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Saudi Journal of Kidney Diseases and Transplantation
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Year : 1998  |  Volume : 9  |  Issue : 4  |  Page : 444-450
Understanding Immunoglobulin IgA Nephropathy


21 Common Road, North Leigh, Oxford, 0X8 6RD, England, United Kingdom

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How to cite this article:
Wardle E N. Understanding Immunoglobulin IgA Nephropathy. Saudi J Kidney Dis Transpl 1998;9:444-50

How to cite this URL:
Wardle E N. Understanding Immunoglobulin IgA Nephropathy. Saudi J Kidney Dis Transpl [serial online] 1998 [cited 2014 Apr 16];9:444-50. Available from: http://www.sjkdt.org/text.asp?1998/9/4/444/39104
Immunoglobulin IgA nephropathy, the commonest nephritis in the world is charac­terized by microscopic hematuria and pro­teinuria and often hypertension. The most typical cases have hematuria following upper respiratory infection or tonsillitis. The article considers the morphological changes and how they can now be explained, and that takes us on to consideration of factors that determine disease activity and prognosis.


   The Morphology Top


IgA nephropathy, the commonest form of glomerulonephritis in the World, is chara­cterized by the deposition of immunoglobulin IgA containing immune complexes in the mesangium of the renal glomeruli. The mesangium is the central stalk of each glomerulus, where the cells are contractile like smooth muscle cells so that they are able to regulate the glomerular filtration rate. They also have phagocytic capacity for circulating immune complexes that seep through into the glomerulus. The immediate outcome of such an event is glomerular inflammation and mesangial cell proliferation. Whilst the usual historical appearance is that of focal mesangial proliferative GN, the picture will vary from minimal proli­feration to diffuse proliferation with glomerular crescents and then fibrosis of damaged glomeruli and tubules [1]

The "proliferation index", as measured by the nuclear marker Ki-67, is increased in the glomeruli, and the more so in the proximal tubules and the renal interstitium. The magnitude of proteinuria and hyper­tension are prognostic. The efferent arterioles of IgA patients show muscle layer thickening and increased matrix, whether or not there is hypertension. Since crescents develop where there are fistulas through into Bowman's capsule, they predict poor prognosis. Renal interstitial fibrosis predicts progression toward an end-stage kidney.


   Genesis of the Morphological Changes Top


Following an upper respiratory tract infection, or pathology of the bowel mucosa, or dysfunction of the Kupffer cells of the liver caused by alcoholism, IgA1 immune complexes are deposited in the glomeruli­Often codeposits of IgG and IgM are seen by immunofluorescence studies. IgA alone is usual in Asians. [2] There is a specific receptor of IgA on rat and human mesangial cells. (Expression of the Fcα R is enhanced on mesangial cells by cytokines like II-6 (6x), TNFα (4X) and lFNγ (2X).

As they are phagocytosed by mesangial cells the immune complexes cause (i) the formation of reactive oxygen molecules, (ii) release of metalloproteinases, (iii) release of chemokines and cytokines [3] , (iv) release of growth factors [4] like PDGF and TGF β . So there is local production of fibronectin and other proteins and collagen that will expand the extracellular matrix of the glomerular mesangia.

Although IgA does not activate the classical complement pathway, it does trigger the alternative path. Furthermore, the associated IgG immune deposits will activate the classical path, even though there is some evidence that IgA dampens that process. So C3 deposition is always seen, and, if those deposits are large, the histology is more severe. [5] Complement depletion of rats abolishes IgA mediated glomerular inflammation.

In IgA nephritis the main leukocytes in the glomeruli are monocyte-macrophages, and there is a significant correlation between macrophage infiltration and the degree of proteinuria. [6] The deposition of IgA is enough to attract monocytes. Their chemotaxis is promoted by chemokines II­8, MCP-1 and Rantes and by PDGF.

It is found that von Willebrand factor is released into the circulation from endothelial cells in IgA disease. Activated glomerular macrophages express "tissue factor " thrombo­plastin and it explains how there is deposition of cross-lined fibrin in the glomeruli. In the related condition of Henoch's purpura, fibrin deposition is even more intense.

CD4 helper lymphocytes and CD8 cytotoxic T cells are found in the glomeruli, and most especially in the periglomerular and interstitial areas. These are Th-1 lymphocytes that produce IFNI3 and II-2. Accordingly their presence can be related to the development of crescents. When there are γ 6T cells, they signify progression. It seems that γ6T cells may often be responding to heat shock protein 65.

How white cells infiltrate areas of inflam­mation has become a preoccupation of recent years. Reviews are available on the major leucocyte adhesion molecules and their counterparts on cytokine activated endothelial cells. [8] The glomeruli of IgA patients release chemokine II-8 and the cytokines II-lα , 11-lβ, 11-6, TNFα and TNFβ. Expression of chemokine MCP-1 (macrophage chemotactic protein) is associated with increased monocyte influx. It is recognized that TNFD will up-grade ICAM adhesion molecule. 1CAM-1 is expressed constitutively by glomerular endo­thelial, mesangial and parietal epithelial cells and by endothelial cells of the peritubular capillaries. LFA-1 of white cells interacts with the enhanced ICAM-1 that is detected in biopsies of IgA patients, both in the glomeruli and in the renal interstitium, and correlating with the degree of proteinuria. One will also expect the endothelial adhesion molecule VCAM-1 (more typical of vasculitides) to be expressed where there are crescents. Moreover VCAM-1 is detectable in the circulation when IgA patients are showing their typical "synpharyngitic hematuria". Intergin α4 β1 of leukocytes adheres to VCAM-1, so that cells like monocytes can emigrate extra­vascularly. One will note also that the vitronectin receptors αV, β3, αV, β1 and αv, β5, that help adhesion of monocytes, appear on mesangial cells in IgA nephropathy. Their expression can be enhanced in-vitro culture by exposure to polymeric IgA, and the more so by glycosylated or desialylated IgA [10] .

So one can now envisage how monocyte­ macrophages, together with some neutro­phils and T lymphocytes, can enter the glomeruli and renal interstitium in IgA disease. The T cells and macrophages, and the fibroblasts that they induce, could so easily interfere with the blood flow down the peritubular capillaries that tubulo­interstitial ischemia goes on to fibrosis. Monocyte-macrophages produce PGE2 and thromboxane A2. In a rat model of IgA nephropathy there was increased synthesis of thromboxane A2 [11] that was not counterbalanced by PGE2 production, so accounting for mesangial cell contraction, and vasoconstriction of the efferent arterioles and development of micro­hematuria. Glomerular cells too synthesis thromboxane A2.


   The Pharmacology of IgA Nephropathy Top


As has just been indicated, particular attention should be paid to thromboxanes, whose properties are listed in [Table - 2].

In fact thromboxane inhibitors attenuate matrix formation. Natural control is by means of nitric oxide (or prostaglandin E2), which suppress thromboxane formation, suppress TGFβ release, and suppress synthesis of fibronectin and of collagen. [13],[14]

Additionally there is undoubtedly a role for PAF and for the leukotrienes that are involved in activation of white cells [15] . Both agents mediate vasoconstriction and proteinuria.


   Chronic Glomerular and Tubular Damage Top


Platelet derived growth factor (PDGF) arises from aggregating platelets, from activated macrophages, from glomerular mesangial cells, and from renal endothelial cells and smooth muscle cells

PDGF expression can be shown on mesangial cells [1] , in cellular crescents and on infiltrating cells [16] in the renal interstitium. Likewise, the expression of PDGF-receptor mRNA has been shown to relate to (a) the degree of glomerular cells proliferation and (b) the extent of interstitial fibrosis of the kidneys.

From studies on ant-Thy-1 induced mesangial cell damage in rats, it was ascertained that mesangial cell proliferation is triggered by release of FGF (fibroblast growth factor) followed by copious PDGF.

Thereafter, transforming growth factor TGFβ is produced, which suppresses mesangial cell proliferation, and induces depositions of matrix proteins like fibronectin and collagen in the mesangial cells [18] .

There is functional evidence that local angiotensin II hyperactivity [19] is relevant in the progressive forms of IgA nephropathy [20] . From the work of Wolf we realize now that angiotensin II not only controls glomerular filtration and rennin release, it has also important actions on renal tubular cells. Angiotensin II causes hypertrophy and proliferation of mesangial cells via its ability to release PDGF [20] . Likewise, angiotensin II promotes the release of TGFβ and so it helps synthesis of extracellular matrix proteins in the glomeruli, so that ultimately glomerulosclerosis ensues [21] . Angiotensin II is known to cause the release of endothelin­1 and, along with those other factors, that will help account for fibrosis in the interstitium.


   Prognosis of IgA Nephropathy Top


The outcome of IgA nephropathy varies. A few patients have progressive course, whilst the majority decline slowly over 10­20 years. Features of poor prognosis are male sex, persistent microscopic hematuria [22] , serum creatinine over (127µmol/L), and proteinuria over 1.5 grams per day and hypertension. Having a persistently raised serum IgA and bearing haplotype HLA-B35 is also adverse. Donadio and Grunde [23] have recently analyzed a detailed histological assessment of prognosis. Mesangial hyper­cellularity was not found to be a bad indicator but signs of glomerular damage were. One should look for (i) capillary narrowing or disruption, (ii) increase of glomerular matrix with evidence of sclerosis, (iii) fibrous adhesions. Secondarily features of interstitial fibrosis, tubular atrophy and extensive proteinaceous casts in the tubules are bad. Others have stressed that the presence of myofibroblasts [24] in the inter­stitium indicates progression, since formation of type III collagen follows.


   Disease Activity Top


The more inflammation there is in the kidneys, the more one expects progression. Nomura et al [25] used gallium-67 scintigraphy and found that patient uptake values varied from 1.3 to 3.5 compared with soft tissue. The isotope uptake correlated inversely with the reciprocal of serum creatinine against time. Other functional studies help. Thus, those patients with marked mesangial and extra-capillary proliferation have urinary excretion of crenate and contracted erythrocytes and urinary loss of platelets. One can monitor urinary mononuclear cells by flow cytometry, [27] using monoclonal antibody CD14 for macrophage. [28]

Yokoyama and colleagues were able to relate serum IFNγ in subjects with IgA nephropathy to expression of MHC class II antigens on glomerular cells and to acute exacerbations of nephritis. IgA patients can excrete II-1 or TNFα in the urine, but not consistently so. Urinary II-6 excretion of 1­-180 pg/mgm creatinine is prognostic. [29]

Even more striking and useful is the finding that plasma PDGF-β is elevated in IgA nephropathy patients at 40-100 ng/ml and the level correlates with the degree of proteinuria. [30] In such patients increased mRNA for PDGF receptor is upregulated in blood monocytes. The authors note that cortico-steroid therapy will usually reduce proteinuria by half. Niemzir et al record the presence of CD68+ monocyte-macrophages in the glomeruli of IgA patients and how mRNA for PDGF-BB/ AB parallels the degree of glomerular proliferation and that there is prominent TGFβ in areas where glomerular sclerosis is developing. [17],[31]

One knows that in progressive renal damage, the interstitium becomes increasingly widened and infiltrated by inflammatory cells and so it can change from a loose matrix to a denser structure with increased fibronectin and collagen fibrils types I, III and IV. To reach such a state there must be marked tubular disturbance. In fact a good test for renal interstitial damage is the urinary excretion of beta-2 microglobulin.

Furthermore, in hypertensive, more advanced or older patients, the production of urine NO2/NO3 is low; so reflecting a poor production of EDRF (endothelium dependent relaxing factor) by the vascular endothelium. Such cases have a poor prognosis.

From this discussion it is apparent that disease activity and progression is related to the intra-renal action of angiotensin II and the thromboxanes. Angiotensin II exerts much of its action via the intermediary of thromboxanes. So it is interesting that polymorphism of the ACE gene has some relevance to the prognosis of IgA nephropathy [34] . It is found that the D allele relates to hypertension. The D allele also determines more rapid decline of renal function. [34] Furthermore Pei, Scholey et al[35] now report that the TT and MT genotypes of the angiotensinogen gene are associated with faster decline of creatinine clearance and higher grades of proteinuria. De novo expression of angiotensinogen does occur in rat endothelial and mesangial cells of the remnant kidney when sclerosis is occurring.

 
   References Top

1.Haas M. Histologic subclassification of IgAnephropathy: a clinicopathologic study of 244 cases. Am J Kidney Dis 1997;29:829-42.  Back to cited text no. 1  [PUBMED]  
2.Gomez-Guerrero C, Gonzalez E, Egido J.Evidence for a specific IgA receptor in rat and human mesangial cells. J Immunol 1993:151:7172-81.  Back to cited text no. 2    
3.Gomez-Guerrero C, Lopez-Armada MJ,Gonzalez E, Egido J. Soluble IgA and IgGaggregates are catabolized by cultured ratmesangial cells and induce production ofTNF-alpha and IL-6, and proliferation. JImmunol 1994;153:5247-55.  Back to cited text no. 3    
4.Stein-Oakley AN, Maguire JA, Dowling J,Perry G, Thomson NM. Altered expressionof fibrogenic growth factors in IgA nephropatliy and focal and segmental glomerulo-sclerosis. Kidney Int 1997;51:I95-204.  Back to cited text no. 4    
5.Muda AO, Feriozzi S, Rahimi S,Faraggiana T. Spatial arrangement of IgAand C3 as a prognostic indicator of IgAnephropathy. i Pathol 1995;177:201-8.  Back to cited text no. 5    
6.Arima S, Nakayama M, Naito M, Sato T, Takahashi K. Significance of mononuclear phagocytes in IgA nephropathy. Kidney Int 1991;39:684-92.  Back to cited text no. 6  [PUBMED]  
7.Li HL, Flancock WW, Hooke DH, Dowling JP,Atkins RC- Mononuclear cell activation anddecreased renal function in IgA nephropathywith crescents. Kidney Int 1990;37: 1552-6.  Back to cited text no. 7    
8.Carlos TM, Harlan JM. Leukocyte­endothelialdhesion molecules. Blood1994;84:2068-101.  Back to cited text no. 8  [PUBMED]  [FULLTEXT]
9.Ootaka T, Saito T, Soma J, Yusa A, Abe K.Intercellular adhesion molecule­1/leukocyte function associated antigen -1 mediated and complement receptor type 4 mediated infiltration and activation of glomerular immune cells in immunoglobulin A nephropathy. Am J Kidney Dis 1996;28:40-6.  Back to cited text no. 9  [PUBMED]  
10.Coppo R, Peruzzi L, Amore A. et al.Mesangial integrins modulation in IgAnephropathy. Nephrol Dial Transpl 1997;12{9):A17."  Back to cited text no. 10    
11.Gesualdo L, Emancipator SN, Kcsselheim C,Lamm ME. Glomerular hemodynamics and eicosanoid synthesis in a rat model of IgA nephropathy. Kidney Int 1992;42:106­14.  Back to cited text no. 11    
12.Studcr RK, Negrete H, Craven PA,DeRubertis FR. Protein kinase C signalsthromboxane induced increases in fibro-nectin synthesis and TGF beta bioactivity inmesangial cells. Kidney Int 1995;48:422-30.  Back to cited text no. 12    
13.Studer RK, DeRubertis FR, Craven PA.Nitric oxide suppresses increases in mesangialcell protein kinase C, transforming growthfactor beta and fibronectin synthesisinduced by thromboxane. J Am SocNephrol 1996;7:999-1005.  Back to cited text no. 13    
14.Trachtman H, Futterweit S, Smghal PC.Nitric oxide modulates synthesis of extracellular matrix proteins in cultured rat mesangial cells. Biochem Biophys Res Communl995;207:120-5.  Back to cited text no. 14    
15.Wardle EN. Understanding Ieukotrienes.BntJHospMed 1986:35:382-7.  Back to cited text no. 15    
16.Taniguchi Y, Yorioka N. Oda H, Yamakido M.Platelet derived growth factor, interlcukin (IL)-l beta, IL-6R and tumor necrosis factor-alpha in IgA nephropathy. Nephron 1996;74;652-60.  Back to cited text no. 16    
17.Niemir ZI, Stem H, Noronha IL; et al.PDGF and TGF beta contribute to the natural course of human IgA glomerulo-nephntis. Kidney Int 1995:48:1530-41.  Back to cited text no. 17    
18.Floege J, Eng E, Young BA, Johnson RJ.Factors involved in the regulation of mesangial cell proliferation in vitro and invivo. Kidney Int Suppl 1993;43:S47-54.  Back to cited text no. 18    
19.Coppo R, Amore A, Gianoglio B, et al.Angiotcnsin II local hypereactivity in theprogression of IgA nephropathy. Am JKidney Dis 1993;21:593-602.  Back to cited text no. 19    
20.Wolf G, Haberstroh U, eilson EG. Angiotensm II stimulates the proliferation and biosynthesis of type-I collagen in cultured murine mesangial cells. Am J Pathol 1992;140:95-107.  Back to cited text no. 20  [PUBMED]  [FULLTEXT]
21.Kagami S, Border WA, Miller DE, NobleNA. Angiotensin II stimulates extracellularmatrix protein synthesis through inductionof transforming growth factor-beta expressionin rat glomerular mesangial cells. J ClinIvnest 1994;93:2431-­7.  Back to cited text no. 21    
22.Ibels LS, Gyory AZ, Caterson RJ, et al.Primary IgA nephropathy: natural historyand factors of importance in the progressionof renal impairment. Kidney Int Suppl1997:61:S67-70.  Back to cited text no. 22    
23.Radford MG Jr, Donadio JV Jr, Bergstralh EJ. Grande JP. Predicting renal outcome in IgA nephropathy. J Am Soc Nephrol 1997:8:199-207.  Back to cited text no. 23    
24.He wits on TD, Becker GJ. Interstitialmyofibroblasts in IgA glomerulonephritis.AmJNephrol 1995;15:111-7.  Back to cited text no. 24    
25.Nomura S, Watanabe Y, OtsukaN, Osawa G.Gallium 67 sciiitigraphy as a predictor of renalprognosis in primary immunoglobulinnephropathy. Am J Kidney Dis 1996;27:204-8.  Back to cited text no. 25    
26.Taira K s Hewitson TD, Kincaid-Smith P.Urinary platelet factor (PF4) levels inmesangial IgA glomerulonephritis and thinbasement membrane disease. Clin Nephrol1992;37:8-13.  Back to cited text no. 26    
27.Hotta O, Taguma Y, Ooyama M, Yusa N,Nagura H. Analysis of CD 14+ cells andCD56+ cells in urine using flow cytometry:a useful tool for monitoring disease activityof IgA nephropathy. Clin Nephrol 1993;39:289-94.  Back to cited text no. 27  [PUBMED]  
28.Yokoyama H, Takaeda M, Wada T. Intraglomerular expression of MHC class II and Ki-67 antigens and serum gamma­interferon in IgA nephropathy. Nephron 1992;62:169-75.  Back to cited text no. 28    
29.Ranieri E; Gesualdo L: Petrarulo F, Schena FP.Urinary IL-6/EGF ratio: a useful prognosticmarker for the progression of renal damagein IgA nephropathy. Kidney Int 1996:50:1990-2001.  Back to cited text no. 29    
30.Naito T, Nitta K, Ozu H: et al. Clinic assessment of the significance of plate derived growth factor in patients v immunoglobuIin-A nephropathy. J Lab C Med 1997;130:63-8.  Back to cited text no. 30    
31.Yang CW, Hsueh S, Wu MS, CT Glomerular transforming growth fac beta-1 mRNA as a marker ofglomera sclerosis - application in renal biopsi Nephron 1997;77:290-7.  Back to cited text no. 31    
32.Reichert LJ, Kocne RA, Wetzcls JUrinary excretion of beta-2 microglobu predicts renal outcome in patients w idiopathic membranous nephropathy. J Soc Nephrol 1995;6:1666-9.  Back to cited text no. 32    
33.Kovacs T, Barta J, Kocsis B, Nagy J. Nitioxide in IgA nephropathy patients with without hypertension. Exp Nephrol 1995 369-72.  Back to cited text no. 33    
34.Yorioka T. Suehiro T,Yasuoka J Hashimoto K, Kawada M. Polymorphism the angiotensin converting enzyme ge and clinical aspects of IgA nephropatl Clin Nephrol 1995;44:80-5.  Back to cited text no. 34    
35.Pei Y, Scholey J, Thai K, Suzuki M; CattnD. Association of angiotensinogen geT235 variant with progression of immunglobulin A nepliropathy in Caucasian patienJ Clin Invest 1997; 100:814-20.  Back to cited text no. 35    

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Correspondence Address:
E Nigel Wardle
21 Common Road, North Leigh, Oxford 0X8 6RD, England
United Kingdom
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