities may be

seen on chest x-ray (CXR)

● Renal involvement characterized by proteinuria,

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

ADLER AND SALANT

● Oral cyclophosphamide dramatically improved

survival in uncontrolled trials

● High incidence of bladder cancer the decade

following prolonged treatment with daily

oral cyclophosphamide

● IV cyclophosphamide advocated to diminish

side effects

● Oral and IV cyclophosphamide protocols

are roughly equivalent in remission induction

efficacy, but oral may be marginally

better than IV in preventing relapse

● Steroids useful adjunctive therapy, particularly

in patients with severe renal or pulmonary

disease, skin or cerebral vasculitis, eye

involvement, or pericarditis

● In situations with severe pulmonary hemorrhage

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 intensive

cyclophosphamide-based regimens;

long-term efficacy and relapse rates not yet

known

● Sulfamethoxazole/trimethaprim may dimin-

CORE CURRICULUM 413

ish relapse rates, particularly respiratory,

but drug intolerance is common

● In refractory patients, the following have

been tried with limited success: mycophenolate

mofetil, IV Ig, anti–tumor necrosis factor

(TNF) drugs (etanercept; infliximab);

antithymocyte globulin, deoxyspergalin, leflunomide

Course and Prognosis

● 80% to 90% 1-year mortality if left untreated

● 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 typical

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 respiratory

tract involvement, although alveolar

capillaritis without granulomatous change

causing hemoptysis can occur

● The following medications have been associated

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 pulmonary

infiltrates

Laboratory Diagnosis

Usually pANCA (MPO) positive

Clinical Presentation

● Eosinophilia and necrotizing vasculitis in

the presence of asthma

● Vasculitis can affect lung, skin, peripheral

nerves, muscles, intestine, and kidneys, although

glomerulonephritis is usually (but

not always) mild

● Associated with leukotriene antagonist

therapy, but causation not proven

Treatment and Course

● Glomerular involvement usually mild; severe

crescentic glomerulonephritis is rare

● Progression to ESRD is uncommon

● Therapy is similar to other forms of vasculitis

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, characterized

by gross or microscopic hematuria,

nonnephrotic proteinuria, red cell urinary

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. Kidney

Int 60:1614-1627, 2001

2. Xiao H, Heeringa P, Hu P, et al: Antineutrophil cytoplasmic

autoantibodies specific for myeloperoxidase cause glomerulonephritis

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 volatile

hydrocarbon exposure, smoking, influenza

● 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 hypercellularity,

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 coincident

with renal symptoms 70% 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 deficiency

characteristics due to pulmonary

hemorrhage

— Hypertension uncommon (20%)

— U/A shows hematuria, red cell casts, nonnephrotic

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 plasmapheresis,

glucocorticoids, and cytotoxic

agents in patients with serum creatinine 5

mg/dL (442 mol/L)

● 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 remissions

reported

● Smoking and volatile hydrocarbon exposure

exacerbates pulmonary hemorrhage and

may precipitate recurrence

● Recurrence in renal allografts is rare if antibody

titers are negative

REFERENCES

1. Salama AD, Levy JB, Lightstone L, Pusey CD: Goodpasture’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

ADLER AND SALANT

● Due to an immune response to infection

with nephritogenic Group A (rarely Groups

CorG)-hemolytic streptococcus

● Deposited antibodies may be directed at

streptococcal antigens and/or intrinsic glomerular

epitopes such as extracellular matrix

● Local activation of the complement cascade,

interleukin-6 (IL-6), intercellular adhesion

molecule-1 (ICAM-1), and the plasminplasminogen

system contribute to local

inflammation

Histopathology (Am J Kidney Dis Vol. 31, No.

5, May 1998, Atlas)

● LM: Glomerular tufts are enlarged, hypercellular,

with leukocytes in glomerular capillaries;

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 415

deposits. Has been associated with chronicity

— Mesangial describes a mesangial-predominant

pattern of immune deposits

— Garland describes predominantly capillary

wall deposits

● EM: Subepithelial “hump” shaped deposits;

some mesangial and subendothelial deposits

Clinical and Laboratory Manifestations

● Typically a preceding throat or skin infection

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 glomerulonephritic

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 elevated

with a preceding throat infection.

Antihyaluronidase and anti-DNAse B titers

are more common with preceding skin infections

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 hypertensive

seizures may occur

● Supportive dialysis as necessary

Course and Prognosis

● Complete resolution of hematuria/proteinuria

may take months to years

● Renal prognosis favorable in children except

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 mesangium

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 patients

with a history of rheumatic heart disease

● May also complicate aortic sclerosis/mitral

valve prolapse

Presentation

● Fever, myalgias, malaise, arthralgias, anemia,

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 involvement

more common

● Hypocomplementemia (low C3 and C4),

416

normochromic normocytic anemia, leukocytosis,

elevated sedimentation rate, and elevated

C-reactive protein are characteristic

● Low-level cryoglobulinemia is frequent

Therapy

● Supportive care in conjunction with treatment

of the underlying infection

● In patients with crescentic glomerulonephritis,

anecdotal reports suggest benefit from

steroids, immunosuppression, and/or plasmapheresis

after or in conjunction with antibiotics

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 proteinuria,

hypertension, and/or azotemia

Other Infection-Related Syndromes

● Chronic visceral abscess

● Shunt nephritis

● Pneumonia

REFERENCE

1. Adler SG, Cohen AH: Glomerulonephritis with bacterial

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 factor

(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 activation

and aggregation, and leads to intravascular

platelet thrombi, organ ischemia, and

necrosis

● Defective vWF cleavage typifies active TTP

and distinguishes it from other causes of

hemolysis, thrombosis, or thrombocytopenia

● vWF cleaving protein is a zinc metalloproteinase

named “a disintegrin and metalloprotease

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, microangiopathic

hemolytic anemia, thrombocytopenic

purpura, renal disease, central nervous

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, cyclophilin

inhibitors, ticlopidine

— Collagen-vascular disorders: SLE, scleroderma

— Malignancy

— Infections: HIV

Therapy

ADLER AND SALANT

● Plasma infusion provides missing enzyme

activity

● Plasma exchange removes any circulating

vWF cleaving protein inhibitor and facilitates

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 417

● 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 defective

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

(DHUS), it is postulated that Shiga-like

toxin binds to colonic epithelium and induces

elaboration of chemokines and cytokines,

causing polymorphonuclear (PMN)

influx and abrogation of barrier function,

permitting Shiga-like toxin to enter the circulation

free or bound to PMNs

● Toxin binds to glomerular/renal arteriolar

and proximal tubular epithelial cell receptors,

resulting in local inflammation, endothelial

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

● DHUS induced by organisms producing a

Shiga-like toxin (predominantly Escherichia

coli O157:H7) or other enteric infections

(Shigella, Salmonella, Campylobacter,

Yersinia)

— Epidemics associated with ingestion of

undercooked hamburger

● May also occur in a nondiarrheal form (D-

HUS)

— Inherited form (complement factor H mutation)

— Medications: calcineurin inhibitors, rapamycin,

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 hemorrhagic

● Other manifestations: fluid/electrolyte disturbances,

hypertension, cerebral edema/seizures,

congestive heart failure, pulmonary

edema, arrhythmias

Therapy

● Supportive

● Of questionable or no value: anticoagulants,

fibrinolytics, IV Ig, plasma infusion, plasmapheresis,

antiplatelet agents

Course and Prognosis

● Poor outcome associated with marked leukocytosis,

older age at onset, D-HUS, pregnancy,

Shigella or pneumococcal infection,

anuria, persistent proteinuria, hypertension,

cortical necrosis

Antiphospholipid Syndrome

Pathogenesis

Induced by antibodies to phospholipid moieties

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 1 clinical and 1 laboratory

manifestation

● Obstetrical: frequent first trimester spontaneous

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 demonstration

of antibodies to phospholipid moieties

and includes any of the following:

prolonged prothrombin time or partial thromboplastin

time, abnormal Russel viper venom

test, anticardiolipin antibody, antiphospholipid

antibody, or false positive VDRL test

● Antibody to the phospholipid binding protein

2-glycoprotein 1 is frequent, but not

yet included in the diagnostic classification

● Thrombocytopenia is frequent

● May occur as a primary syndrome or associated

with SLE

● May occur in a “catastrophic” form (presence

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 antagonists,

oral contraceptives, hydralazine,

procainamide, chlorpromazine)

● ASA in women with prior pregnancy complications

● Hydroxychloroquine/chloroquine in SLE

● Role in prevention of thrombosis is controversial

● Pregnancy management

● Addition of steroids, plasmapheresis, IVIg

implemented as salvage therapy in patients

with severe and/or multiple organ involvement

Course and Prognosis

ADLER AND SALANT

● Long-term anticoagulation required

● Mortality of “catastrophic” syndrome approximately

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 exchange

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 deficient

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 microangiopathies.

N Engl J Med 347:589-600, 2002

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An Outline of Essential Topics in Glomerular Pathophysiology ... An Outline of Essential Topics in Glomerular Pathophysiology ...