Differences between membranoproliferative glomerulonephritis types I and III in clinical presentation, glomerular morphology, and complement perturbation

Data for 26 patients with membranoproliferative glomerulonephritis, type I (MPGN I) and 22 with membranoproliferative glomerulonephritis, type III (MPGN III), as distinguished by glomerular ultrastructure, were analyzed to determine differences in presentation, complement perturbation, and glomerular morphology by light microscopy. MPGN III was detected with greater frequency by the chance discovery of hematuria and proteinuria in the otherwise healthy individual (MPGN III, 63%; MPGN I, 30%; P = .01) and never, in the absence of renal failure, presented with systemic symptoms such as ease of fatigue, weight loss, and pallor, as may patients with MPGN I. The more frequent detection of MPGN III by chance is evidence that its onset is insidious and that for long periods it produces no symptoms or signs. Glomerular proliferation is also less than in MPGN I. Further, in MPGN III, the complement perturbation and glomerular immunofluorescence give no evidence of classical pathway activation, for which there is abundant evidence in MPGN I. Even with severe hypocomplementemia in MPGN III, C3 nephritic factor, another cause of hypocomplementemia, is rarely detectable and then in very low concentration. The cause of the complement perturbation in MPGN III has so far escaped identification. Although these observations give evidence that MPGN III is distinct from MPGN I, there is compelling evidence from other studies that a predisposition to both types is inherited and that similar genetic factors are operative in the two types. Because their genetic basis appears to be the same, it must be concluded that despite their differences, types I and III are variants of the same disease.     

Control of complement activation in membranous and membranoproliferative glomerulonephritis

Renal biopsy specimens from 22 membranous (MGN) and 19 membranoproliferative glomerulonephritis (MPGN) patients were examined for the presence of the three regulators of the complement system; C1- inhibitor (C1--INH), C3b inactivator (C3b-INA), and beta 1H. The serum concentrations of these proteins, at the time of biopsy, were also measured. To study the modulation of complement activation by these three control proteins in MGN and MPGN, we examined the relationship between each control protein and the protein whose activity it regulates, in four ways; (a) the concordance between the presence of the control proteins and the components regulated was studied, (b) the correlations in intensity of deposition of the control and complement proteins were measured, (c) the patterns of distribution of the proteins within the glomeruli were compared, and (d) the serum levels of control proteins and components, regulated were examined. C1--INH (23 of 35 biopsies) and beta 1H (34 of 36 biopsies) were frequently deposited in both disease groups. C3b-INA was found only rarely in MPGN (4 of 19 biopsies). This is probably because the former two proteins modulate complement activation stoichiometrically, whereas C3b-INA acts enzymatically. A relationship was demonstrated between C1--INH and C1s and between beta 1H and C3 in both groups, but no such relationship was found between C3bINA and C3. Conclusion. There is no generalized deficiency in modulation of complement activation in MGN or MPGN.     

Terminal complement complexes in childhood type I membranoproliferative glomerulonephritis

BACKGROUND: The role of terminal complement complexes (TCCs), which are the final products of complement activation, in the pathogenesis of human glomerulonephritis has not been completely elucidated. To clarify the clinical significance of TCCs in type I membranoproliferative glomerulonephritis (MPGN), we studied TCCs in plasma, renal tissue and urine in pediatric patients with this disease. PATIENTS AND METHODS: We measured the concentrations of TCC in plasma (n=25) and urine (n=13) using enzyme-linked immunosorbent assay. Frozen tissue from 18 renal biopsies were evaluated for the presence of TCC by direct immu-noperoxidase staining. RESULTS: At the early stage of the disease, TCC concentrations in plasma were elevated to above 0.5 arbitrary units (AU)/mL in 14 of 25 patients (high-TCC group), while the remaining 11 patients showed less than 0.5 AU/mL (low-TCC group). In the high-TCC group, TCCs were deposited more diffusely and intensely in the glomerulus, compared with those in the low-TCC group (p=0.034). Furthermore, urinary TCC concentrations in the high-TCC group were higher than those in the low-TCC group (p=0.0001). The high-TCC group showed not only a poorer response to steroid treatment, but also poorer prognosis than the low-TCC group. CONCLUSIONS: These results suggest that, in pediatric patients with type I MPGN, TCCs in circulation may play a particular role in TCC formation in the glomerulus and in urine. The TCC concentration in plasma could be used as a marker of responsiveness to steroid treatment and long-term prognosis.     

Glomerular paramesangial deposits: association with hypocomplementemia in membranoproliferative glomerulonephritis types I and III

Of 22 subjects previously reported with some form of factor H dysfunction, 12 had a glomerulonephritis that appeared to not be of immune complex origin. Factor H dysfunction results in elevated circulating levels of the C3b-dependent C3 convertase, C3b,Bb. Of the 12 cases with glomerulonephritis, the glomerular deposits in the six whose biopsy specimens were studied were predominately subepithelial on the paramesangial portion of the glomerular basement membrane. In a subsequent study, similar deposits were found in patients with membranoproliferative glomerulonephritis (MPGN) type II, also a nephritis that is probably not of immune complex origin. Paramesangial deposits were found in these patients only in biopsy specimens obtained when the C3 level was low, at which time convertase stabilized by nephritic factor would be present in the circulation. This association of paramesangial deposits with circulating convertase was further tested by correlating these deposits with the level of C3 at the time of biopsy in MPGN types I and III. The results in type III MPGN were similar to those in type II; paramesangial deposits were frequently present when the C3 level was low as a result of circulating nephritic factor of the terminal pathway, NFt, and were usually absent when the C3 level was in the upper two thirds of the normal range. Deposits persisted in those patients with C3 levels that had been low but that had increased during the year before biopsy to within the lower one third of the normal range. The persistence of paramesangial deposits in MPGN type III, as compared with MPGN type II, may be related to the differences in composition and function of the two NF stabilized convertases (C3bn,Bb,P,NFt and C3b,Bb,NFa, respectively) that circulate in these two disorders. In contrast to MPGN type III, the hypocomplementemia in MPGN type I is thought to be, for the most part, the result of classical pathway activation, which is not associated with elevated circulating convertase levels. In agreement with this, paramesangial deposits were found in only two of 34 biopsy specimens. At the time of those two biopsies, both patients had a complement profile indicating that the NFt was circulating, as in MPGN type III. In three other cases with profiles compatible with circulating NFt, paramesangial deposits were not found. In all patients with type I MPGN, electron microscopy and immunofluorescence of the glomeruli gave results typical of an immune complex nephritis. Thus, even though the complement profile in MPGN type I may at times indicate the presence of a nephritic factor, circulating immune complexes appear to be basic to pathogenesis. The observations support the hypothesis that elevated levels of the C3b-dependent convertase, as found in the "experiments of nature" with factor H dysfunction and in MPGN types II and III, are associated with paramesangial deposits. The nature of this association and the role of these deposits in producing the nephritis is not clear.     

Pathways of complement activation in membranoproliferative glomerulonephritis and allograft rejection.

The complement system is comprised of at least 18 plasma proteins and consists of four functional divisions: two pathways for activation (classical and alternative), a common amplification mechanism for the activating pathways, and a final common effector pathway to which the activating and amplifying sequences are directed. The classical pathway is activated by certain antigen-antibody complexes, while the alternative pathway may be initiated non-immunologically by various microbial polysaccharides. Indeed, mixtures of purified C3, B, D, and P regulated to low-grade interaction by the presence of C3bINA and beta1 H respond to zymosan with amplified C3 and B inactivation. Both pathways form enzymes termed C3 convertases that cleave C3 to generate its major fragment, C3b. C3b interacts with each C3 convertase to permit C5 cleavage in activation of the effector complement sequence, and it interacts with alternative-pathway factors B and D to generate additional C3 convertase, C3bBb, in the amplification pathway. As C3 cleavage represents the most critical step in the elaboration of the biologic effects of the complement system, modulation of this reaction by generation, stabilization, and inactivation of the amplification convertase C3bBb may well determine whether initial activation of the complement sequence eventuates in beneficial or detrimental effects for the host. Initial generation of C3bBb is dependent on prior cleavage of C3, which may occur by the classical pathway or the alternative pathway. Stabilization of C3bBb is achieved with either P or C3NeF after their binding to C3b and C3bBb, respectively. Control of this amplifying step occurs at three levels: intrinsic decay of the inherently labile C3bBb complex, extrinsic decay-dissociation of Bb from the complex by beta1H, and inactivation of C3b by C3bINA. In the presence of stabilizing factors the control proteins must function in sequence, since C3bINA cannot act on C3bBb; beta1H-mediated decay of protective Bb must precede C3b inactivation by C3bINA. C3NeF, which is found in the sera of some patients with MPGN and persistent depressions of serum C3, circumvents all three controls because of its capacity to create a stabilized convertase that is relatively resistant to decay-dissociation by beta1H. The effector complement sequence is activated by cleavage of C3 and C5, which releases vasoactive and chemotactic peptides, C3a and C5a, and generates the major fragments C3b and C5b. C3b, in addition to its function in the amplifying reaction and the C5 convertases, mediates immune adherence to cells possessing membrane-associated receptors for C3b; this in turn promotes the phagocytic and secretory functions unique to each cell type. Cell-bound C5b serves to assemble the cytolytic complex C5b6789, while fluid-phase C5d generates the hemolytically inactive chemotactic complex C567d...     

Inherited complement component deficiencies in membranoproliferative glomerulonephritis

Anecdotal reports of complement component deficiencies in patients with immune complex disease led to a systematic study of the levels of seven complement components in serum specimens from 178 patients with glomerulonephritis and 163 normal subjects. Deficiencies were found with significantly higher frequency (22.7%) among 44 patients with membranoproliferative glomerulonephritis (MPGN) types I and III, than among the normal subjects (6.7%, P less than 0.002) or among 134 patients with other glomerulonephritides (5.2%, P less than 0.001). The component deficiencies in MPGN were partial in nine patients and subtotal in one. They could not be ascribed to acquired hypocomplementemia or to a nephrotic syndrome. They were present over long periods, were found in family members, and involved C2, C3, factor B, C6, C7, and C8. Six were presumably the result of null structural genes, two were associated with a structurally abnormal component, and two were of unknown cause. The results give evidence that partial deficiency of one or more complement components is a factor predisposing to MPGN.     

Rapidly progressive glomerulonephritis (crescentic glomerulonephritis) in the course of type I idiopathic membranoproliferative glomerulonephritis

Membranoproliferative glomerulonephritis is a chronic glomerulopathy with a generally progressive course toward end-stage renal disease and a high recurrence rate in renal allografts. Described herein is the appearance of rapidly progressive glomerulonephritis (crescentic glomerulonephritis) in the course of type I membranoproliferative glomerulonephritis. This transition occurred within 6 weeks, documented histologically by an initial and subsequent renal biopsy. No recurrence of the disease was noted in a living donor graft 18 months posttransplantation.     

Clinical significance of the terminal complement complex in children with type I membranoproliferative glomerulonephritis

We measured the concentrations of terminal complement complex (TCC) in plasma (n =25) and urine (n=13) using an enzyme-linked immunosorbent assay in pediatric patients with type I membranoproliferative glomerulonephritis(MPGN). Frozen tissue from 18 renal biopsies was evaluated for the presence of TCC by direct immunoperoxidase staining. In the acute phase of the disease, TCC concentrations in plasma were elevated above 0.5 AU/ml in 14 of 25 patients (High TCC group), while the remaining 11 patients showed less than 0.5 AU/ml (Low TCC group). In the High TCC group, TCC was deposited more diffusely and intensely in the glomerulus, compared to that in the Low TCC group (p= 0.034). Furthermore, urinary TCC concentrations in the High TCC group were higher than those in the Low TCC group (p=0.0001). The High TCC group showed not only a poorer response to steroid treatment, but also a poorer prognosis than the Low TCC group. These results suggest that, in pediatric patients with type I MPGN, TCC in circulation may play a certain role in TCC formation in the glomerulus and in urine. The TCC concentration in plasma could be used as a marker of responsiveness to steroid treatment and long-term prognosis.     

Long-term follow-up of type III membranoproliferative glomerulonephritis in children

Seven patients with type III membranoproliferative glomerulonephritis (MPGN) were followed for 9–17 years. Their mean age at presentation was 11.0 years. Their urinary abnormalities were detected by school urinary screening in five, and two patients presented with nephrotic syndrome. With time, urinalysis became normal in five, proteinuria persisted in one and nephrotic syndrome persisted in one. All had serum creatinine levels below 1 mg/dl at the last follow-up. All were initially hypocomplementemic. Serum C3 levels became normal in five patients but decreased again in three without clinical changes. Mesangial proliferation was initially slight or moderate in five but, except for one patient, histological changes persisted in follow-up biopsies even though in two the urinalysis became normal. Electron micrographic studies using silver-methenamine staining revealed subepithelial and subendothelial deposits associated with basement membrane disruption and layering of the lamina densa, an abnormality typical of MPGN type III. These observations suggest long-term outcome of type III MPGN is good despite persisting changes in type III lesions. Received: 11 July 2001 / Revised: 11 October 2001 / Accepted: 12 October 2001     

Cutaneous telangiectasias, sparse hair, and type I membranoproliferative glomerulonephritis

 We report the unusual association of normocomplementemic type I membranoproliferative glomerulonephritis in a 10-year-old girl with sparse red hair, absent eyebrows and eyelashes, cutaneous telangiectasias, and an atrial septal defect. Received: 29 December 1997 / Revised: 6 May 1998 / Accepted: 21 May 1998     

Turner's syndrome, 46X, del (X) (p 11), persistent complement activation and membranoproliferative glomerulonephritis

An adolescent girl with short stature and learning disability was found to have an unusual variant of Turner's syndrome, 46X, del (X) (p 11) and an abnormal urinary sediment. Further studies demonstrated persistent depression of C3 and histologic evidence of membranoproliferative glomerulonephritis (MPGN). The occurrence of MPGN in this case may have been a manifestation of the known tendency for Turner patients to develop immunologic disease.     

Absence of hepatitis B and C viruses in pediatric idiopathic membranoproliferative glomerulonephritis

The blood-borne hepatitis viruses, hepatitis B virus (HBV) and hepatitis C virus (HCV), have similar epidemiological features. The association of chronic HBV infection and glomerulonephritis is well established, particularly in children. Recent reports have shown an association between HCV infection and glomerulonephritis in adults. In order to assess the role of these hepatotropic viruses in membranoproliferative glomerulonephritis (MPGN) we screened 34 children with idiopathic MPGN for the presence of HBV and HCV infection using highly sensitive polymerase chain reaction techniques for the detection of HBV DNA and HCV RNA. Also, enzyme-linked immunosorbent assays were used to detect the presence of antibody to hepatitis B surface antigen and antibody to HCV. No evidence of HBV or HCV infection was demonstrated in any of the patients. We conclude that HBV and HCV are not significant causes of idiopathic MPGN in children in the United States.     

Treatment of idiopathic membranoproliferative glomerulonephritis with mycophenolate mofetil and steroids.

BACKGROUND: Treatment of adults with idiopathic membranoproliferative glomerulonephritis (IMPGN) is often unrewarding with approximately 60% of patients progressing to end-stage renal failure within 10 years. Although children with IMPGN may respond to steroid therapy, there is no significant benefit to treating adult IMPGN patients with immunosuppression. METHODS: Outcome measures in five patients with IMPGN who were treated with oral prednisolone and mycophenolate mofetil (MMF) (treatment group) were compared with six patients with IMPGN who did not receive immunosuppression (control group). RESULTS: There was no significant difference between either group in baseline clinical characteristics or systolic and diastolic blood pressure during observation. In the treatment group, there was a significant reduction in proteinuria from a baseline of 5.09 to 1.97 g/24 h (P = 0.003) at 6 months, 1.96 g/24 h (P = 0.003) at 12 months and 2.59 g/24 h (P = 0.015) at 18 months. There was no significant change in proteinuria over 18 months in the control group. Serum creatinine concentration and creatinine clearance did not change significantly over 18 months in the treatment group. In the control group, there were significant changes in serum creatinine and creatinine clearance over 18 months [baseline 103 to 159 micromol/l (P = 0.004) and baseline 108 to 67 ml/min (P > 0.001), respectively] when compared to baseline, although the differences were not significant when the two groups were compared directly. CONCLUSIONS: This preliminary study suggests that in the short term, the combination of MMF and prednisolone can significantly reduce proteinuria and may preserve renal function in patients with IMPGN.     

Long-term follow-up of diffuse membranoproliferative glomerulonephritis type I

In Japan, the school urinary screening system facilitates early detection and treatment of membranoproliferative glomerulonephritis (MPGN) in childhood. The present study investigated the long-term prognosis in 19 children with diffuse MPGN type I who received steroid therapy. Before signs of glomerulonephritis were confirmed, all patients displayed abnormal urinalysis results, predominantly through school urinary screening. Treatment comprised a regimen of alternate-day prednisolone after steroid pulse or cyclophosphamide therapy, and follow-up was continued for 10–24 years. Excluding 1 patient on short-term therapy, 18 patients received long-term alternate-day prednisolone therapy for 4–12 years. Treatment was discontinued when amelioration was confirmed on renal biopsy. As of the last observation, urinary abnormalities and hypocomplementemia had disappeared in 15 patients, while mild proteinuria without hypocomplementemia remained in 4 patients. No patients required hemodialysis. Moreover, no severe adverse effects attributable to treatment were identified other than mild short stature. Early detection and therapy using pulse methylprednisolone followed by alternate-day prednisolone was thus confirmed as safe and useful for treating diffuse MPGN type I.     

Overexpression of complement inhibitor Crry does not prevent cryoglobulin-associated membranoproliferative glomerulonephritis

BACKGROUND: Mice overexpressing thymic stromal lymphopoietin (TSLP) develop mixed cryoglobulinemia with renal disease closely resembling human cryoglobulin-associated membranoproliferative glomerulonephritis (MPGN), including glomerular deposits of immunoglobulins and complement. We assessed the effect of complement inhibition through overexpression of Crry (complement receptor-1 related gene/protein Y), which blocks the classic and alternative pathway of complement activation through inhibition of the C3 convertase, in cryoglobulinemia-associated immune complex glomerulonephritis. METHODS: TSLP transgenic mice were crossbred with animals overexpressing Crry. Mice were sacrificed after 50 days (females) or 120 days (males), and kidneys, blood, and urine were collected from seven mice of each experimental group (wild type, Crry transgenic, TSLP transgenic, and Crry/TSLP doubly transgenic). RESULTS: TSLP/Crry doubly transgenic animals demonstrated expected serum levels of Crry. Renal involvement, both in TSLP transgenic and TSLP/Crry doubly transgenic animals, was characterized by glomerular matrix expansion, macrophage influx, activation of mesangial cells, and deposition of immunoglobulins and complement. Overexpression of Crry did not result in significant improvement of renal pathology or laboratory findings. Expression of recombinant soluble Crry was confirmed by enzyme-linked immunosorbent assay (ELISA) in Crry transgenic animals. However, formation of the membrane attack complex C5b-9 as a marker of terminal active complement components and represented by glomerular C9 staining could not be inhibited in Crry transgenic TSLP mice. CONCLUSION: These results indicate that overexpression of Crry was not sufficient to prevent renal injury in TSLP transgenic mice. We suggest that the inhibitory capacity of Crry may be overwhelmed by chronic complement activation. Further studies need to address the role of complement in cryoglobulinemic glomerulonephritis before therapeutic complement inhibition can be attempted.     

Specific eye fundus lesions in type II membranoproliferative glomerulonephritis

In three adolescents, suffering from membrano-proliferative glomerulonephritis type II, ophthalmoscopy and fluorescein angiography revealed retinal pigment epithelium lesions, referred to as basal laminar drusen. The patient with the longest renal history had the most pronounced fundus changes. These lesions, earlier described in adult patients, are believed to be specific for this particular form of chronic glomerulonephritis.