alport syndrome, goodpasture syndrome2.pdf

8/11/2019 Alport syndrome, Goodpasture syndrome2.pdf

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of the six chains of collagen IV has three domains:there is a short 7S domain at the N-terminal; along, collagenous domain occupies the midsec-tion of the molecule; and a noncollagenous domain(NC1) is positioned at the C-terminal (Fig. 1). In spiteof many potential permutations, the six chains of

collagen IV apparently form only three sets of triple helical molecules called protomers, whichare designated as a

1.

a

1.

a

2(IV), a

3.

a

4.

a

5(IV),and a

5.

a

5.

a

6(IV).

35-37,39

These protomers createcollagenous networks by uniting two NC1 trimersto form hexamers and uniting four 7S domains toform tetramers with other protomers, as shownin the a

3.

a

4.

a

5(IV) network in Figure 2A. Only three canonical sets of hexamers form networks:

a

1.

a

1.

a

2(IV)

a

1.

a

1.

a

2(IV),a

3.

a

4.

a

5(IV)

a

3.

a

4.

a

5(IV), and a

1.

a

1.

a

2(IV)

a

5.

a

5.

a

6(IV). The x-ray crystallographic structure of the a

1.

a

1.

a

2(IV) NC1hexamer provides novel insight into the molecular

interactions that govern chain assembly and thepathophysiological mechanisms underlying Good-pastures and Alports syndromes.

48,49

A computer-generated, space-filling model of the a

3.

a

4.

a

5(IV)hexamer (Fig. 2B) shows how three NC1 domainsfold and associate as a trimeric cap for each pro-tomer, which, in turn, interacts with the trimericcap of an adjoining protomer.

36,48

Assembly of collagen IV networks is regulateddevelopmentally. The a

1.

a

1.

a

2(IV)

a

1.

a

1.

a

2(IV)network is a component of all basement membranesof all animal phyla,

50-53

whereas the a

3.

a

4.

a

5(IV)

a

3.

a

4.

a

5(IV) and a

1.

a

1.

a

2(IV)

a

5.

a

5.

a

6(IV) net-

works have a restricted distribution in mammaliantissues. The a

3.

a

4.

a

5(IV) network occurs in thekidney (in glomerular basement membrane andsome tubular basement membranes), lung, testis,cochlea, and eye,

47,54,55

and the a

5.

a

5.

a

6(IV) network is a feature of skin, smooth muscle, esopha-

gus, and kidney (Bowmans capsule).

36,37,44,56,57

During embryonic development of human glomer-ular basement membrane, the a

1.

a

1.

a

2(IV) network appears at the start of early capillary-loopformation (by embryonic day 75 [E75]) but is gradu-ally replaced by the a

3.

a

4.

a

5(IV) network in themature glomerular capillary (by day E150)

47,58,59

or by the a

5.

a

5.

a

6(IV) network in Bowmans cap-sule.

37,44,59

This developmental switch is a criticalstep in the maturation of the kidney (Fig. 3A) andperhaps other specialized tissues.

Classically, Alports syndrome consists of hematu-ria, proteinuria (less than 1 to 2 g of protein excretedper day), progressive renal failure, and sensorineu-ral deafness.

60

Lenticonus of the anterior lens cap-sule (positive oil droplet sign), retinopathy (dot and fleck reflections), and rarely, mental retardationor leiomyomatosis occur in some patients.

61,62

Clin-ical variability among kindreds with Alports syn-drome reflects the complexity of collagen genetics(involving one of three loci with multiple sites formutation), inconsistency in the assembly of col-lagen IV protomers in selected tissues, and uneven

a lpo r t s synd rome

Figure 1. Triple Helical Organization of the Type IV Collagen Family.

Six genetically distinct a

chains are arranged into three triple helical protomers that differ in their chain composition. Each protomer has a 7Striple helical domain at the N-terminal; a long, triple helical, collagenous domain in the middle of the molecule; and a noncollagenous (NC1)trimer at the C-terminal. Interruptions in the GlyXaaYaa amino acid sequence at multiple sites along the collagenous domain (white rings)confer flexibility, allowing for looping and supercoiling of protomers into networks. The selection of a

chains for association into trimeric pro-tomers is governed by molecular recognition sequences encoded within the hypervariable regions of NC1 domains.

35,37

Type IV collagen chains Protomers

NC1 monomer 7S

211

435

655

3

2

1

4

5

6

a 1.a 1.a 2

a 3.a 4.a 5

a 5.a 5.a 6

NC1 trimer

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expression of these defects. 18,19 New pedigrees usu-ally come to attention after clinical evaluation of apatient for progressive deafness or hematuria.

genetics

In approximately 85 percent of patients with Alports

syndrome there is X-linked inheritance of muta-tions in the COL4A5gene encoding the a 5(IV) col-lagen chain on chromosome Xq2648. 20,63 In fe-male carriers, penetrance is variable and dependson the type of mutation or degree of mosaicism fol-lowing lyonization of the X chromosome. Patients

with autosomal recessive disease are either com-pound heterozygotes or have homozygous muta-tions in the COL4A3 or COL4A4 gene encoding thea 3(IV) or a 4(IV) chain, respectively, on chromo-some 2q3537. 64,65 Rarely, some kindreds have anautosomal dominant inheritance of dominant neg-

ative mutations in the COL4A3 or COL4A4 gene.18

The types of mutations in these genes include mis-sense mutations, premature stop codons, splice mu-tations, and in-frame deletions. Concomitant mu-tations in the COL4A6 gene encoding the a 6(IV)chain are associated with leiomyomatosis. 66-68

Figure 2. Assembly and Network Organization of Collagen IV Protomers.Protomers create basement-membrane networks with other protomers by uniting two NC1 trimers to form an interface hexamer at the C-ter-minal and by uniting four triple helical 7S domains at the N-terminal (Panel A). A network composed of a 3.a 4.a 5(IV) protomers is illustrated,showing end-to-end connections of individual protomer units, supercoiling and looping of the triple helixes, and disulfide cross-links betweentriple helical domains. 35-37,39 The structure of the NC1 hexamer is determined by the particular a chains that form a triple helical protomerand by the particular canonical protomers that can connect to adjoining protomers (NC1 box). Molecular recognition sequences encodedwithin NC1 domains govern the selection of partner chains for both protomer and network assembly. The 7S domains also play a key part indetermining the specificity, affinity, and geometry of the tetramer formed through the connection of four protomers (7S box). 39,45,46 Two othernetworks are composed of pairs of a 1.a 1.a 2(IV) hexamers or a 1.a 1.a 2(IV)a 5.a 5.a 6(IV) NC1 hexamers.35-37,39 The a 3.a 4.a 5(IV)a 3.a 4.a 5(IV) network differs from the others in that it has a greater number of disulfide cross-links between triple helical domains, which in-creases its resistance to proteolysis. 47

Panel B shows the three-dimensional model of the a 3.a 4.a 5(IV) NC1 hexamer that is depicted in the NC1 box in Panel A. The three-dimen-sional structure and the location of epitopes were determined by computer modeling of the crystal structure of the a 1.a 1.a 2(IV)a 1.a 1.a 2(IV) hexamer48 and the apparent quaternary structure of the a 3.a 4.a 5(IV) hexamer.36 The hexamer is composed of two trimericcaps, each derived from adjacent protomers. Each trimer consists of an a 3 monomer (red), an a 4 monomer (blue), and an a 5 monomer(green). The monomers have a novel tertiary structure with two homologous subdomains, each of which is characterized by b -sheet motifs.The model depicts the location of the E A (yellow) and EB (gold) regions that encompass two dominant epitopes for Goodpasture antibodies.The epitopes reside in the a 3(IV) NC1 domain, near the triple helical junction, and they are partially sequestered by interactions with thea 5(IV) and a 4(IV) NC1 domains, respectively.

A B

7S

43

54

53

a 4

a 4

a 5

EA EB

a 5

a 3

a 3

NC1



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Figure 3. Distribution and Switches of Collagen IV Networks in Glomerular Development.

During early embryonic development (Panel A, left), the a 1.a 1.a 2(IV) network is present at all stages. In the mature glomerulus (Panel A,right), this network is a component of Bowmans capsule, mesangial matrix, and glomerular basement membrane. In contrast, the a 3.a 4.a 5(IV)and a 5.a 5.a 6(IV) networks first appear at the early capillary-loop stage. They appear to replace (dotted line) most of the a 1.a 1.a 2(IV) net-work within the glomerular basement membrane and Bowmans capsule, respectively, and they persist in the mature glomerulus. In theX-linked form of Alports syndrome (Panel B), the switch in networks is arrested (red Xs), as a result of mutations in the a 5(IV) chain. Thesemutations result in the persistence of the a 1.a 1.a 2(IV) network and the absence of the a 3.a 4.a 5(IV) and a 5.a 5.a 6(IV) networks.

EmbryonicA

Developmental

switch

35

4

55

6

11

211

2

3

5

45

3

4

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6

Immature Mature

Embryonic

Developmental

switch

Childhood Adulthood

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Immature Mature

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Most evidence suggests that chain mutationsproduce a post-translational defect in protomer as-sembly. The COL4A3 and COL4A4 genes 69 and genesthat encode for nephrin, podocin, and CD2-asso-ciated protein, forming the glomerular slit dia-phragm and allowing filtration, 70 are regulated by

a transcription factor called LMX1B, which is mu-tated in patients with the nailpatella syndrome.Carriers of a mutant LMX1B gene have a renal le-sion of variable severity, which is consistent with areduction in the a 3.a 4.a 5(IV) network in glomer-ular basement membrane 71,72 and loss of the glo-merular filtration barrier. 70

pathogenesis

Mutations present in Alports syndrome that pro-duce post-translational defects in a 3(IV), a 4(IV),or a 5(IV) chains may result in incorrect folding orassembly of monomers; such defective monomers

are rapidly degraded. These mutations, therefore,arrest the normal developmental switch (Fig. 3A)and cause the persistence of a 1.a 1.a 2(IV) networksin glomerular basement membrane (Fig. 3B). 47 Inpatients with X-linked Alports syndrome, a 3(IV),a 4(IV), and a 5(IV) collagens in most glomeruli, tu-bules, and Bowmans capsules are undetectable by immunostaining (female carriers can be mosaics).In patients with autosomal recessive Alports syn-drome, there is a 5(IV) collagen in Bowmans cap-sule but no detectable a 3(IV) ora 4(IV) collagens inglomerular or tubular basement membranes. 73 Thereason for this difference is that the a 5(IV) chain isshared by two different protomers one in the glo-merular basement membrane and the other in Bow-mans capsule. 36,57 Some a 5(IV) mutations that al-low for partial formation of a 3.a 4.a 5(IV) networksmay produce less severe phenotypes. 19

The replacement of the a 1.a 1.a 2(IV) network by the a 3.a 4.a 5(IV) network during fetal develop-ment may be related to oxidative and physical stressin renal basement membranes 74 (and perhaps alsoin the cochlea 75 and the lens capsule 76 ). In the kid-ney, as plasma traverses glomerular capillaries, theprotein content, including the levels of serum pro-teases, increases. The embryonic a 1.a 1.a 2(IV) network is more susceptible to endoproteolysis thanthe more heavily cross-linked a 3.a 4.a 5(IV) network. 47,74 It seems, then, that basement mem-branes that are more exposed to proteases or oxi-dants need the protection of a resistant collagen IVnetwork. Over time, patients with Alports syndromeprobably become more sensitive to selective base-

ment-membrane proteolysis, which may explain why their glomerular membranes thicken unevenly,split, and ultimately deteriorate. 47

The primary filtration barrier of the glomerularcapillary consists of the glomerular basement mem-brane and the outer slit diaphragm formed between

adjacent podocytes. Deterioration of the glomeru-lar basement membrane produces mild proteinuria, whereas loss of the slit diaphragm leads to massiveproteinuria. 70 Proteinuria in Alports syndrome isassociated with damage to the glomerular basement membrane that leads to sclerosis, rather than pri-mary loss of the slit pore. In pedigrees with a history of renal failure, disease usually progresses from con-comitant interstitial nephritis and the renal fibrosisthat accompanies sclerosis of the glomerular base-ment membrane. 78,79 Macrophages and lympho-cytes are found in areas of disrupted tubular base-ment membrane, 80,81 and fibroblasts are formed

by epithelialmesenchymal transition. 82,83 This fi-brogenic response destroys the renal architecture.

clinical presentation

Pedigrees with Alports syndrome vary in the ra-pidity of onset of organ failure (Table 1). In pa-tients with nonsense or missense mutations, read-ing-frame shifts, or large deletions, renal failureand sensorineural deafness generally develop by 30 years of age (in the juvenile form). In patients with splice variants, exon-skipping mutations, ormissense mutations of glycines in the collagenhelix, health usually begins to deteriorate after 30 years of age (in the adult form), and these patientshave mild or late-onset deafness. 19,84,85 A family history of early, severe deafness or lenticonus por-tends a poor prognosis in young progeny at risk. 86

The presenting sign of Alports syndrome is of-ten hematuria. Members of kindreds with a stronghistory of renal failure and deafness do not need toundergo kidney biopsy. These patients usually re-quire only an imaging study of the genitourinary tract to rule out a tumor or other defect that couldcause hematuria. The mutations in families withX-linked, recessive, or dominant Alports syndromeare not confined to a few regions of the COL4A3,COL4A4, or COL4A5 gene. Rather, they are scatteredthroughout many exons, making it difficult to develop predictive genetic tests.

findings on kidney biopsy

When examined by electron microscopy, the le-sions in kidney-biopsy specimens from patients



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* ANCA denotes antineutrophil cytoplasmic autoantibody.

Table 1. Clinical Pathophysiology of Alports and Goodpastures Syndromes.

Disease Mechanism Clinical Description

Alports syndromes

X-linkedAdult

Juvenile

Some missense mutations or splice vari-ants in the COL4A5 gene, producing areduction or distortion in a 3.a 4.a 5(IV)and a 5.a 5.a 6(IV) networks

Deletions, nonsense mutations, or mis-sense mutations in the COL4A5 gene,producing a loss of a 3.a 4.a 5(IV) anda 5.a 5.a 6(IV) networks

Delayed onset of renal failure (>30 yr of age),with mild deafness in men; less severein female carriers

Early onset of renal failure (


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with Alports syndrome are variable. The typically thin glomerular basement membranes thicken overtime into multilamellations surrounding lucent ar-eas that often contain granules of varying density the so-called split basement membrane (Fig.4A).16,87 In any one kidney from a patient with

Alports syndrome, there are areas of thinning andsplitting glomerular basement membrane. Tubulesdrop out, segmental glomerular scars progress, andthe kidneys eventually fail because of interstitial fi-brosis. Thin basement membranes are also foundin 5 to 10 percent of the normal population. 88 Inthese cases, the blood pressure is normal, there islittle proteinuria, and progression to renal failureis rare. When such patients present with hematuria,they often receive a diagnosis of benign familial he-maturia. 62 Many of these patients have mutationsin the same genetic loci that encode for the a 3(IV)or a 4(IV) chains associated with autosomal reces-

sive or dominant Alports syndrome, 21,22 but thinglomerular basement membranes are occasionally seen in other forms of glomerulopathy. 22 In kin-dreds with Alports syndrome, the carriers have thinglomerular basement membranes and a phenotypesimilar to that in patients with benign familial he-maturia. 24 For this reason, the boundary betweenAlports syndrome and benign familial hematuriahas become increasingly vague. 18,24

treatment

Patients with Alports syndrome who have early renal failure can be treated conservatively with an-tihypertensive drugs and angiotensin-convertingenzyme inhibitors to attenuate proteinuria and slow progression, although the indications for treatment in children are still unclear. 89 Patients who requiredialysis are candidates for renal transplantation. Al-though the development of nephritis with antiglo-merular basement membrane alloantibodies in thetransplanted kidney is not very common, 90 sensi-

tive assays can detect these antibodies in the serumof most transplant recipients, and they are nearly always directed against multiple epitopes along thea 3(IV), a 4(IV), or a 5(IV) chain of collagen (Fig. 5and Table 1). 91,92 Female patients who are hetero-

A

B

C

Figure 4. Histopathological Features of Kidneysin Alports and Goodpastures Syndromes.An electron micrograph of a glomerular capillary from a

patient with Alports syndrome and proteinuria (Panel A)demonstrates the multilamellations and lucent spacesresulting in the split appearance of the basement mem-brane (arrows). Panel B (hematoxylin and eosin) showsfocal, segmental necrosis of the glomerular tuft in a kid-ney from a patient with Goodpastures syndrome. Panel C(hematoxylin and eosin) shows the crescent formation ofthe glomerular tuft in such a kidney.



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zygous for mutations in the COL4A5 gene occasion-ally have progression to renal failure. When they un-dergo transplantation, the donor kidney does not develop antiglomerular basement membrane al-loantibodies. Patients with Alports syndrome gen-erally do no worse after renal transplantation thanpatients with other forms of progressive renal fail-ure. 93 Lenticonus can be treated with lens implants,as in cataract surgery. 94

Patients with antiglomerular basement mem-brane antibodies in whom glomerulonephritis andlung hemorrhage develop have Goodpastures syn-drome. 95 In the differential diagnosis of pulmo-naryrenal syndromes, antiglomerular basement membrane disease can be distinguished from un-

derlying immune-complex nephritis or antineu-trophil cytoplasmic autoantibody (ANCA)associ-ated nephritis by the presence of antiglomerularbasement membrane antibodies, which, on stain-ing of a renal-biopsy specimen, appear in a linearpattern in inflamed glomeruli along the glomeru-lar basement membrane. 27

genetics

Goodpastures syndrome is a multigenic disorder.Hudson and coworkers identified the a 3(IV) NC1domain as the Goodpasture autoantigen. 29,96 Thistarget antigen must be present as a component of the native a 3.a 4.a 5(IV) network (Fig. 2 and 5) of se-lected basement membranes in order for pulmonary and renal disease to develop. Consequently, thereare no reported cases in patients with Alports syn-drome. In mice, the induction of antiglomerular

g o o d p a s t u r e s s y n d r o m e

Figure 5. Goodpasture Autoantibodies and Alport Alloantibodies, Which Target Different Epitopes of the a 3.a 4.a 5(IV)NC1 Hexamer.Antiglomerular basement membrane antibodies derive from an antigen-specific T-cell and B-cell response (T+B). Theepitopes for the Goodpasture autoantibodies are inaccessible to antiglomerular basement membrane antibodies un-less there is a dissociation of the hexamer, which may be caused by oxidative stress. These epitopes reside in the a 3(IV)NC1 domain and are partially sequestered by the adjacent a 5(IV) NC1 and a 4(IV) NC1 domains. In contrast, theepitopes for the Alport alloantibodies are accessible on the hexamer surface and reside on the a 3(IV),a 4(IV), and a 5(IV)NC1 domains.

Goodpastureautoantibodies

Immune reaction T+B

Oxidant

Antiglomerular basementmembrane antibodies

35

453

43

5

4

5

3

4

3

5

4

5

3

4

35

453

4

Alport alloantibodiesafter transplantation



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basement membrane disease is limited to selectedstrains that express susceptibility genes in the major histocompatibility complex (MHC). 97

Goodpastures syndrome in humans is restrict-ed by the MHC; HLA-DRB1*1501 and DRB1*1502alleles increase susceptibility, whereas HLA-DR7

and DR1 are protective.98

The thymus expressesa 3(IV) NC1 peptides that can cause eliminationof autoreactive CD4+ helper T cells, 99 but a few such T cells escape deletion and can subsequently engage in the production of antiglomerular base-ment membrane antibodies. 100 The immunologicspecificity of the antibodies is notable, since anti-bodies against a 1.a 1.a 2(IV) NC1 domains do not cause antiglomerular basement membrane ne-phritis. 101-103

pathogenesis

Human antiglomerular basement membrane an-

tibodies can initiate glomerulonephritis when in-fused into primates 104 or when human allograftsare transplanted into patients with active Goodpas-tures syndrome. 105 In genetically engineered micethat produce human IgG antibodies, immunization with a 3(IV) NC1 domains results in the productionof human antiglomerular basement membraneantibodies and proliferative glomerulonephritis. 106Human antiglomerular basement membrane an-tibodies, usually of the IgG class (or, rarely, IgA), areof particularly high affinity and remain attached toglomerular basement membrane for prolongedperiods 107 ; the antiglomerular basement mem-brane antibodies eluted from tissues faithfully rep-resent the antiglomerular basement membraneantibodies found in serum. 33

Two dominant epitopes (E A and EB) have beenidentified in the a 3(IV) NC1 domain. 108-112 Bothare inaccessible for antibody binding unless disso-ciation of the hexamer occurs (Fig. 5). The E A and EBepitopes are located in close proximity to each oth-er, near the triple helical junction (Fig. 2B), 36 andthey are sequestered at the interface between NC1domains within a triple helical protomer, rather thanbetween adjacent protomers. 36,48 Although thereare several subpopulations of antiglomerular base-ment membrane antibodies in the serum of patients with Goodpastures syndrome, 109,113,114 immuno-logic specificity for the two dominant epitopes ismost important. 109,110

Since the a 3(IV) NC1 epitope is hidden with-in the a 3.a 4.a 5(IV) protomer, 110,114,115 it is pre-sumed that an environmental factor, such as ex-

posure to hydrocarbons 116 or tobacco smoke, 117is required in order to reveal cryptic epitopes to theimmune system (Fig. 5). Endogenous oxidants canopen this privileged site, 74 as can certain subpop-ulations of antiglomerular basement membraneantibodies. 110

Anti-a 3(IV) NC1 antibodies are structurally similar 118 and are highly regulated by T cells. 119Lymphocytes and macrophages are present in thekidneys of mice with antiglomerular basement membrane disease, 120,121 and in rats, T cells cantransfer disease in the absence of antibody. 122,123Moreover, the antiglomerular basement membranealloantibodies produced after renal transplantationin patients with Alports syndrome 91 or the antiglomerular basement membrane antibodies pro-duced in patients with Goodpastures syndrome 124may not always be sufficient for the development of nephritis. In this regard, transfer of antiglomeru-

lar basement membrane antibodies into mice that are deficient in ab T-cell receptors fails to produceglomerulonephritis, suggesting that T cells arealso effectors of the inflammatory response. 97

The mechanism of renal injury in Goodpasturessyndrome is complex. When antiglomerular base-ment membrane antibodies bind glomerular base-ment membrane, they activate complement 125 andproteases 126 ; such activation disrupts the filtrationbarrier and Bowmans capsule, causing protein-uria and facilitating crescent formation. CD4+ andCD8+ T cells and intrinsic renal epithelium inducethe migration of macrophages and neutrophilsinto the kidney. 121,123,127-129 Interleukin-12 andinterferon- g mediate crescent formation. 130,131The initial inflammatory reaction in the glomerulusproduces proteinuria with attendant downstreamconsequences for tubular epithelium, 132 the devel-opment of interstitial nephritis, and the subsequent appearance of fibrosis. 79

clinical presentation

Goodpastures syndrome occurs primarily in youngmen in their late 20s and in men and women over60 years of age. 28 In the younger age group, thedisease is usually eruptive, with hemoptysis, a sud-den decrease in the hemoglobin level, pallor, cough,fever, dyspnea, hematuria, non-nephrotic protein-uria, and red-cell casts. Chest radiography showsdiffuse alveolar infiltrates. Hemoptysis is largely confined to smokers. 117 Goodpastures syndrome isgenerally detected earlier in patients who present with lung hemorrhage, and such patients may do



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better than those who present with silent renal injury alone. Presentation with oliguria is a particu-larly bad sign. 133,134

antiglomerular basement membrane

antibodies

Almost all antiglomerular basement membraneantibodies from patients with Goodpastures syn-drome are directed against the a 3(IV) NC1 domain;a few patients also produce antibodies against thea 1(IV) or a 4(IV) NC1 domain (Table 1). 30 Com-mercial assays for antiglomerular basement mem-brane antibodies have varying degrees of sensitivity and specificity; often, immunofluorescent stainingof a kidney-biopsy specimen for antiglomerularbasement membrane antibody and C3 complement is needed for confirmation. Kidney-biopsy speci-mens from 2 to 3 percent of patients with Good-pastures syndrome that appear on standard assays

to contain no circulating antiglomerular basement membrane antibodies show linear staining for anti-a 3(IV) NC1 antibody along the glomerular base-ment membrane; circulating antibodies in thesepatients are detectable only with the use of a highly sensitive biosensor. 135

In testing serum in antiglomerular basement membrane assays, it is important that the a 3(IV)NC1 domain be used as the sole target, because as-says that use all collagen IV fragments cannot dis-tinguish Goodpasture antibodies from antibodiesagainst the a 1(IV) NC1 domain in patients with aparaneoplastic syndrome. 102 Approximately 25 per-cent of patients with Goodpastures syndrome alsoproduce ANCA, mainly against myeloperoxidase(Table 1). 136 Patients in this subgroup probably havea vasculitis-associated variant for which the prog-nosis is surprisingly good with treatment. 137

findings on kidney biopsy

The performance of an urgent kidney biopsy ratherthan a lung biopsy (lung tissue can have a great deal of autofluorescence) is important in suspectedcases of Goodpastures syndrome in order to estab-lish the diagnosis and the degree of irreversibledamage. Renal biopsies typically show focal or seg-mental glomerular necrosis (Fig. 4B), which later, with destruction of the glomerular basement mem-brane and cellular proliferation, leads to crescent formation (Fig. 4C). Breakdown of the Bowmanscapsule by periglomerular inflammation is of con-cern, and vasculitis on renal biopsy suggests the si-multaneous presence of ANCA-related disease. 136

As these lesions progress, there is concomitant in-terstitial nephritis with fibrosis and tubular atrophy.

treatment

The prognosis at presentation is worse if there isoliguria, advanced fibrosis or more than 50 per-

cent crescents on renal biopsy, a serum creatinineconcentration of more than 5.7 mg per deciliter(500 mol per liter), or a need for dialysis. 134 Most patients with advanced disease do not have a re-sponse to plasmapheresis or immunosuppression.Patients with end-stage kidney disease who present with hemoptysis, however, should be treated forlung hemorrhage, which does respond to plasma-pheresis. 133 Patients who have the fewest featuresknown to predict a poor outcome typically have aresponse when given 8 to 10 treatments with plas-mapheresis during the first two weeks, accompa-nied by oral prednisone and cyclophosphamide

therapy. Although the evidence is largely experien-tial, those who have a response to treatment involv-ing an enduring absence of antiglomerular base-ment membrane antibodies can have their dose of prednisone tapered after a few months, while con-tinuing to receive cyclophosphamide for varyingperiods of up to a year. Kidney transplantation ispossible, but because there is a risk of recurrence,experience has suggested that patients should wait for six months and certainly until antiglomeru-lar basement membrane antibodies are undetect-able in serum. 124

The family of type IV collagens continues to providean important source of new information about base-ment-membrane molecules in epithelial tissues.Given the additional knowledge available today, wepropose renaming the a 3.a 4.a 5(IV) protomer theGoodpasture protomer. This change honors thecornerstone role of the Goodpasture antigen in en-larging our knowledge of collagen IV biochemistry and relates the molecular understanding of pro-tomer assembly to the pathogenesis of Goodpas-tures and Alports syndromes.

The insights provided by the work completedto date suggest that a number of therapeutic ad- vances may be forthcoming. Recognition that base-ment membranes in patients with Alports syn-drome are particularly susceptible to proteolysis 47may eventually lead to the prophylactic use of spe-cific protease inhibitors or even gene-replacement

summary



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therapy. 138 Work with experimental models of antiglomerular basement membrane disease al-ready predicts a role for costimulatory blockade of T-cell activation, 139 immune modulation with in-terleukin-4 and interleukin-10, 121 or inhibition of macrophage migration. 140 If nothing else, the fu-

ture will be interesting, and work in this area will

undoubtedly provide a new understanding of col-lagen-related diseases.

Supported in part by grants (DK-46282 and DK-55926, to Dr.Neilson; DK-18381 and DK-53763, to Dr. Hudson; and DK-62524,to Dr. Sundaramoorthy) from the National Institutes of Health anda grant (to Dr. Tryggvason) from the Swedish Medical ResearchCouncil.

We are indebted to Larry Howell for assistance in the preparationof the figures.

r e f e r e n c e s

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