Re: IGA - Hereditary??

[Guest guest]

Hi

Gosh, I am so sorry to hear you all three probably have IgAN. There is a

good article on IgAN being hereditary at <A HREF= " www.igan.ca " >www.igan.ca</A>

Actually, there are

differing opinions on if it is hereditary or not. My personal opinion is that

it

is hereditary, since in my case, my sister has blood and protein in her urine

too. She just has a much milder case of IgAN than I do. My paternal

grandmother also died of kidney failure, so it seems to run in my family.

RBC stands for red blood cells, which comprise about 40% of your total blood

volume, so yes RBC means blood in your urine.

[Guest guest]

In a message dated 7/17/2003 5:16:56 PM Central Daylight Time,

mlehmanusa@... writes:

> and " casts " in my urine

" Casts " are things shaped like your ureters - I don't know what they're

composed of exactly, but they do show up in the urine.

I don't think they're normal constituents of the urine.

Roibn s

http://www.bloggingnetwork.com/Blogs/Affil/?587

[Guest guest]

,

You do inspire me.

Having been through so much you will certainly have an edge on the other

nurses.

[Guest guest]

I do believe it is hereditary because my brother has protein and

blood in his urine, but I'm sure he has a much milder case than I

do. My Mom and Dad both have to get tested now, to see if either

one of them has the disease as well. It's horrible, because I don't

wnat to see any loved ones go through this. Gosh, anyone in that

case.

God bless-

> In a message dated 7/17/2003 5:16:56 PM Central Daylight Time,

> mlehmanusa@y... writes:

>

>

> > and " casts " in my urine

>

> " Casts " are things shaped like your ureters - I don't know what

they're

> composed of exactly, but they do show up in the urine.

>

> I don't think they're normal constituents of the urine.

>

> Roibn s

> http://www.bloggingnetwork.com/Blogs/Affil/?587

>

>

>

[Guest guest]

These are two articles I obtained a while ago which are both very

interesting......sorry if it hasn't cut and pasted very well.....I know that

has a copy of it too.

Sally UK

Is Henoch-Schonlein Purpura the Systemic Form of IgA Nephropathy?

F. Bryson Waldo MD.

(From the Dept of Pediatrics.The Children's Hospital. The University of

Alabama at Birmingham. American Journal of Kidney Deseases Vol.X1I, NO 5

(November), 1988: pp 373-377 373

(c. 1988 by the National Kidney Foundation, Inc.)

INDEX WORDS: IgA nephropathy, Henech-Schonlein purpura, nephritis;

pathegenesis.

Despite different clinical features, 1GA nephropathy (1gAN) and

Henoch-Schonlein purpura (HSP) are indistinguishable by histopathology,

leading to the suggestion that HSP is a systemic form of IgAN. This review

compares and contrasts the clinical, pathologic and experimental

similarities and differences of these two disorders. Many patients with HSP

have minimal extrarenal disease, while up to 30% of patients with IgAN will

subsequently have systemic symptoms. Although patients with HSP are usually

much younger than those with IgAN, the age distributions often overlap. Both

may have recurrent macroscopic hematuria associated with pharyngitis, a

similar risk of developing renal insufficiency, and recurrent disease after

kidney transplantation. Although the pattern of IgAN subclasses and

complement component deposition are similar, monocytic and

T. lymphocytic infiltrates have been observed only in HSP. Dermal blood

vessels of many patients with IgAN have lgA immunofluorescence similar to

that in HSP, supporting a systemic process in IgAN. Although the

pathogenesis is not clearly understood for either disease, investigations of

potential disease mechanisms have revealed striking similarities. These

include an upregulated invitro IgA immune response, circulating

IgA-containing immune complexes and autoantibodies, and decreased Fc

recepter-mediated immune clearance.

Finally, immunogenetic studies suggest that patients with both conditions

inherit a predisposition for disease.

HENOCH-SCHONLEIN. purpura (HSP) was first described in 1874 as a distinctive

clinical syndrome of an acute systemic vasculitis of the skin, joints, gut,

and kidney. In

1968 Berger and Hinglais described IgA nephropathy (IgAN) characterized by

mesangial proliferation and immunofluarescent staining for IgA in patients

with mild nephritis manifested by hematuria, minimal proteinuria, and normal

renal function, but without systemic symptoms. Berger also noted mesangial

lgA immunofluorescence in renal biopsy specimens from patients with HSP. In

the subsequent years, despite their different clinical features, HSP and

lgAN have remained indistinguishable by standard renal pathology. Several

investigators have postulated that HSP is a systemic form of lgAN. This

report will not attempt to prove or disprove that thesis, but rather will

review the numerous clinical and laboratory similarities between the two

conditions. Some distinctive, and potentially important, differences that

may provide helpful clues in the quest to understand their pathogenesis will

also be discussed.

CLINICAL FEATURES. The typical systemic presentation of HSP is so unique

that the diagnosis is usually made on clinical criteria alone; renal biopsy

is reserved for patients with severe or persistent nephritis. In contrast,

the diagnosis of lgAN always requires a renal biopsy. Patients with HSP

usually do not have all the major organ systems clinically involved.

Depending on the criteria to define nephritis, renal involvement occurs in

20 to 100% of patients. Although the systemic disease and nephritis in HSP

usually occur together, the renal involvement may either precede the

systemic symptoms or, conversely, appear months after the systemic signs

have resolved. Similarly, although most patents with IGA do not have

systemic signs or symptoms at presentation, over 30% will develop abdominal

pain, atypical rash, or arthralgia during followup. Most patients with HSP

present in childhood, while those with lgAN present in adolescence or early

adult life. However, the age ranges in the two groups significantly overlap;

patients as young as 2 yrs have been reported

with lgAN, and 70yr old adults have developed HSP. The reason for this age

distribution is unclear. The lgA mucosal system is poorly developed at birth

and undergoes continual antigen-driven and antigen-dependent development

throughout childhood. The response of the immature immune system to an

antigenic challenge may more frequently produce circulating immune complexes

that deposit in tissue. Alternatively, differences in antigen exposure,

handling of immune complexes, or other unknowns in children may favor

development of systemic disease. A systemic infection commonly precedes the

onset of HSP in children, while in many patients with 1gAN, macroscopic

hematuria is often noted first

concomitant with an infection, leading to diagnosis. Because of the

insidious nature of IgAN the date of the true onset of the disease may not

be discernible. Many patients may develop the initial immunologic renal

lesion of IgAN months or even years, before the disease is

clinically manifest. Therefore, some patients with IgAN may develop their

initial renal lesion following an infection, as do patients with HSP. During

follow-up,10% to 30% of patients with either condition cxperience recurrent

bouts of macroscopic hematuria associated with upper respiratory tract

infections.

The long term clinical course of both HSP and IgAN are quite variable and

thus difficult to compare. Few series of unselected patients with HSP are

available and prognostic data are drawn from groups of patients with

significant renal

involvement. Most patients with HSP with or without renal disease resolve

their initial systemic symptoms within 3 months of onset. Many have one or

more relapses of purpura and systemic symptoms, which may include nephritis,

in the first 12 months after presentation but most will ultimately remit.

Similarly, patients with lgAN presenting with macroscopic hematuria

frequently have recurrent episodes associated with upper respiratory tract

infections during the first 2 years after diagnosis. As with HSP these

episodes usually become less frequent or cease during extended observation.

Approximately one third of patients with lgAN will progress to end-stage

renal disease (ESRD).In an unselected series of patients with HSP, only 5%

progressed to ESRD.However, in patients with HSP referred for renal disease

and followed for six to 21 years one third developed renal in-sufficiency. A

few patients with HSP presenting with a severe necrotizing, cresentic

glomerulo-nephritisprogress to ESRD. Most patients with HSP show persistent

glomerular deposits of lgA containing immune complexes indistinguishable

from those in patients with lgAN.

The renal transplant experience in patients with lgAiN has been very

instructive. Thirty percent to 40% of patients develop recurrent IgA

deposits in their allografts, suggesting that lgAN is a systemic disease. In

contrast, recurrence of the extrarenal manifestions of HSP after renal

transplantation is rare. However, one third of patients with HSP with a

renal allograft had recurrent IgA deposits in the kidney, although none had

systemic symptoms or allograft dysfunction. In both HSP and lgAN, recurrent

disease rarely causes loss of the allograft. The reasons for this are

unclear. The use of immunosuppressive drugs during the potential initiation

period of disease (ie, immediately posttransplant) is one possibility; a

" " burn out " " effect as described with systemic lupus

erythematosus (SLE) is another.

PATHOLOGY. As noted above, the similar pathology of IgAN and HSP initially

suggested that they represented a spectrum of a single disorder. By light

microscopy, both diseases have mesangial proliferation and sometimes focal

sclerosis or necrosis and crescent formation. Both exhibit electron-dense

deposits containing IgA in the mesangium. The lgA is accompanied by C3 and

IgG or IgM, or both, in 80% of patients. Complement components Clq and C4

are usually absent, but properdin, C5, and the membrane attack complex are

detected. Furthermore, deposits may also occasionally occur in

subendothelial and less commonly, sub epithelial locations. Patients with

deposits in the capillary loops more often have necrotic lesions and

crescent formation. Crescentic disease was initially described more

conunonly in patients with HSP, but larger series have shown this pathologic

finding in a comparable number of patients with lgAN.

Much debate has focused on the subclass of lgA deposited in either disease.

Initial data indicated that lgA2 predominated, while many subsequent

reports using several different monoclonal antibodies found predominantly

lgAI. Although some authors expressed concern about possible nonreactivity

of the monocional antibodies with tissue-bound immunoglobulin, no study

found a different predominant lgA subclass in lgAN cormpared with HSP.

The hypercellularity in HSP and lgAN has traditionally been attributed to

mesangial cells.

A recent study Of infiltration of leukocytes in several forms of

glomerulonephritis found significant numbers of monocytes and T cells in the

glomeruli of patients with HSP but not with lgAN. All renal biopsies Of the

patients with HSP were performed early in the disease course

(13 = 1.4 weeks), compared with those of patients with IgAN (158 = 18.5

weeks). This time difference may explain a temporal difference in

immunopathology or, alternatively, it may suggest a basic difference in the

mechanism of glomerular injury. Further studies will be needed to clarify

this issue.

In patients with HSP, immune complexes containing lgA and C3 are not only

deposited in the kidney but also in blood vessels of the gut, joints, and

skin. Immunotluorescence staining of purpuric and normal skin in patients

with HSP reveals perivascular deposits of lgA. Although most patients with

lgAN have no rash, many have perivascular deposits of lgA in clinically

normal skin. This dermatologic finding suggests that the absence of purpura

in patients with lgAN may represent a quantitative rather than qualitative

difference in inununopathology.

DEMOGRAPHICS. Worldwide, lgAN is the most common primary inflammatory

glomerular disease however, its prevalence and incidence are not evenly

distributed. It is very common in the Orient, Australia, and southern

Europe, but less common in northern Europe and the United States. Within the

United States, some regions have a particularly high prevalence. The actual

prevalence in a given area is difficult to determine because of the varied

indications for renal biopsy. In the southern United Stares, IGAN and HSP

are common in whites, although rare in blacks. In Nigeria, the African

origin of many blacks in the southern United States, neither IGAN nor HSP is

seen (personal communication. Professor O.O. Akinkugbe, lbadan, Nigeria.

1987). The data on the geographic and racial distribution of HSP are

limited. HSP is common in western Europe, the United States, and Japan areas

where lgAN is also seen. No population has yet been described in which only

HSP or lgAN is commonly seen.

PATHOGENESIS. First, the pathogenesis of neither HSP nor lgAN is understood.

However, several general lines of active investigation have produced a

variety of stimulating results. Whether these data point to

causal mechanisms or epiphenomena is unclear. Nevertheless, the similarities

between HSP and lgAN have been striking and will be briefly reviewed.

Immune Complex Deposition. It has been hypothesized that mesangial

deposition of circulating immune complexes containing 1gA occur in lgAN and

HSP. Circulating immune complexes that bind to anti-C3 antibody or

conglutinin (a C3bi ligand) and contain IgA are easily detected in both

conditions. These complexes may also contain IgG and lgM. Although no large

series from a single center has compared the characteristics of circulating

immune complexes in lgAN and HSP, no obvious or significant differences are

apparent from small studies. The relationship between disease activity and

circulating immune complex levels in either disease is unclear. Despite a

few reports in which the two correlated, most investigators agree that a

correlation exists at best in only selected patients.

The possible role of autoimmunity in both diseases has generated recent

interest. lgA rheumatoid factor (anti-lgG Fc) has been found in patients

with either disease. One report revealed cross- reactive antibodies eluted

from kidney sections of patients with HSP and lgAN.These antibodies did not

bind to sections of normal kidney but did bind to diseased renal tissue. lgA

antibody against the Fab portion of normal IgG has recently been reported in

patients with lgAN. Similar studies have not been done in patients with HSP.

Immune Response. An upregulated lgA immune response has also been

hypothesized to occur in both diseases. About one third to one half of

patients with either condition had increased serum lgA concentrations. The

in vitro production of lgA by cultured lymphocytes from patients with lgAN

and HSP has been investigated.Whole mononuclear cells or B cells from

patients with HSP spontaneously produced increased amounts of lgA in culture

without mitogen stimulation. Pokeweed miitogen stimulation of whole

mononuclear cells decreased lgA production, presumably by activating T

suppressor cells; a similar response was shown for patients with systemic

lupus erythematosus.

Some studies of IgAN found similarly increased IgA production by

unstimulated cells. However, other investigators have shown lgA

production by cells from patients with lgAN was increased only after

pokeweed mitocen stimulation. Thus, the IgA irmmune response in patients

with either HSP or IgAN may be upregulated, although the responsible

cellular mechanisns may differ. Two of the studies that showed increased

spontaneous production of lgA by lymphocytes from patients with IgAN

(similar to that in HSP) used cells from children. Age-related variations in

the IgA

immune response, as noted earlier, may be important in the apparent

differences bewetn HSP and IgAN.

Immune Clearance. Defective clearance of IgA-containing immune complexes

has been hypothesized for both conditions. Fe-mediated clearance is

abnormal. in patients with IgAN or active HSP, but not in those

with inactive HSP. The etiology and significance of the reduced clearance

is unclear. In primates, soluble immune complexes containing C3b, such as

those in the circulation of these patients, bind to erythrocyte complement

receptor (CRI) and are transported to the liver for clearance. No data on

the clearance of soluble immune complexes are currently available for either

HSP or lgAN. Data from baboons suggest that immune complexes containing only

IgA and no C3 are not cleared normally and deposit in the kidney and other

tissue. This delayed clearance may also be true in lgAN. If abnormal immune

complex clearance is indeed important in the pathogenesis of lgAN, it will

be important to determine if this abnormality is also present in HSP.

Genetics. Neither lgAN nor HSP is usually considered a genetic disorder.

However, increasing evidence suggests that individuals inherit a

predisposition to develop lgAN, and probably also HSP. Scattered case

reports describe families with more than one member with lgAN. Several

families include one member with lgAN and another with HSP. One remarkable

family had twins, one with HSP the other with lgAN. In addition to these

families, I am aware of two others with one brother with lgAN and the other

with HSP. Brothers from one family were HLA typed and found to be

HLA-identical(AI1,31; B51, w62; DR 1,4). The fourth component of complement

is encoded by two loci on chromosome 6 within the major histocompatability

complex. Null genes(genes producing a nonfunctional gene product) occur at

one of the two loci on both chromosomes (homozygous null)

in < 10% of normal individuals. The frequency of homozygous null C4 genes at

either locus is significantly increased in patients with IgAN or HSP.

Whether this genetic finding relates to gene linkages within the major

histocompatibility complex or to a functional difference in the

compliment system, is unclear. An increased frequency of an unusual

restriction fragment length poly-morphism allele of the immunoglobulin heavy

chain switch region chromosome 14 was recently described in patients with

IgAN but not HSP. The patients with HSP in this study were unselected. Might

this allele be more common in the subgroup of patients with HSP with a

chronic course of renal involvement, similar to patients with IgAN?

IgA NEPHROPATHY: AN AUTOIMMUNE CHARACTER OF THE DISEASE

J. Mestecky, J. Novak, B.A. n, M.Tomana

Departments of Microbiology and Medicine, University of Alabama at

Birmingham, USA

IgA1 nephropathy (IgAN), the most common glomerulonephritis in the world, is

characterized by the deposition of IgA1, C3 and IgG, and/or IgM in the

glomerular mesangium, elevated serum levels of IgA1, and of circulating

immune complexes (CIC) containing IgA1, IgG, and C3. Recent studies indicate

that IgA1 molecules in CIC and in mesangial deposits display aberrant

glycosylation patterns of O-linked glycan chains in the IgA1 hinge region:

there is a deficiency of galactose (Gal) linked by beta 1,3 glycosidic bond

to N-acetylgalactosamine (GalNAc) that is usually sialylated. Direct

carbohydrate analyses, and reactivities with lectins and sets of monoclonal

and polyclonal antibodies indicate that terminal GalNAc residue(s) generate

an antigenic determinant apparently shared with microorganisms that colonize

and infect mucosae. Consequently, sera of healthy individuals and IgAN

patients contain high titers of antibodies to GalNAc in the IgA1 hinge

region. In IgAN patients, these antibodies form CIC with Gal-deficient IgA1

with subsequent mesangial deposition. Thus, IgAN should be considered as an

autoimmune disease with Gal-deficient hinge region of IgA1 as an antigen.

Undergalactosylation of the IgA1 hinge region may involve deficiency of beta

1,3 galactosyltransferase and/or increased intracellular activity of alpha

2,6 sialytransferase resulting in premature sialylation and deficient

galactosylation of GalNAc. Intracellular activities of these

glycosyltransferases are influenced by various cytokines and viral

infections that frequently induce episodes of macroscopic hematuria.

[Guest guest]

Hi and Cecile,

Welcome to our group. I am sorry you have cause to be here, but glad you are

finding the site supportive.

It is terrible that your wife and her family have been affected so profoundly

with IgAN. Please accept my condolences on the loss of your wife's sister. I

am truly very sorry that your wife has progressed to dialysis too.

I am one with a family history of IgAN too. My sister has a very mild case

of IgAN also. There is a good article on IgAN and hereditary at <A

HREF= " www.igan.ca " >www.igan.ca</A>

I would be very interested in what you find out with the group in Italy.

Welcome again, and God bless you.