Experimental gold nephropathy in guinea pigs: detection of autoantibodies to renal tubular antigens

Renal tubular dysfunction was induced in Hartley guinea pigs by injection of sodium aurothiomalate (gold) as manifested by excretion of tubular basement membrane (TBM) antigen and renal tubular epithelial (RTE) antigen in urine and tubular proteinuria. Following the tubular dysfunction, autoimmune tubulointerstitial nephritis (TIN) and/or immune complex nephropathy (ICN) developed in a large proportion of animals. TIN was associated with anti-TBM antibodies, and the histological features were characterized by tubular lesions with interstitial mononuclear cell infiltration, destruction of tubules, and interstitial fibrosis. In ICN, the glomerular lesions consisted of partial thickening of capillary walls and mesangial cellularity, and granular immune deposits were seen in the mesangial area and on capillary walls. Furthermore, electron-dense deposits were demonstrated in the mesangial area and in the glomerular basement membrane (GBM) by electron microscopy. Anti-RTE antibodies were detected in the sera and eluates from the kidney of animals with ICN. RTE antigens were also detected in the glomerular deposits by indirect immunofluorescence using anti-guinea pig RTE antibody. These results suggest that TBM and RTE antigens released from renal tubules damaged by a direct toxic action of gold may lead to antibody formation against these antigens and induce TIN and/or ICN.     

Histology of human tubulo-interstitial nephritis associated with antibodies to renal basement membranes.

Twenty-seven patients with diffuse "crescentic" glomerulonephritis (CSGN) were identified in 1,174 renal biopsies from nephritic patients. Patients were assigned to three groups on the basis of the immunofluorescent study of renal biopsy specimens and serologic findings. Group I included eight patients with antibodies to glomerular (anti-GBM) and tubular (anti-TBM) basement membranes; group II had eight patients with only anti-GBM antibodies; and group III had eleven patients with CSGN unassociated with antibodies to either GBM or TBM. Patients with anti-GBM/anti-TBM antibodies (group I) had severe tubulointerstitial (TI) nephritis, as characterized by the infiltration of polymorphonuclear leukocytes and macrophages along the TBM and peritubular vessels. In some patients, focal proliferation of epithelial cells of proximal convoluted tubules (PCT), gaps or extensive destruction of TBM, lesions in the walls of small peritubular vessels, and interstitial giant cells were also observed. Patients with anti-GBM antibodies (group II) had mild to moderate interstitial cellular infiltration and mild tubular changes. Five patients with CSGN not associated with antibodies to renal basement membranes (group III) had mild to moderate interstitial cellular infiltration and tubular changes. A sixth patient, with Wegener's disease had severe granulomatous TI lesions. The results of this study show that TI nephritis is most frequent and severe with anti-TBM antibodies are demonstrable and suggest that anti-TBM antibodies contribute to the development of TI lesions.     

Tubulointerstitial nephritis during the heterologous phase of nephrotoxic serum nephritis

This study was designed to characterize the immunopathology of acute tubulointerstitial disease in nephrotoxic serum nephritis in nonsensitized rats. Groups of Lewis rats were studied at 12 time periods ranging from 10 min to 28 days after nephrotoxic serum injection. Nephritic rats developed interstitial nephritis during the acute heterologous phase of renal injury. Coincident with the focal deposition of nephrotoxic antibodies along tubular basement membranes at 24 h, an influx of polymorphonuclear cells and macrophages was evident. The most prominent infiltrate, present between days 3 and 7, was dominated by macrophages with smaller numbers of lymphocytes that were mainly cytotoxic T cells. Dual-labeling studies demonstrated the colocalization of linear tubular basement membrane deposits of the nephrotoxic antibody with focal clusters of interstitial lymphohemopoietic cells. Increased complement deposition was not evident along the tubular basement membranes; moreover, C3 depletion with cobra venom factor failed to attenuate the interstitial inflammation. During the late autologous phase of glomerulonephritis, tubular basement membrane deposits of rat IgG did not appear and the interstitial disease resolved. The results of this study demonstrate that the heterologous phase of nephrotoxic serum nephritis is an antibody-mediated disease directed against the basement membranes not only of the glomeruli but also of some tubules. Antibody deposition is followed by an acute influx of phagocytic cells to both regions of the kidney. These cells may play an important role in the genesis of acute interstitial injury and chronic interstitial fibrosis associated with antiglomerular basement membrane nephritis.     

Role of antibodies directed against tubular basement membranes in human renal transplantation

Direct immunofluorescence studies of graft biopsies from 662 renal transplant recipients demonstrated linear IgG deposition along tubular basement membranes (TBM) in 18 cases. In ten of them, circulating anti-TBM antibodies, whose detectable levels varied from 1/4 to 1/100, were demonstrated by indirect immunofluorescence on normal human kidneys. These antibodies reacted with every human kidney tested and in two cases, it could be demonstrated that they recognized the TBM of the patient's own end-stage kidney. Hence, they reacted as autoantibodies. Circulating anti-TBM antibodies were detected within the first 6 months after transplantation, remained present for an average of 3 months, and never recurred once they had disappeared. Serial biopsies demonstrated the loss of IgG linear fixation on TBM. Neither tubular nor interstitial injury was significantly associated with the presence of anti-TBM antibodies, and the transplant survival was not different in these patients who developed anti-TBM antibodies compared to our entire population of transplant biopsies.     

Predominant tubulointerstitial nephritis in a patient with systemic lupus erythematosus: phenotype of infiltrating cells

A 63-year-old man with systemic lupus erythematosus developed tubular proteinuria. All subclasses of serum IgG increased, and the largest IgG subclass increase was IgG4. A renal biopsy showed lupus nephritis (Class II) with severe tubulointerstitial nephritis (so-called predominant tubulointerstitial lupus nephritis, an unusual form of lupus nephritis). Immunofluorescence microscopy revealed positive granular staining for IgG, C3 and C1q in the mesangium and peritubular interstitium, and along the tubular basement membranes (TBM). Electron microscopy also showed electron-dense deposits in the mesangium and TBM. Immunophenotyping of interstitial infiltrating cells disclosed a predominance of T cells. CD8-positive cytotoxic T cells infiltrated the peritubular interstitium, and some of these cells infiltrated the tubules. B cell-rich lymphoid follicles were also observed. IgG subclass analyses showed glomerular IgG1, IgG2 and IgG4 deposition, positive staining of IgG4 in the peritubular interstitium and along the TBM, and abundant IgG1-, IgG3- and IgG4-positive plasma cells in the interstitium. The patient responded well to moderate-dose steroid therapy. This is the first report of immunophenotyping of interstitial infiltrates in predominant tubulointerstitial lupus nephritis. The results suggest CD8-positive cytotoxic T cell-mediated tubular injury. Furthermore, immune complexes containing IgG4 might be one of etiologic factors.     

Detection of nephritogenic antigen from the Lewis rat renal tubular basement membrane

Immunopathogenicity of trypsin-solubilized or non-solubilized renal tubular basement membrane (TBM) of the Lewis (LEW) rat was investigated. Autoimmune tubulointerstitial nephritis (TIN) was induced in BALB/c mice by immunization with trypsin-solubilized LEW rat TBM, while immunization with non-solubilized TBM did not produce the disease. Based on this preliminary experiment we studied the characterization of immunogenic and nephritogenic TBM antigen of the LEW rat. TIN was characterized by severe mononuclear cell infiltrates with multi-nucleated giant cells in the interstitium, tubular destruction and intensive IgG and C3 deposits along the TBM. Anti-TBM antisera and eluate from the nephritic mouse kidneys reacted with the TBM of normal LEW rat kidney by immunofluorescence. LEW rat TBM was also detected immunofluorescently by using antisera from BALB/c mice immunized with autologous trypsin-solubilized TBM. A competitive inhibition test revealed a higher titer of anti-TBM antibody in the eluate than in the adsorption-treated antisera per microgram IgG. Immunoblotting showed one reactive band with a molecular weight of 45,000 daltons, and the blotting patterns in tryptic TBM of the Brown Norway (BN) and LEW rats appeared similar. Amino acid analysis of nephritogenic LEW rat tryptic TBM showed that it contained no hydroxyproline and hydroxylysine, suggesting that this TBM preparation was not collagenous. These findings suggest that tryptic digestion contributes to the release of nephritogenic antigen from the LEW rat TBM and that this antigen system might participate in the immune system involved in the anti-TBM associated TIN that is well known to be induced by non-digested TBM of TBM antigen positive animals.     

Experimental autoimmune glomerulonephritis induced by homologous and isologous glomerular basement membrane in Brown-Norway rats

In order to study disease mechanisms and potential forms of therapy in glomerulonephritis, a model of experimental autoimmune glomerulonephritis (EAG) has been developed in the rat. We have examined the response of Brown-Norway (BN) rats to a single i.m. injection of collagenase-solubilised homologous (Sprague-Dawley, SD) or isologous (BN) glomerular basement membrane (GBM), with and without complete Freund's adjuvant (CFA). There was a dose-dependent circulating anti-GBM antibody response to all preparations of rat GBM. Animals given either antigen alone at a dose of 2 mg/kg developed circulating anti-GBM antibodies, which reached peak values by 6 weeks (63 +/- 5% following SD GBM; 53 +/- 8% following BN GBM), but did not develop glomerular deposits of IgG or nephritis. Animals given 2 mg/kg SD GBM in CFA developed greater concentrations of anti-GBM antibody by 6 weeks (122 +/- 20%) together with linear deposits of IgG on glomerular and tubular basement membranes (TBM), albuminuria (mean 7 mg/24 h), and variable focal segmental necrotising glomerulonephritis with mild interstitial nephritis. The same dose of BN GBM in CFA produced similar concentrations of circulating antibody (144 +/- 26%), with linear deposits of IgG on GBM but rarely TBM, little albuminuria, and variable mild focal glomerulonephritis. Other strains injected with SD GBM in CFA showed a variable circulating anti-GBM antibody response, which was similar to that of BN rats in PVG and DA rats but lower in LEW and WAG rats. Linear deposits of IgG on the GBM were detected in a proportion of PVG and DA rats, but not in LEW or WAG rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Down modulation of Heymann's nephritis by mercuric chloride

The time course of Heymann's nephritis (HN), assessed on proteinuria and immunomorphology, has been compared in Lewis (LEW) rats immunized with BB alone (group A) or injected with HgCl2 and subsequently immunized in a similar manner (group B). Whereas all rats from group A developed typical HN characterized by heavy proteinuria and abundant glomerular immune deposits, rats from group B did not develop or developed a markedly attenuated form of HN; proteinuria was never detectable, immune deposits were absent or minimal. No abnormalities were found in rats injected with HgCl2 alone. In order to explain our findings, we have studied the glomerular and tubular expression of the 330 kD nephritogenic glycoprotein (gp330) as well as the corresponding antibody response. In rats receiving HgCl2, gp330 was normally expressed on BB and glomerular epithelial cells as indicated by in vitro and in vivo binding of anti-gp330 antibodies, but titers of anti-BB and anti-gp330 antibodies were considerably lower than in group A control rats. These findings therefore suggest that HgCl2 acts by its immunodepressive effect recently related to an increase in T suppressor cells. This effect is paradoxical since HgCl2 induces autoimmunity in Brown-Norway rats, and we suggest that it may be akin to observations reported in clinical practice where drugs may be immunostimulatory in some patients and immunodepressive in others. The mercury model may therefore represent a unique tool to evaluate the relationship between genetics and drug-induced immune dysregulation.     

Childhood membranous nephropathy, circulating antibodies to the 58-kD TIN antigen, and anti-tubular basement membrane nephritis: an 11-year follow-up

Childhood membranous nephropathy (MNP) with anti-tubular basement membrane (anti-TBM) nephritis is a rare disorder that may have extrarenal manifestations. This article describes a new case to be added to the 10 previously reported. A renal biopsy specimen from a 1-year-old white boy with nephrotic syndrome, microhematuria, and hypertension showed MNP (granular global IgG, IgA and C3, and segmental IgM and C1q) associated with hypercellularity and granular deposits of IgM and C1q in the mesangium, arteriolar IgA, and linear TBM IgG, IgA, and C3. A biopsy at age 4 years showed MNP (IgG and C3) and linear IgG and C3 along the TBM. Six months later, temporary glucosuria suggested a mild tubular dysfunction. Biopsy at age 8 years showed sclerosing MNP (IgG and C3), linear TBM IgG and C3, and chronic active tubulointerstitial nephritis (TIN). Indirect immunofluorescence showed circulating anti-TBM antibodies, and the enzyme-linked immunosorbent assay (ELISA) approach verified strong reactivity with the 58-kd TIN antigen. Despite trials with steroids, chlorambucil, azathioprine, and cyclosporine, end-stage renal disease developed by the age of 9 years. At age 10 years, the patient received a cadaveric kidney transplant. With the patient now aged 12 years, the graft is still functioning well, without any clinical evidence of disease recurrence. Neurological, ocular, and abdominal symptoms, including nonbacterial diarrhea, were observed during the follow-up period. The pathophysiology of these extrarenal symptoms remains unclear. Serotyping and genotyping of HLA antigens (A2, A10, B12, B41, DR5 [1101, 1103-4, 1106 or 1108-1113], DR6 [1303, 1312, or 1413], DRB3 [*0101 and 0201-2 or 0301], DQA1 [*0501 homozygous], and DQB1 [*0301 homozygous]) did not indicate any HLA association similar to those described previously in childhood MNP with anti-TBM nephritis (HLA-B7 in four patients, HLA-DR8 in two patients). The presented case is the fifth in the literature that displays reactivity with the 58-kd TIN antigen, and for which data on HLA antigens are reported.     

Immunofluorescent deposits on the tubular basement membrane in human renal transplant

In this retrospective study, the presence of tubular basement membrane (TBM) deposits of IgG and/or C3 was demonstrated in 41 renal transplants (out of 95 studied). The follow-up of these transplants varied from 9 to 19 years. The deposits were of 'linear' type in 9 cases (circulating anti-TBM antibodies were detected in 7 cases by radioimmunoassay tests and/or indirect immunofluorescence), 'granular' type in 22 cases and 'atypical' with linear and granular segments in 10 cases. Light microscopic diagnosis was acute rejection in 26 cases (33 biopsies) associated with deposits along the TBM:linear (6 cases), granular (13 cases) and atypical (7 cases). Chronic rejection present in 15 transplants (21 biopsies) was associated with linear (2 cases), granular (9 cases) and atypical (4 cases) deposits along the TBM. Electron microscopic study of renal tubules showed altered TBM with thickening, lamellation and splitting. Electron-dense deposits were not demonstrated in cases of linear deposits. A long-term follow-up study did not show any difference in survival of transplants presenting acute or chronic rejection associated or not with TBM deposits. If we consider the outcome of the transplants with TBM deposits, those with granular type seemed to have the poorest prognosis at long term, whatever the type of rejection. In the linear TBM deposits group, all the transplant nephrectomies which occurred (7 out of 9 cases) have been performed within 5 years.     

High nephritogenicity of monoclonal antibodies belonging to IgG2a and IgG2b subclasses in rat anti-GBM nephritis

BACKGROUND: To examine a subclass-effect relationship and a dose-effect relationship of autoantibodies in the rat antiglomerular basement membrane (GBM) antibody-induced glomerulonephritis (anti-GBM nephritis) model, we injected homologous monoclonal antibodies against the NC1 domains of rat type IV collagen into inbred Wistar-Kyoto (WKY) rats. METHODS: Eight different autoantibodies from each of the IgG1, IgG2a, and IgG2b subclasses were established and administered to groups of four WKY rats at a dose of 300 microg/rat. To examine the dose-effect relationship, we administered 0 to 300 microg/rat of autoantibodies from each subclass to rats. RESULTS: All IgG1 antibodies induced mild nephritis, whereas the IgG2a and IgG2b antibodies induced moderate to severe nephritis. Some IgG2a and IgG2b antibodies induced pulmonary hemorrhage as well. These antibodies were reactive with alpha3(IV)NC1, alpha4(IV)NC1, or alpha5(IV)NC1. The minimum dose of antibody required to induce nephritis was 30 microg/rat for IgG1, 3 microg/rat for IgG2a, and 1 microg/rat for IgG2b. At doses of 30 microg/rat or less, antibody deposition was generally restricted to the GBM. At doses of 100 microg/rat or greater, antibody deposition extended to both the GBM and tubular basement membrane (TBM). Pulmonary hemorrhage was observed only when a large amount of pulmonary hemorrhagic antibody was administered. CONCLUSION: The severity of nephritis was dependent on both subclass and dose of autoantibodies. It becomes clear that pulmonary hemorrhage in anti-GBM nephritis is induced by autoantibodies.     

A case of an ABO-incompatible renal transplant with abundant intratubular basement membrane immune deposits

Abstract: We present a case of a 30-year-old man who received an ABO-incompatible renal transplant from his mother in 1996 after haemodialysis for 3 years. Although his renal function was stable, a renal biopsy was performed while he was in hospital for treatment of herpes zoster in 1999. Light microscopy provided no evidence of obvious acute or chronic rejection but a double contour pattern was observed in many tubular basement membranes (TBM). Immunofluorescence microscopy revealed deposits of IgG and C3 on the TBM in the absence of glomerular deposition. Massive electron-dense deposits were observed clearly by electron microscopy within TBM, revealing splitting and lamellation. This implies that the deposits resulted from the formation of immune complexes, but not from anti-TBM antibody. Although the role of TBM deposits in tubular injury is controversial, careful observation of patients with such deposits may be required because of their potential ability to induce immune reactions.     

Induction of tubular basement membrane (TBM) antigen specific suppressor T cells in BALB/c mice]

Transfer of tubular basement membrane (TBM)-primed thymocytes from BALB/c mice that had been immunized with allogeneic TBM antigen without adjuvant prevented the development of interstitial nephritis (IN) in recipient BALB/c mice that had been immunized with TBM antigen with complete Freund's adjuvant (CFA) to produce IN. TBM antigen was prepared from TBM of normal ddY mice (ddY TBM antigen). BALB/c mice were highly susceptible to IN and showed a high immune response to TBM antigen when they were immunized with TBM antigen in CFA. Development of IN in high responder BALB/c mice was clearly suppressed by transfer with ddY TBM-thymocytes. The anti-TBM antibody response and the proliferative response of splenic T cells to TBM antigen were also depressed by the transfer. The cell extract of ddY TBM-thymocytes had also suppressive activity on the development of IN and on the immune response to TBM antigen. This simple system without any adjuvant for inducing the thymocytes, which has strong suppressive activity on the development of IN and on the immune response to TBM antigen, may allow us to analyse the role of suppressor T cells in negative regulation of IN.     

Persistent proximal tubule dysfunction late in Heymann nephritis

To determine whether proximal tubule function returned to normal after cessation of active immunological injury in Heymann nephritis, we compared kidney function in an acute stage of the disease, when antibodies were being deposited on the brush border, to a later, chronic stage. Renal blood flow measurements via a flow probe, along with clearance and micropuncture techniques, were used to measure renal plasma flow, glomerular filtration rate, protein and albumin excretion, organic ion (PAH and TEA) extraction and tubule fluid inulin concentration. Proximal tubule fluid reabsorption, which was depressed in the acute stage of injury, returned to normal in chronic Heymann nephritis, but both PAH and TEA extraction continued to be depressed. PAH extraction was also decreased in isolated perfused kidneys from rats with Heymann nephritis. A three fold increase in PAH content of these perfused kidneys indicated that there was a defect in luminal PAH transport. Reconstitution of the proximal tubule brush border in chronic Heymann nephritis was not accompanied by functional recovery of secretory processes.     

Diabetic nephropathy with interstitial nephritis presenting with a false-positive anti-GBM antibody

A 56-year-old male with DM and HTN presented with flank pain and nausea. Review of systems was negative, physical examination was notable for mild hypovolemia and laboratory revealed BUN 51 mg/dl, creatinine (Cr) 5.1 mg/dl (baseline 1.5), Westergren ESR 122 mm/h, fractional excretion of sodium 0.2% and UA positive for blood and protein. Despite volume resuscitation the Cr continued to rise. Urine sediment analysis revealed granular casts, renal tubular epithelial cells and a negative Hansel's stain. Hemodialysis was initiated with Cr 13.7 mg/ dl for dyspnea and dysgeusia. Subsequent laboratory data revealed 2 separate positive anti-GBM antibody titers and prednisone therapy was initiated. Renal biopsy was performed for further diagnostic, therapeutic and prognostic information and demonstrated interstitial nephritis with linear IgG and albumin deposition consistent with diabetic nephropathy. Follow-up antibody titers were negative. prednisone was discontinued and Cr stabilized with conservative therapy. Anti-GBM antibody disease is characterized by circulating IgG antibodies directed against the glomerular basement membrane, specifically the alpha-3 (IV) collagen chain. Anti-GBM nephritis is a rapidly progressive, isolated glomerulonephritis in association with circulating anti-GBM antibodies. A positive immunofluorescence (IF) test is considered diagnostic in the appropriate clinical setting. Therapies include immunosuppressive agents to suppress new antibody production and plasmapheresis to eliminate circulating antibodies. Anti-GBM antibody is not rapidly cleared by steroid therapy and the recovery of renal function is rare if initiation Cr is greater than 7 mg/dl. This case demonstrates that the current ELISA for alpha-3 (IV) collagen is not pathognomonic for anti-GBM nephritis and that renal biopsy with IF for IgG and albumin may be indicated to prevent administration of potentially toxic treatment.     

Linear C3 deposits on the tubular basement membrane in renal allograft biopsies

Linear and granular tubular basement membrane (TBM) deposits of C3 occur in renal allograft biopsies, but their significance is unknown. We retrospectively analyzed the predictive importance of C3 deposits in 88 biopsied transplant patients with allograft dysfunction. All patients were followed for greater than or equal to 2 years from biopsy. Patients were divided into three groups: group I: no C3 deposits, 47 patients; group II: granular deposits of C3, 28 patients; and group III: linear TBM deposits, 13 patients. The incidence of acute and chronic rejection was not different. In group III, 12 grafts were lost by 5 years (92%), and the remaining patient has chronic rejection. Group III survival was significantly less than groups I and II (Kaplan-Meier curves), P = 0.02, but graft survival in groups I and II were similar. There was no association of anti-TBM antibody deposits with C3, and the mechanism of deposition is unknown. We conclude that the presence of linear C3 deposits along the TBM in the setting of allograft dysfunction is associated with decreased allograft survival.     

Immune Complex Tubulointerstitial Nephritis Due to Autoantibodies to the Proximal Tubule Brush Border

Immune complex tubulointerstitial nephritis due to antibodies to brush border antigens of the proximal tubule has been demonstrated experimentally and rarely in humans. Our patient developed ESRD and early recurrence after transplantation. IgG and C3 deposits were conspicuous in the tubular basement membrane of proximal tubules, corresponding to deposits observed by electron microscopy. Rare subepithelial deposits were found in the glomeruli. The patient had no evidence of SLE and had normal complement levels. Serum samples from the patient reacted with the brush border of normal human kidney, in contrast with the negative results with 20 control serum samples. Preliminary characterization of the brush border target antigen excluded megalin, CD10, and maltase. We postulate that antibodies to brush border antigens cause direct epithelial injury, accumulate in the tubular basement membrane, and elicit an interstitial inflammatory response.     

Local formation of immune deposits in rabbit renal proximal tubules

Rabbits passively immunized with goat antibodies to rabbit angiotensin converting enzyme (ACE), an enzyme synthesized in the endoplasmic reticulum and mainly expressed on the apical membranes of the cells of proximal tubules, developed mild and transient immune deposits in this segment of the nephron. Granular deposits of goat IgG, rabbit ACE and C3 were found in the basolateral compartment and were maximal during the first week of immunization when the highest titers of anti-ACE antibodies were present. As the antibody titer fell to an undetectable level, the immune deposits were rapidly cleared and were virtually absent 21 days after the injections. Artificial increase of glomerular permeability allowed focal binding of ACE antibodies to the brush border of some tubules, but did not significantly alter the pattern of immune injury at the base of tubular cells. The data are consistent with the interpretation that the immune deposits result from in situ formation of immune complexes. This mechanism would involve passage of circulating antibodies across the tubular basement membrane and their combination with ACE associated with tubular cell surface membranes.     

Linear glomerular IgG fixation in renal allografts: incidence and significance in Alport's syndrome

Twelve of 767 renal allograft recipients developed linear fixation of IgG along the glomerular basement membrane (GBM) by direct immunofluorescence technique. This was associated with linear fixation along the tubular basement membrane in 7 of them. Circulating anti-GBM antibodies were not detected by indirect immunofluorescence or radioimmunoassay in any patient whereas anti-TBM antibodies were found in 2 of 4 with linear TBM fixation. Among the 12 patients with linear GBM fixation, 5 had Alport's syndrome; the 7 others had various renal diseases, excluding anti-GBM nephritis. Among the 767 patients, 34 had Alport's syndrome or variants (i.e., 4.5%). The incidence of linear GBM fixation is much higher in Alport's syndrome than in other renal diseases. Linear GBM fixation was not clearly related to anti-GBM antibodies and was not accompanied by significant deterioration of graft function. These findings may be relevant, however, to the missing GBM antigen in Alport's syndrome.     

Antiglomerular basement membrane antibody: antibody specificity in different forms of glomerulonephritis

Components were solubilized from human glomerular basement membrane by digestion with collagenase and pepsin or by extraction with guanidine-HCl either directly or after previous digestion with the enzyme. The diverse preparations were used as antigens in the enzyme-linked immunosorbent assay (ELISA) of antibody titers in sera from patients with Goodpasture syndrome and patients with other forms of glomerulonephritis, that is, systemic lupus erythematosus, periarteritis nodosa, and IgA-related nephropathy. Patients with Goodpasture syndrome had high titers of IgG antibodies reacting most strongly with collagenase digests. The antigen(s) was only partly solubilized by guanidine-HCl extraction, was destroyed by pepsin digestion as well as reduction, and partly destroyed by trypsin digestion. The antigen(s) is most likely noncollagenous protein. Antibodies from patients with other forms of nephritis were directed primarily against antigens in guanidine-HCl extracts, while the antigen(s) was not solubilized by collagenase digestion. Pepsin digestion destroyed the antigen(s). The antibodies were of a different class, that is, the patients with systemic lupus erythematosus had IgG and IgA as well as IgM antibodies; the patients with periarteritis nodosa had IgM or IgG and IgA antibodies, while the patients with IgA-related nephritis had the highest recorded titers of IgA but also had IgG as well as IgM antibodies. None of the patients had antibodies directed against triple helical collagen. The antibody response in anti-GBM antibody-related nephritis, then, is different both with respect to antigen and antibody class and depends on the underlying disease syndrome.