Nephritis-associated Plasmin Receptor Research Articles

Clinico-Pathogenic Similarities and Differences between Infection-Related Glomerulonephritis and C3 Glomerulopathy.

Recently, the comprehensive concept of "infection-related glomerulonephritis (IRGN)" has replaced that of postinfectious glomerulonephritis (PIGN) because of the diverse infection patterns, epidemiology, clinical features, and pathogenesis. In addition to evidence of infection, hypocomplementemia particularly depresses serum complement 3 (C3), with endocapillary proliferative and exudative GN developing into membranoproliferative glomerulonephritis (MPGN); also, C3-dominant or co-dominant glomerular immunofluorescence staining is central for diagnosing IRGN. Moreover, nephritis-associated plasmin receptor (NAPlr), originally isolated from the cytoplasmic fraction of group A Streptococci, is vital as an essential inducer of C3-dominant glomerular injury and is a key diagnostic biomarker for IRGN. Meanwhile, "C3 glomerulopathy (C3G)", also showing a histological pattern of MPGN due to acquired or genetic dysregulation of the complement alternative pathway (AP), mimics C3-dominant IRGN. Initially, C3G was characterized by intensive "isolated C3" deposition on glomeruli. However, updated definitions allow for glomerular deposition of other complement factors or immunoglobulins if C3 positivity is dominant and at least two orders of magnitude greater than any other immunoreactant, which makes it challenging to quickly distinguish pathomorphological findings between IRGN and C3G. As for NAPlr, it was demonstrated to induce complement AP activation directly in vitro, and it aggravates glomerular injury in the development of IRGN. A recent report identified anti-factor B autoantibodies as a contributing factor for complement AP activation in pediatric patients with PIGN. Moreover, C3G with glomerular NAPlr deposition without evidence of infection was reported. Taken together, the clinico-pathogenic features of IRGN overlap considerably with those of C3G. In this review, similarities and differences between the two diseases are highlighted.

Nephritis-Associated Plasmin Receptor (NAPlr): An Essential Inducer of C3-Dominant Glomerular Injury and a Potential Key Diagnostic Biomarker of Infection-Related Glomerulonephritis (IRGN).

Nephritis-associated plasmin receptor (NAPlr) was originally isolated from the cytoplasmic fraction of group A Streptococci, and was found to be the same molecule as streptococcal glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and plasmin receptor (Plr) on the basis of nucleotide and amino acid sequence homology. Its main functions include GAPDH activity, plasmin-binding capacity, and direct activation of the complement alternative pathway (A-P). Plasmin trapped by deposited NAPlr triggers the degradation of extracellular matrix proteins, such as glomerular basement membranes and mesangial matrix, and the accumulation of macrophages and neutrophils, leading to the induction of plasmin-related endocapillary glomerular inflammation. Deposited NAPlr at glomerular endocapillary site directly activates the complement A-P, and the endocapillary release of complement-related anaphylatoxins, C3a and C5a, amplify the in situ endocapillary glomerular inflammation. Subsequently, circulating and in situ-formed immune complexes participate in the glomerular injury resulting in NAPlr-mediated glomerulonephritis. The disease framework of infection-related glomerulonephritis (IRGN) has been further expanded. GAPDH of various bacteria other than Streptococci have been found to react with anti-NAPlr antibodies and to possess plasmin-binding activities, allowing glomerular NAPlr and plasmin activity to be utilized as key biomarkers of IRGN.

Acute Post-Streptococcal Glomerulonephritis in Children: A Comprehensive Review.

Acute post-streptococcal glomerulonephritis (APSGN) is an immune- complex (ICs) mediated glomerular disease triggered by group A β-hemolytic streptococcus (GAS) or Streptococcus pyogenes infections. APSGN represents a major cause of acquired kidney injury in children. This non-systematic review summarizes recent evidence on APSGN. We discuss the epidemiology, pathogenesis, clinical and laboratory findings, histopathology, treatment and prognosis of the disease. The median APSGN incidence in children in developing countries is estimated at 24.3/100,000 per year, compared with 6.2/100,000 per year in developed countries. Nephritis-associated plasmin receptor, identified as glyceraldehyde-3-phosphate dehydrogenase, and the cationic cysteine proteinase streptococcal pyrogenic exotoxin B are thought to be two leading streptococcal antigens involved in the pathogenesis of APSGN, which activate the complement system, mainly via the alternative but also the lectin pathway. This process is critical for the generation of inflammation by the ICs deposited in the glomerulus. The classic phenotype is an acute diffuse proliferative glomerulonephritis leading to features of the nephritic syndrome, including hematuria, oliguria, hypertension and edema. The histopathology shows that the glomeruli are diffusely affected, mostly presenting enlarged glomerular tuffs due to hypercellularity. Proliferative endothelial and mesangial cells and inflammation have also been observed. APSGN frequently has spontaneous recovery. There is no specific therapy, but its morbidity and mortality are drastically reduced by the prevention and/or treatment of complications. Despite recent advances, the pathogenesis of APSGN is not fully understood. There is no specific treatment for APSGN. The prognosis is generally good. However, some cases may evolve into chronic kidney disease.

Nephritis-associated plasmin receptor (NAPlr) in streptococcal infection associated cutaneous IgA vasculitis

Nephritis-associated plasmin receptor (NAPlr) in streptococcal infection associated cutaneous IgA vasculitis

Thrombotic microangiopathy with transiently positive direct Coombs test in an adult with poststreptococcal acute glomerulonephritis: a case report

BackgroundTo date, a few case reports have described the association between poststreptococcal acute glomerulonephritis (PSAGN) and hemolytic anemia/thrombocytopenia, both with or without a pathology similar to that of thrombotic microangiopathy (TMA). However, the detailed mechanism leading to the complication of TMA in PSAGN patients remains to be clarified. In contrast, infection with neuraminidase-producing Streptococcus pneumoniae is a well-known cause of TMA, and it has been reported that transient positivity of the direct Coombs test is observed in up to 90% of such patients.Case presentationA 44-year-old man was hospitalized for acute nephritic syndrome 3 weeks after developing pharyngitis. PSAGN was suspected owing to a low complement C3, increased antistreptolysin-O and serum creatinine (5.46 mg/dL), and hematuria/proteinuria. The throat antigen test for group A Streptococcus was positive. He developed hemolytic anemia with thrombocytopenia from hospital day 9. TMA was suspected owing to minimal coagulation abnormalities. ADAMTS-13 activity was normal, whereas the direct Coombs test was transiently positive. Renal biopsy demonstrated glomerular endocapillary proliferation without crescents, but with severe tubulitis and peritubular capillaritis on light microscopy. Immunofluorescence demonstrated C3 deposition along the glomerular capillary walls, and many subepithelial humps were observed on electron microscopy. The deposition of nephritis-associated plasmin receptor (NAPlr), a nephritogenic protein of Streptococcus pyogenes, was observed only in glomeruli. Thus, the histological diagnosis was typical PSAGN, but with atypical severe tubulointerstitial lesions. A positive direct Coombs test is often observed in pneumococcal TMA patients, which is attributed to the exposure of Thomsen–Friedenreich (T) antigen by neuraminidase. As Streptococcus pyogenes is one of the neuraminidase-producing bacteria other than Streptococcus pneumoniae, T-antigen exposure was analyzed in the renal tissue of this patient using labelled peanut lectin as a probe, which has strong and specific binding affinity for T-antigen. Exposure of T-antigen was found on tubular epithelial cells and small vessels in the tubulointerstitial area, but not in the glomeruli of this patient.ConclusionThese findings suggest that 2 pathogenic proteins of Streptococcus pyogenes, i.e., NAPlr and neuraminidase, induced glomerular lesions of PSAGN and tubulointerstitial inflammation with TMA, respectively, resulting in severe acute kidney injury in this patient.

The influences of α-hemolytic Streptococcus on class switching and complement activation of human tonsillar cells in IgA nephropathy.

While β-hemolytic streptococcus (β-HS) infections are known to predispose patients to acute poststreptococcal glomerulonephritis, there is evidence that implicates α-hemolytic streptococcus (α-HS) in IgA nephropathy (IgAN). The alternative pathway of the complement system has also been implicated in IgAN. We aimed to explore the association between α-HS and complement activation in human tonsillar mononuclear cells (TMCs) in IgAN. In our study, α-HS induced higher IgA levels than IgG levels, while β-HS increased higher IgG levels than IgA levels with more activation-induced cytidine deaminase, in TMCs in the IgAN group. Aberrant IgA1 O-glycosylation levels were higher in IgAN patients with α-HS. C3 and C3b expression was decreased in IgAN patients, but in chronic tonsillitis control patients, the expression decreased only after stimulation with β-HS. Complement factor B and H (CFH) mRNA increased, but the CFH concentration in culture supernatants decreased with α-HS. The percentage of CD19 + CD35 + cells/complement receptor 1 (CR1) decreased with α-HS more than with β-HS, while CD19 + CD21 + cells/complement receptor 2 (CR2) increased more with β-HS than with α-HS. The component nephritis-associated plasmin receptor (NAPlr) of α-HS was not detected on tonsillar or kidney tissues in IgAN patients and was positive on cultured TMCs and mesangial cells. We concluded that α-HS induced the secretion of aberrantly O-glycosylated IgA while decreasing the levels of the inhibitory factor CFH in culture supernatants and CR1 + B cells. These findings provide testable mechanisms that relate α-HS infection to abnormal mucosal responses involving the alternative complement pathway in IgAN.

Glomerular Deposition of Nephritis-Associated Plasmin Receptor (NAPlr) and Related Plasmin Activity: Key Diagnostic Biomarkers of Bacterial Infection-related Glomerulonephritis.

It is widely known that glomerulonephritis (GN) often develops after the curing of an infection, a typical example of which is GN in children following streptococcal infections (poststreptococcal acute glomerulonephritis; PSAGN). On the other hand, the term “infection-related glomerulonephritis (IRGN)” has recently been proposed, because infections are usually ongoing at the time of GN onset in adult patients, particularly in older patients with comorbidities. However, there has been no specific diagnostic biomarker for IRGN, and diagnosis is based on the collection of several clinical and pathological findings and the exclusion of differential diagnoses. Nephritis-associated plasmin receptor (NAPlr) was originally isolated from the cytoplasmic fraction of group A streptococcus as a candidate nephritogenic protein for PSAGN and was found to be the same molecule as streptococcal glyceraldehyde-3-phosphate dehydrogenase and plasmin receptor. NAPlr deposition and related plasmin activity were observed with a similar distribution pattern in the glomeruli of patients with PSAGN. However, glomerular NAPlr deposition and plasmin activity could be observed not only in patients with PSAGN but also in patients with other glomerular diseases, in whom a preceding streptococcal infection was suggested. Furthermore, such glomerular staining patterns have been demonstrated in patients with IRGN induced by bacteria other than streptococci. This review discusses the recent advances in our understanding of the pathogenesis of bacterial IRGN, which is characterized by NAPlr and plasmin as key biomarkers.

Crescentic poststreptococcal acute glomerulonephritis accompanied by small vessel vasculitis: case report of an elderly male

BackgroundPoststreptococcal acute glomerulonephritis (PSAGN) in the elderly tends to have a severe clinical course and often presents with crescentic necrotizing glomerulonephritis in the renal biopsy. However, vasculitis lesions are unusual.Case presentationWe present a 71-year-old man who was admitted to our hospital for a recurrent gout attack with a rapid decline of renal function. Low C3 levels and a high anti-streptolysin O titer were observed, while myeloperoxidase- and proteinase 3- antineutrophil cytoplasmic antibody (ANCA) were negative. In addition to cellular crescent and necrosis lesions, diffuse peritubular capillaritis and venulitis as well as small arteriole vasculitis in the glomerular hilus were also apparent. Although granular C3c deposits in the capillary wall and hump lesions were not found, immunofluorescent staining for nephritis-associated plasmin receptor (NAPlr) and in situ zymography for plasmin activity were both positive. We thus diagnosed PSAGN accompanied by small vessel vasculitis. Steroid therapy gradually improved the patient’s renal function, and hemodialysis was discontinued after 1 month.ConclusionsIn our case, streptococcus infection might have concurrently provoked vasculitis, and NAPlr staining was useful for confirming diagnosis.

Acute Post-Streptococcal Glomerulonephritis in Children

Acute post-streptococcal glomerulonephritis is the most common form of glomerulonephritis in children, continues to be a major concern for pediatricians and nephrologists worldwide. The disease is caused by prior streptococcal infection caused by -hemolytic streptococcus of A group. Nephritis-associated plasmin receptor and streptococcal pyrogenic exotoxin B are considered to be major renotrophic antigens. Clinical findings of the disease can vary from asymptomatic gross hematuria to the full-blown acute nephritic syndrome (edema, gross hematuria, hypertension, renal failure). The main laboratory findings of acute post-streptococcal glomerulonephritis include an abnormal common urine analysis (dysmorphic erythrocytes, varying degrees of proteinuria, red blood cell casts, and segmentonuclear neutrophils), an elevated titer of antibodies to antistreptococcic antigens, and hypocomplementemia. Treatment of patients is mainly supportive and is focused upon the elimination of hypervolemia and its complications (edema, hypertension). In this situation, the most effective agents are loop diuretics and antihypertensive agents. The prognosis in children is generally favourable. The review analyses the current understanding of the pathogenesis, clinical manifestations, diagnosis, treatment and prognosis of acute post-streptococcal glomerulonephritis.

Acute Poststreptococcal Glomerulonephritis: The Most Common Acute Glomerulonephritis

Acute Poststreptococcal Glomerulonephritis: The Most Common Acute Glomerulonephritis

A case of post-pneumococcal acute glomerulonephritis with glomerular depositions of nephritis-associated plasmin receptor.

We report the case of a 12-year-old girl who was referred to our hospital with anuria associated with pneumonia. On admission, the patient's blood test results revealed severe renal failure, hypoproteinemia, and hypocomplementemia. Her urinalysis results revealed hematuria, proteinuria, and a positive titer for Streptococcus pneumoniae. S. pneumoniae was also detected in her sputum and blood cultures. The patient was diagnosed with post-pneumococcal acute glomerulonephritis (AGN) with acute renal failure. A renal biopsy demonstrated the infiltration of neutrophils and mononuclear cells into capillary loops. Immunofluorescence studies showed dominant-positive deposition of C3c along the capillary loops and nephritis-associated plasmin receptor (NAPlr) depositions in the mesangial area and capillary loops. Electron microscopy revealed dense deposits in the glomerular basement membrane without a hump in the subepithelial area. These findings were consistent with endocapillary proliferative glomerulonephritis. AGN associated with pneumococcal infection is very rare. This case suggests that NAPlr is the causative antigen not only of post-streptococcal AGN, but also of post-pneumococcal AGN. To our knowledge, this is the first report that shows a relationship between post-pneumococcal AGN and NAPlr depositions in the glomeruli.

Acute poststreptococcal glomerulonephritis with acute interstitial nephritis related to streptococcal pyrogenic exotoxin B.

A 20-year-old man presented with symptoms of edema. Three weeks prior to admission, he experienced an upper respiratory tract infection. On admission, blood pressure was 177/118 mmHg. Initial laboratory investigations revealed serum creatinine, 170 µmol/L; complement C3, 130 mg/L and antistreptolysin O titer, 538 IU/mL (reference, <239 IU/mL). Urinalysis showed nephrotic range proteinuria and hematuria. A percutaneous kidney biopsy was performed. Light microscopy contained 20 glomeruli, 4 of which were globally sclerotic and 1 of which showed cellular crescent formation. Diffuse endocapillary proliferative glomerulonephritis was identified (Figure 1A). Forty percent of the interstitium was infiltrated by inflammatory cells (Figure 1B). Immunofluorescent staining revealed complement C3, mainly on capillary walls. Fig. 1. (A and B) Findings of the kidney biopsy. Hematoxylin and eosin-stained section showing diffuse endocapillary proliferation with massive infiltration of neutrophils (A) and inflammatory cells infiltration in the cortical interstitium (B). (C–F ... Acute poststreptococcal glomerulonephritis (APSGN) with acute interstitial nephritis (AIN) was diagnosed. We administered methylprednisolone pulse therapy (1 g/day) for 3 days, followed by prednisolone at 80 mg/day. The serum creatinine level declined to 74 µmol/L and proteinuria decreased to <1 g/day. Transient type 4 renal tubular acidosis was observed during steroid treatment. AIN is found in the infectious diseases of children, particularly in streptococcal infection [1]. We investigated the localization of two streptococcal antigens, streptococcal pyrogenic exotoxin B (SPEB) and nephritis-associated plasmin receptor (NAPlr), using an anti-SPEB antibody (Abcam, Cambridge, MA) and a fluorescein isothiocyanate-conjugated anti-NAPlr antibody [1F10] (Abcam). Although NAPlr was not detected, SPEB was positive in the interstitium as well as glomeruli (Figure 1C–F). Chang et al. [2] reported a case of streptococcal infection-related AIN, in which SPEB was found in both tubular epithelial cells and interstitium. In the present case, negative results were obtained for SPEB in tubular epithelial cells. Similarly, SPEB and its precursors have been detected only in glomeruli and interstitium in the rat kidney [3]. SPEB has been reported in association with the pathogenesis of APSGN. The mechanisms of leukocyte infiltration could be mediated by chemotactic effects and the migration inhibitor factor-like activities of SPEB [3]. SPEB also induces proliferation of human mononuclear leukocytes [4]. SPEB may be one of the causes of streptococcal infection-related AIN.

Acute Post-streptococcal Glomerulonephritis with Acute Kidney Injury in Nephrotic Syndrome with the Glomerular Deposition of Nephritis-associated Plasmin Receptor Antigen

We herein report the case of a 17-year-old man who developed an increased plasma creatinine level (11.1 mg/dL) and oliguria with massive proteinuria (27.3 g/day) four weeks after an abraded wound to his right knee. The histology of the renal biopsy specimens showed diffuse endocapillary proliferative glomerulonephritis with the deposition of nephritis-associated plasmin receptor in the glomerulus. A case of acute kidney injury due to nephrotic syndrome caused by acute post-streptococcal glomerulonephritis was diagnosed. His renal function and proteinuria were improved with supportive care, including hemodialysis, without the administration of immunosuppressive agents.

The Role of Nephritis-Associated Plasmin Receptor (NAPlr) in Glomerulonephritis Associated with Streptococcal Infection

It is well known that glomerulonephritis can occur after streptococcal infection, which is classically referred to as acute poststreptococcal glomerulonephritis (APSGN). The pathogenic mechanism of APSGN has been described by so-called immune complex theory, which involves glomerular deposition of nephritogenic streptococcal antigen and subsequent formation of immune complexes in situ and/or the deposition of circulating antigen-antibody complexes. However, the exact entity of the causative antigen has remained a matter of debate. We isolated a nephritogenic antigen for APSGN from the cytoplasmic fractions of group A streptococcus (GAS) depending on the affinity for IgG of APSGN patients. The amino acid and the nucleotide sequences of the isolated protein revealed to be highly identical to those of reported plasmin(ogen) receptor of GAS. Thus, we termed this antigen nephritis-associated plasmin receptor (NAPlr). Immunofluorescence staining of the renal biopsy tissues with anti-NAPlr antibody revealed glomerular NAPlr deposition in essentially all patients with early-phase APSGN. Furthermore, glomerular plasmin activity was detected by in situ zymography in the distribution almost identical to NAPlr deposition in renal biopsy tissues of APSGN patients. These data suggest that NAPlr has a direct, nonimmunologic function as a plasmin receptor and may contribute to the pathogenesis of APSGN by maintaining plasmin activity.

A case of idiopathic membranoproliferative glomerulonephritis with a transient glomerular deposition of nephritis-associated plasmin receptor antigen

The differential diagnosis of acute poststreptococcal glomerulonephritis (APSGN) and idiopathic membranoproliferative glomerulonephritis (MPGN) is sometimes difficult, as they share several key features in their laboratory and histological findings, especially during the acute phase of the diseases. We herein report an idiopathic case of MPGN in which the glomerular deposition of nephritis-associated plasmin receptor (NAPlr), a recently identified nephritic antigen for APSGN, was demonstrated. A 24-year-old postpartum woman developed nephrotic syndrome and hypocomplementemia. Although she showed no apparent findings of a prior infection, her serum titer of antistreptolysin O antibody was elevated. Renal biopsies were performed twice at intervals of 6months, both of which showed findings fully consistent with those of MPGN. Of note, fluorescent immunostaining for NAPlr was positive in the glomeruli of the first biopsy but not in the second. Despite the use of a corticosteroid, hypocomplementemia persisted for more than 1year. It was therefore suggested that a streptococcal infection may have influenced the development of glomerular injury in this idiopathic case of MPGN.

Clinical and Histologic Resolution of Poststreptococcal Glomerulonephritis With Large Subendothelial Deposits and Kidney Failure

A 16-year-old male adolescent who had fallen and scratched his knee developed cold-like symptoms. Gross hematuria, oliguria, and peripheral edema appeared about 2 weeks after his fall. Tests showed hypocomplementemia, increased antistreptolysin O titers, and severe kidney failure with hematuria/proteinuria. Kidney biopsy showed endocapillary proliferative glomerulonephritis visible using light microscopy and deposits of complement C3 on capillary walls, detectable using immunofluorescence microscopy. Although these findings suggested that he had acute poststreptococcal glomerulonephritis (APSGN), electron microscopy failed to detect subepithelial humps, a feature typical of APSGN; instead, massive electron-dense deposits were visible in the subendothelial space. A second biopsy performed 3 months later showed mesangial cell proliferation without endocapillary proliferation using light microscopy and the disappearance of subendothelial electron-dense deposits in electron micrographs, suggesting that APSGN had resolved. Glomerular deposition of nephritis-associated plasmin receptor, a nephritogenic streptococcal antigen, was observed in the first biopsy specimen, but not the second. The patient required 4 hemodialysis treatments, and within 1 year of supportive therapy only, kidney function and urinalysis had normalized. This is an interesting case of APSGN presenting with acute kidney injury and atypical massive subendothelial deposits, but no subepithelial deposits on electron microscopy, a pattern resembling that in membranoproliferative glomerulonephritis type I.

Localization of nephritis-associated plasmin receptor in acute poststreptococcal glomerulonephritis

The nephritis-associated plasmin receptor is a recently identified nephritogenic antigen associated with acute poststreptococcal glomerulonephritis and proposed to play a pathogenic role, but its precise glomerular localization in acute poststreptococcal glomerulonephritis has not been elucidated. We therefore analyzed renal biopsy sections from 10 acute poststreptococcal glomerulonephritis patients by using immunofluorescence staining with anti-nephritis-associated plasmin receptor antibody and various markers of glomerular components. Nephritis-associated plasmin receptor was detected in the glomeruli of all patients, and double staining for nephritis-associated plasmin receptor and collagen IV showed nephritis-associated plasmin receptor to be predominantly on the inner side of the glomerular tufts. Nephritis-associated plasmin receptor-positive areas within glomerular tufts were further characterized with markers for neutrophils, mesangial cells, endothelial cells, and macrophages. In 6 of the patients, nephritis-associated plasmin receptor staining was seen mainly in neutrophils and to a lesser degree in mesangial and endothelial cells. In the other 4 patients, nephritis-associated plasmin receptor staining was seen mainly in mesangial cells and to a lesser degree in neutrophils and endothelial cells. In all patients, macrophages showed little staining. Elevated plasmin activity in glomerular neutrophils was identified by combining in situ zymography staining for plasmin activity and immunofluorescence staining for neutrophils. The glomerular localizations of nephritis-associated plasmin receptor and another nephritogenic antigen, streptococcal pyrogenic exotoxin B, were compared by double immunofluorescence staining and found to be similar. These findings indicate the nephritogenic potential of nephritis-associated plasmin receptor and offer valuable information with respect to the pathogenic mechanism of acute poststreptococcal glomerulonephritis.

A case of dense deposit disease associated with a group A streptococcal infection without the involvement of C3NeF or complement factor H deficiency

A 14-year-old girl presented with acute glomerulonephritis. Tests revealed hypocomplementemia and elevated Antistreptolysin-O titers, and renal biopsy revealed endocapillary and mesangial proliferative glomerulonephritis with double contours of the glomerular basement membrane (GBM). Despite methylprednisolone pulse therapy and the administration of oral prednisolone, overt proteinuria and hypocomplementemia persisted. A second renal biopsy 6 months later confirmed the initial diagnosis of dense deposit disease (DDD) based on electron-dense deposits in the GBM. C3 nephritic factor (C3NeF) and a deficiency of complement factor H (CFH) were not evident. A nephritis-associated plasmin receptor (NAPlr), nephritogenic group A streptococcal antigen, and the plasmin activity by in situ zymography were been in both the first and second biopsy specimens. The patient received combined immunomodulatory therapy with prednisolone and mizoribine, and the urinary protein decreased to a mild level at 27 months after disease onset. These findings suggest that persistent glomerular NAPlr deposition may be associated with the pathogenesis of DDD in some patients without the involvement of C3NeF or CFH mutation and that DDD patients of this type may respond to immunomodulatory treatment.

A prolonged course of Group A streptococcus-associated nephritis: a mild case of dense deposit disease (DDD)?

We herein report the case of a 12-year-old boy with dense deposit disease (DDD) evoked by streptococcal infection. He had been diagnosed to have asymptomatic hematuria syndrome at the age of 6 during school screening. At 12 years of age, he was found to have macrohematuria and overt proteinuria with hypocomplementemia 2 months after streptococcal pharyngitis. Renal biopsy showed endocapillary proliferative glomerulonephritis with double contours of the glomerular basement membrane. Hypocomplementemia and proteinuria were sustained for over 8 weeks. He was suspected to have dense deposit disease due to intramembranous deposits in the first and the second biopsies. 1 month after treatment with methylprednisolone pulse therapy, proteinuria decreased to a normal level. Microscopic hematuria disappeared 2 years later, but mild hypocomplementemia persisted for more than 7 years. Nephritis-associated plasmin receptor (NAPlr), a nephritic antigen for acute poststreptococcal glomerulonephritis, was found to be positive in the glomeruli for more than 8 weeks. DDD is suggested to be caused by dysgeneration of the alternative pathway due to C3NeF and impaired Factor H activity. A persistent deposition of NAPlr might be one of the factors which lead to complement dysgeneration. A close relationship was suggested to exist between the streptococcal infection and dense deposit disease in this case.

Elevated urinary plasmin activity resistant to 2-antiplasmin in acute poststreptococcal glomerulonephritis

A pathogenic role of intraglomerular plasmin bound to nephritogenic antigen (nephritis-associated plasmin receptor, NAPlr) and resistant to physiologic inhibitors such as alpha(2)-antiplasmin (alpha(2)-AP) has recently been proposed in acute poststreptococcal glomerulonephritis (APSGN). To confirm this concept, we analysed the urinary profile of plasmin cascade in APSGN patients. Urine samples from 10 patients with APSGN, 12 patients with IgA nephropathy (IgAN), 10 patients with streptococcal infection without nephritis (SI) and 10 healthy control subjects were analysed. The alpha(2)-AP-resistant plasmin activity was assessed by a chromogenic assay after alpha(2)-AP was added to each urine sample. Urinary plasminogen activator (PA) and plasmin were further analysed by polyacrylamide gel zymography. Urinary NAPlr was assessed by western blot analysis in selected samples. Urinary alpha(2)-AP-resistant plasmin activity corrected for creatinine concentration (units/g x creatinine) was significantly higher in patients with APSGN (2.99 +/- 0.63) than in patients with IgAN (1.02 +/- 0.20, P < 0.01), SI (0.79 +/- 0.17, P < 0.01), or in healthy control subjects (0.73 +/- 0.18, P < 0.01). This tendency was confirmed by casein gel zymography. However urinary PA activity assessed by plasminogen-casein gel zymography did not differ between groups. NAPlr was detected in the urine of APSGN patients. We found elevated urinary plasmin activity resistant to alpha(2)-AP, which may be due to urinary excretion of NAPlr in patients with APSGN. This result supports the pathogenic role of the NAPlr-plasmin complex in the development of APSGN. Furthermore, alpha(2)-AP-resistant urinary plasmin activity may be useful as a diagnostic marker for APSGN.