Including IgA Nephropathy Research Articles

HIV-associated renal disorders: Recent insights into pathogenesis and treatment

Renal electrolyte disorders, acute renal failure, and a variety of chronic renal diseases are common in HIV-infected patients. Glomerular disorders include IgA nephropathy, cryoglobulinemia, amyloidosis, and a lupus-like immune complex glomerulopathy. The most attention has been focused on collapsing glomerulopathy associated with nephrotic syndrome and progressive renal failure, which appears to be unique for patients with HIV/AIDS, called HIV-associated nephropathy (HIVAN), and it occurs predominantly in African American patients. Investigations in humans and in a transgenic mouse model reveal direct infection of renal epithelial cells by HIV and toxic cellular and immunologic processes mediated by HIV glycoproteins as the principal pathophysiology of HIVAN. Highly active antiretroviral treatment may be associated with an improved renal outcome and even reversal of kidney disease in some patients. Treatment with angiotensin-converting enzyme inhibitors may avert progression of HIVAN to end-stage kidney disease and result in superior patient and kidney survival as compared with untreated patients.

Mycophenolate mofetil in nonlupus glomerulonephropathy

Mycophenolate mofetil (MMF) initially found widespread use in the immunoprophylaxis of rejection in organ transplantation. It has subsequently been used in lupus glomerulonephritis, where early studies have shown it to be effective in induction and maintenance therapy. The randomized studies have mostly studied small groups of patients and their conclusions do need to be confirmed in larger studies. MMF has also been used in small numbers of patients in a variety of nonlupus glomerulopathies, which have different underlying immunopathology as well as clinical course, including IgA nephropathy, membranous nephropathy, focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, hepatitis-C-associated glomerulonephritis and even Goodpasture's syndrome. In this article, we discuss its use in such nonlupus glomerular diseases.

Mycophenolate mofetil in nonlupus glomerulonephropathy

Mycophenolate mofetil (MMF) initially found widespread use in the immunoprophylaxis of rejection in organ transplantation. It has subsequently been used in lupus glomerulonephritis, where early studies have shown it to be effective in induction and maintenance therapy. The randomized studies have mostly studied small groups of patients and their conclusions do need to be confirmed in larger studies. MMF has also been used in small numbers of patients in a variety of nonlupus glomerulopathies, which have different underlying immunopathology as well as clinical course, including IgA nephropathy, membranous nephropathy, focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, hepatitis-C-associated glomerulonephritis and even Goodpasture's syndrome. In this article, we discuss its use in such nonlupus glomerular diseases.

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers for IgA nephropathy

The lengthy course of IgA nephropathy and the possibility of good outcomes without therapy suggest nontoxic therapies such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs.) Among patients with IgA nephropathy, both ACE inhibitors and ARBs reduce the transglomerular passage of large, but not small, molecules, reducing proteinuria. The antiproteinuric effects of ACE inhibitors and ARBs are probably equivalent. Dual ACE inhibitor-ARB therapy reduces proteinuria by 54% to 73% and is more effective than either agent alone. To determine whether ACE inhibitors or ARBs preserve renal function long-term, one must rely on trials studying nondiabetic, proteinuric renal diseases rather than on trials specific to IgA nephropathy. Among this group of patients, several randomized, controlled trials, including the AIPRI trial, the REIN trial, and a metaanalysis of 11 randomized, controlled trials, have established clearly that the ACE inhibitors preserve renal function. There is no reason to believe that this information is not applicable to IgA nephropathy. The COOPERATE trial, in which 50% of the subjects had IgA nephropathy, established that ACE inhibitors and ARBs preserve renal function equally, and that dual ACE inhibitor-ARB therapy preserves renal function more effectively than either therapy alone. These data suggest that most individuals with proteinuric renal diseases, including IgA nephropathy, should be treated with ACE inhibitors and ARBs, ideally in combination. Polymorphisms of the angiotensinogen gene, the ACE gene, and the angiotensin II type I receptor gene have, so far, failed to predict either susceptibility to or progression of IgA nephropathy. However, the D allele of the ID polymorphism, particularly the DD genotype, could predict a favorable response to renin-angiotensin blockade.

PDGF-D: a novel mediator of mesangioproliferative glomerulonephritis

In view of the increasing number of patients with end-stage renal disease (ESRD), new approaches to common underlying diseases such as mesangioproliferative glomeruionephritis, including igA nephropathy, are urgently needed. Whereas the role of platelet-derived growth factor (PDGF) B-chain (PDGF-B) in mediating mesangloproliferative changes is well established, the role of PDGF D-chain (PDGF-D) has only recently been elucldated. Like PDGF-B, PDGF-D signals through the POGF β-receptor and therefore shares a number of biological activities with PDGF-B. Recent studies have shown that PDGF-D induces mesangial cell proliferation in vitro and is overexpressed in mesangioproliferative giomerulonephritis in vivo. In addition, hepatic transfection with a PDGF-D expression plasmid induced prominent mesangioproliferative nephritis in mice, whereas antagonism of PDGF-D in a rat model of mesangioproliferative disease ameliorated the renal changes. These observations establish PDGF-D, along with PDGF-B, as an important mediator of mesangioproliferative nephritis in vivo and suggest that it may be an attractive therapeutic target. in addition, preliminary observations suggest that PDGF-D may also contribute to secondary renal changes that characterize progressive renal failure, i.e., tubulointerstitial fibrosis.

Lipoprotein glomerulopathy associated with psoriasis vulgaris: report of 2 cases with apolipoprotein E3/3

Lipoprotein glomerulopathy (LPG) is a rare disease, characterized by a special histology, including dilated glomerular capillaries filled with pale-stained and meshlike lipoprotein thrombi. It always presents with proteinuria or nephrotic syndrome. Although hyperlipidemia is not always seen, most patients have type III hyperlipoproteinemia with apolipoprotein (apo) E2/3 phenotyping. Although the clinical feature of LPG is rarely described, LPG associated with other glomerulopathy, including IgA nephropathy, membranous nephropathy, and lupus nephritis, has been documented. Until now, there have been no reports of psoriasis vulgaris associated with LPG. The authors present 2 cases of LPG with apo E3/3 genotyping associated with psoriasis vulgaris. The first patient was a 65-year-old woman who presented with nephrotic syndrome with daily urinary protein loss of 9.05 g and itchy erythematous scaly plaques on her trunk and lower limbs for 1 year. The renal biopsy results showed LPG, and the skin biopsy results showed psoriasis. The second patient was a 50-year-old man with history of psoriasis over his trunk and 4 limbs for 30 years. He also presented with nephrotic syndrome with daily urinary protein loss of 7.55 g. The renal biopsy results also showed LPG. The genotype of apo E showed E3/3, and lipoprotein electrophoresis showed a type III hyperlipoproteinemia-like pattern in both cases. The authors suggest that presence of apo E3/3 genotype cannot rule out the diagnosis of type III hyperlipoproteinemia and LPG. Besides, LPG should be included in the differential diagnosis of psoriatic patients with nephrotic syndrome, especially in Asian patients who show poor response to traditional therapy. Renal biopsy should be performed to make the definitive diagnosis.

Protease-activated receptor-2 expression in IgA nephropathy: a potential role in the pathogenesis of interstitial fibrosis.

An increasing body of evidence suggests that proteases may play a key role in the pathogenesis of tissue fibrosis. Protease-activated receptor-2 (PAR-2) is cleaved and activated by trypsin-like proteolytic enzymes, including tryptase and activated coagulation factor X (FXa). Both these soluble mediators have been demonstrated, directly or indirectly, at the interstitial level in progressive renal diseases, including IgA nephropathy (IgAN). PAR-2 mRNA and protein levels were investigated by RT-PCR and immunohistochemistry, respectively, in 17 biopsies from IgAN patients and 10 normal kidneys. PAR-2 expression was also evaluated, by RT-PCR and western blotting, in cultured human mesangial and proximal tubular cells. Finally, gene expression of plasminogen activator inhibitor-1 (PAI-1) and TGF-beta, two powerful fibrogenic factors, was evaluated in FXa-, trypsin-, and PAR-2 activating peptide-stimulated human proximal tubular cells by Northern blot. In normal kidneys, PAR-2 gene expression was barely detectable, whereas in IgAN biopsies the mRNA levels for this protease receptor were strikingly increased and directly correlated with the extent of interstitial fibrosis. Immunohistochemical staining demonstrated that PAR-2 protein expression in IgAN biopsies was mainly localized in the proximal tubuli and within the interstitial infiltrate. Proximal tubular cells in culture expressed PAR-2. Activation of this receptor by FXa in tubular cells induced a striking increase in intracellular calcium concentration. In addition, incubation of both cell lines with trypsin, FXa, or PAR-2 activating peptide caused a marked upregulation of PAI-1 gene expression that was not counterbalanced by an increased expression of plasminogen activators. Finally, PAR-2 activation induced a significant upregulation of TGF-beta gene and protein expression in both mesangial and tubular cells. On the basis of our data, we can suggest that PAR-2 expressed by renal resident cells and activated by either mast cell tryptase or FXa may induce extracellular matrix deposition modifying the PAI-1/PA balance and inducing TGF-beta expression. These molecular mechanisms may underlie interstitial fibrosis in IgAN.

Mesangial Cell Proliferation Inhibitors for the Treatment of Proliferative Glomerular Disease

AbstractFor Abstract see ChemInform Abstract in Full Text.

Mesangial cell proliferation inhibitors for the treatment of proliferative glomerular disease.

Mesangial cells (MC) serve a number of functions in the renal glomerular capillary including structural support of the capillary tuft, modulation of glomerular hemodynamics, and a phagocytic function allowing removal of macromolecules and immune complexes. The proliferation of MC is a prominent feature of glomerular disease including IgA nephropathy, membranoproliferative glomerulonephritis, lupus nephritis, and diabetic nephropathy. In experimental animal models of nephritis, MC proliferation frequently precedes and is linked to the increase of extracellular matrix in the mesangium and glomerulosclerosis. Reduction of MC proliferation in glomerular disease models by treatment with heparin, low-protein diet, or antibodies to platelet-derived growth factor (PDGF), have been shown to reduce extracellular matrix expansion and glomerulosclerotic changes. Therefore, MC proliferation inhibitors may offer therapeutic opportunities for the treatment of proliferative glomerular disease. It is also known that the MC proliferation is inhibited by many kinds of pharmacological drugs, for example, angiotensin converting enzyme (ACE) inhibitors, leukotriene D(4) (LTD(4)) antagonists, PDGF inhibitors, matrix metalloproteinases (MMP) inhibitors, 3-hydroxy-3 methyl glutaryl-coenzymeA (HMG-CoA) inhibitors, cyclin-dependent kinases (CDK) inhibitors, and others. This review summarizes the recently reported MC proliferation inhibitors with their pharmacological properties on the basis of their chemical structures.

Meaning of retrograde phenotypic change of mesangial cells in IgA nephropathy

SUMMARY: Mesangial cells show phenotypic changes such as that of glomerular differentiation at the fetal stage in various nephropathies, including IgA nephropathy. Such a process seems necessary for reparative or regenerative reactions in post‐inflammatory or post‐injury glomerular tissues, particularly for the rearrangement of glomerular capillary networks. Glomerular sclerosis may be the end result of failure or maldevelopment of this phenotypic glomerular transformation.

Meaning of retrograde phenotypic change of mesangial cells in IgA nephropathy

SUMMARY: Mesangial cells show phenotypic changes such as that of glomerular differentiation at the fetal stage in various nephropathies, including IgA nephropathy. Such a process seems necessary for reparative or regenerative reactions in post‐inflammatory or post‐injury glomerular tissues, particularly for the rearrangement of glomerular capillary networks. Glomerular sclerosis may be the end result of failure or maldevelopment of this phenotypic glomerular transformation.

Tissue renin angiotensin system in IgA nephropathy

The inhibition of angiotensin II (AngII) by use of angiotensin converting enzyme (ACE) inhibitor or AngII receptor blocker is effective for prevention of the progression of renal diseases including IgA nephropathy (IgAN). AngII plays a variety of biological roles via AngII receptors. Through AngII type 1 receptor (AT1R), AngII induces vasoconstriction, cellular proliferation, extracellular matrix production and fibrosis, while it leads vasodilatation, apoptosis and inhibition of cell proliferation through AngII type 2 receptor (AT2R). Recent studies showed the local production of AngII in many tissues including the heart, vessel and kidney, suggesting that local AngII may be more important than circulating AngII in tissue injury. AngII is generated from angiotensin I by ACE or ACE independent pathway, such as chymase which is a serine protease. Since chymase was shown to be synthesized 80% of AngII in human heart, chymase also may play an important role in converting to AngII in the kidney. Although it was reported that ACE was produced in renal tissue, the localization of chymase and AngII receptors is unclear in the human kidney. To research the local renin‐angiotensin system in renal tissue of patients with IgAN, we localized chymase mRNA, ACE mRNA, AT1R mRNA and AT2R mRNA by in situ hybridization and investigated the relationship between the expression of these mRNAs and tissue injury. Fresh frozen sections of renal tissue from 21 patients with IgAN were examined. The sections were fixed with 4% paraformaldehyde and hybridized with the digoxigenin (DIG)‐labelled oligonucleotide probes for chymase mRNA, ACE mRNA, AT1R mRNA and AT2R mRNA. Using anti‐DIG antibody, immunohistochemistry was performed to visualize the DIG‐labelled probe. Colour was developed by reaction with H2O2 and 3,3′diaminobenzidine/=tetrahydrochloride. As identifying the exact locations of the cells positive for chymase mRNA, ACE mRNA and AngII receptor mRNA, we stained using periodic acid‐Schiff after in situ hybridization. We classified the histological grading of the glomerular and tubulointerstitial injury. Two to five glomeruli were analysed in each biopsy tissue and the degree of injury in each glomerulus was graded from 1 to 3 based on the proportion of the lesion in the sectioned areas of each glomerulus. In the tubulointerstitium, three to five fields of cortical interstitium in each section were examined under low magnification (×200). In each designated field, we determined the degree of tubular atrophy and interstitial fibrosis from grade 1 to 3. In situ hybridization showed that the signals of chymase mRNA, ACE mRNA, AT1R mRNA and AT2R mRNA were observed in mesangial cells, glomerular epithelial cells, cells of the Bowman’s capsule, cells of crescent, tubular epithelial cells and some infiltrating mononuclear cells. In the glomeruli, the percentage of cells positive for chymase mRNA, ACE mRNA, AT1R mRNA and AT2R mRNA per glomerulus decreased as the glomerular injury progressed. Chymase mRNA and ACE mRNA were diffusely expressed in the glomeruli with mild injury. The expression significantly increased in the area of mesangial cells proliferation without mesangial matrix expansion, however, it decreased as the glomerular lesion progressed. In the tubulointerstitium, the expression of chymase mRNA, ACE mRNA and AT1R mRNA positively correlated with the degree of tubulointerstitial injury. The expression of AT2R became significantly strongest in moderate injury lesions and diminished in severe lesion. All mRNAs were highly expressed in atrophic tubuli. We also examined the relation of the cells positive for chymase mRNA and ACE mRNA on serial sections. Most cells positive for chymase mRNA also stained for ACE mRNA in the glomeruli and the tubulointerstitium. In situ hybridization for AT1R mRNA and AT2R mRNA in serial sections showed that some cells produced the both mRNAs, while other cells expressed only AT1R mRNA or AT2R mRNA. In the present study, we identified that chymase, ACE and AngII receptor were synthesized in renal tissue with IgAN. Our results suggest that AngII was generated by local ACE and ACE independent pathway (chymase) and that the regulation of local renin angiotensin system in renal tissue was different between glomerulus and tubulointerstitium. Local renin angiotensin system may contribute the progression of tissue injury in IgAN.

Human glomerulonephritis accompanied by active cellular infiltrates shows effector T cells in urine.

Leukocyturia is associated with postinfectious glomerulonephritis (GN), interstitial nephritis, and renal allograft rejection. In addition, prominent infiltration of T cells and macrophages is commonly observed in the renal tissues of patients with GN, accompanied by cellular crescent formation and/or interstitial cell infiltration. Because these infiltrating T cells were thought to participate in the development of the diseases and to appear in the urinary space while functioning as effector cells in the renal inflammatory lesion, the study focused on the characterization of T cells that appeared in urine. Freshly voided urine cells were analyzed by flow cytometry to determine their phenotype and by reverse transcriptase-PCR to detect cytokine mRNA. In urine from patients with different forms of GN, including IgA nephropathy, Henoch-Schönlein purpura nephritis, and anti-neutrophil cytoplasmic antibody-associated GN, T cells appeared together with macrophages. The urine T cells were mainly CD45RA(-), CD45RO(+), and CD62L (L-selectin)(-), which are the phenotypic features of effector T cells. In agreement with this finding, T cells infiltrating glomeruli, crescents, and tubulointerstitial lesions were also effector type. Moreover, these urine cells expressed mRNA of the T helper lymphocyte 1 cytokines, interleukin-2, and/or interferon-gamma. These findings suggest that the appearance of effector T cells in urine may reflect the cellular immune reaction that occurs in the kidneys of patients with GN accompanied by active cell infiltration.

Angiotensin Converting Enzyme Gene Insertion/Deletion Polymorphism in Idiopathic Nephrotic Syndrome in Kuwaiti Arab Children

Angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism influence the circulating and cellular levels of ACE and has been shown to be a risk factor in a number of diseases including IgA nephropathy. We have investigated the association of ACE gene I/D polymorphism with the clinical presentation of idiopathic nephrotic syndrome (INS) in Kuwaiti children. The genotypes for ACE gene I/D polymorphism were determined in 102 subjects (54 INS cases and 48 healthy controls) using a PCR method. The distribution of DD, ID and II genotypes was 70%, 20% and 10% in INS cases compared with 52%, 46% and 2% in the controls. The mean age of onset of the disease was significantly lower in the INS cases with DD genotype (37 months) compared with cases with II genotype (65 months, p < 0.05). The clinical manifestation of the disease was considerably severe in cases with DD genotypes compared with cases having ID and II genotypes. The INS cases with DD genotype also showed a significantly higher incidence of steroid sensitivity and steroid dependence. Seventy-three per cent of the INS cases with minimal change lesion had a DD genotype. Also 70% of the cases which needed cytotoxic drugs had DD genotype. Our data suggest an association of the D-allele of the ACE gene I/D polymorphism with the clinical manifestation of INS in Kuwaiti Arab children.

Apoptosis and extracellular matrix–cell interactions in kidney disease

Apoptosis and extracellular matrix-cell interactions in kidney disease. Extracellular matrix (ECM)-cell interactions have major effects on phenotypic features such as cell growth, differentiation, and gene expression. Apoptosis is an active form of cell death that is crucial for maintaining an appropriate number of cells as well as tissue organization. Recent reports have implied that ECM can influence survival and apoptosis of several cell lineages including glomerular mesangial cells (MC). Numerous glomerular diseases are associated with the expansion of the mesangial ECM, which may eventually produce glomerular scarring. Glomerular cell apoptosis is associated with the deletion of glomerular cells and the accumulation of ECM in the progression of glomerulosclerosis in rat remnant kidney model induced by 5/6 nephrectomy. Our recent study indicated that basement membrane matrix (a model for normal ECM components) prevented cultured MC from undergoing apoptosis after serum deprivation, thus promoting their survival, compared with type I collagen matrix (a model for abnormal ECM components). Inhibition of matrix-derived signals by antisense oligonucleotides against beta1 integrin increased MC apoptosis. Data suggest that the survival and death of MC are regulated by the surrounding ECM through integrin molecules. The mechanism of regulation of MC apoptosis by ECM requires further in vivo study to gain new insight into the treatment of glomerular diseases as well as the pathophysiology of the mesangium. Diabetic nephropathy is characterized by the abnormal ECM accumulation and the phenotypic change of MC. Some speculations on the possible involvement of apoptosis in diabetic nephropathy are also discussed.

へん摘により尿中１Ｌ‐６値が改善したＩｇＡ腎症例

We present a case of IgA nephropathy associated with chronic tonsillitis. The patient had experienced continuous microhematuria, repeated proteinuria and visible hematuria every time when he had acute tonsillitis. Both proteinuria and microhematuria were worse after tonsillar provocation. Because of these results and history, this patient underwent with tonsillectomy. Proteinuria and microhematuria were disappeared two and three months after the operation, respectively. Levels of both serum IgA and urinary IL-6 were slightly higher than the normal levels before the operation. Serum IgA was decreased to the normal level one month after the operation. Urinary IL-6 was also decreased to normal two months after the operation. It is known that there is a correlation between the levels of urinary IL-6 and the pathological stage of mesangial proliferative glomerulonephritis (mesPGN), and that high urinary IL-6 activity indicates the histological progression of mesPGN including IgA nephropathy. The decrease of urinary IL-6 after the operation indicates the pathological improvement of the kidneys in this patient. Our observations suggest that the measurement of urinary IL-6 is helpful for monitoring not only the progression but also the improvement after tonsillectomy of pathological changes of the kidneys in IgA nephropathy.

Non-diabetic renal disease in patients with non-insulin dependent diabetes mellitus.

The diagnosis of diabetic nephropathy (DN) is almost always based on clinical grounds. The diagnosis is supported by a long history of diabetes, evidence of target organ damage and proteinuria preceding azotemia. The validity of this clinical approach is well established in insulin dependent diabetes mellitus but not in non-insulin dependent diabetes mellitus (NIDDM). It is thus important to determine which patients with NIDDM accompanied by non-diabetic renal disease (NDRD) should have a biopsy. However, factors clinically associated with NDRD in patients with NIDDM remain unclear. Therefore we reviewed clinical data, laboratory data and renal biopsies from 22 NIDDM patients who underwent renal biopsy between 1992 and 1998 in Wonju Christian Hospital. From this data, we identified important features that would discriminate between DN and NDRD. There were 8 women and 14 men. Age ranged from 33 to 68 (51.2 +/- 10.7) years. The duration of diabetes at biopsy ranged from 0 to 13 (4.2 +/- 4.2) years. Nephrotic syndrome was present in 13 patients. The patients with NDRD (n = 14) and DN (n = 8) had comparable 24-hour proteinuria, 24-hour albuminuria, creatinine clearance, serum creatinine, albumin, as well as incidences of neuropathy and hypertension. The significant factors that predict the NDRD included a short duration of the diabetes mellitus, the presence of dysmorphic red blood cells in urine, the absence of retinopathy and HbA1c below 9% (p < 0.05, respectively). NDRD included IgA nephropathy (n = 6), minimal change disease (n = 3), membranous nephropathy (n = 3), membranous lupus nephritis (n = 1) and acute interstitial nephritis (n = 1). Multiple logistic regression analysis revealed that the short duration of DM and the absence of retinopathy were factors significantly associated with NDRD. In summary, when there is a short duration of diabetes mellitus, or an absence of retinopathy seen in patients with NIDDM, then renal biopsy in diabetic patients aids in the detection of NDRD.

Detection of urinary interleukin-8 in glomerular diseases

To clarify the mechanism of neutrophil infiltration in glomerulonephritis, both urinary and plasma levels of a potent neutrophil chemotactic cytokine, interleukin-8 (IL-8), were measured in 40 healthy volunteers and 96 patients with various renal diseases. The plasma IL-8 levels were less than 16 pg/ml. The urinary IL-8 levels were elevated in several renal diseases including IgA nephropathy (17 of 43), acute glomerulonephritis (4 of 6), lupus nephritis (11 of 15), purpura nephritis (2 of 4), membranoproliferative glomerulonephritis (1 of 1), and cryoglobulinemia (2 of 2). IL-8 was detected immunohistochemically in diseased glomeruli, suggesting its local production. Elevated urinary IL-8 levels during the acute phase or exacerbations were found to be decreased during spontaneous or steroid pulse therapy-induced convalescence in all patients examined. The urinary IL-8 levels were higher in patients with glomerular leukocyte infiltration than in those without infiltration. Collectively, local production of IL-8 in diseased glomeruli might be involved in the pathogenesis of the glomerular diseases and measurement of IL-8 in the urine might be useful for monitoring the glomerular diseases.

Tenascin is an important component of the glomerular extracellular matrix in normal and pathologic conditions

Tenascin (TN), a large oligomeric glycoprotein, is a recently described component of the extracellular matrix (ECM). Previous reports focusing largely on the role of TN in nephrogenesis have documented the strong expression of TN in embryonic kidney tissue and implied an important role for TN in nephrogenesis. However, the expression of TN in normal and pathologic kidneys in adults has not been systematically evaluated. In this study immunohistochemical staining for TN was applied to 184 renal specimens diagnosed as: normal kidney (23 cases); minimal change disease and its variants (8); mesangial proliferative glomerulonephritis (GN) including IgA nephropathy and mesangial proliferative lupus nephritis (9); endocapillary proliferative GN including membranoproliferative GN, lupus nephritis, and post-infectious GN (25); crescentic GN (11); membranous GN (19); focal segmental sclerosis (15); thrombotic microangiopathy (8); amyloidosis (5); diabetic nephropathy (9); primary tubulointerstitial nephritis (14); transplant rejection (14); and ischemia (24). It was found that: (a) there was unequivocal global diffuse staining limited to the mesangium in normal kidney; (b) regardless of the etiologies and the morphologic types of glomerular disease, whenever there was expansion of the ECM, whether in the mesangial, endocapillary, or extracapillary spaces, there was a concomitant and proportional in situ increase in the TN staining; (c) globally sclerotic glomeruli, regardless of causes, showed diffuse, strong staining, especially in the subcapsular fibrous deposition seen in ischemic sclerosis; (d) non-sclerotic glomeruli showing early ischemic change uniformly displayed a marked decrease or complete loss of staining; (e) in cases of thrombotic microangiopathy, there was segmental or global staining of the capillary wall, probably corresponding to the enlarged lamina rara interna; (f) all nodular lesions in diabetic glomerulosclerosis showed strong staining, but in several of them this staining was much more pronounced in the periphery than in the center of the lesion. Our study proves that TN is probably a component of the normal mesangial matrix, that TN is an ubiquitous component of the expanded glomerular ECM in pathologic conditions regardless of morphologic subtypes, and that further studies on the cell types and mechanisms responsible for TN synthesis may provide a new venue for the understanding of the process of glomerular sclerosis.

An immunohistological study of epidermal growth factor receptor and neu receptor expression in proliferative glomerulonephritis

Many forms of glomerulonephritis including IgA nephropathy are characterized by mesangial cellular proliferation. Since epidermal growth factor is a potent mitogen for cultured human mesangial cells, we have attempted to localize and quantify the expression of its receptor in normal and abnormal renal biopsies using immunohistochemistry. Using a particular antibody (Amersham, clone EGFR1), the epidermal growth factor receptor (EGF-R) was shown to be predominantly localized in the mesangium of the glomerulus. Visual estimates of intensity of staining suggested that expression of this receptor may be increased in some IgA disease patients with mesangial proliferative glomerular lesions. The neu receptor which has a 50% homology with EGF-R was, however, absent from the glomerulus and cultured mesangial cells did not express detectable levels. Expression of EGF-R by cultured mesangial cells, as assessed by immunostaining, was weak and it was not possible to induce detectable upregulation using different cytokines. The factors leading to increased expression of EGF-R in glomerulonephritis, therefore, remain unknown. Our findings suggest that signalling via EGF-R may play a role in the pathogenesis of proliferative glomerulonephritis. Despite its homology with EGF-R, the neu receptor is unlikely to have similar importance.