Atypical Membranous Nephropathy Research Articles

#1941 About a case: ABBA disease in a patient with thymoma

Abstract Background and Aims ABBA (antibrush border antibody) disease is a rare autoimmune tubulointerstitial kidney disease with few descriptions in the literature. Diagnosis is based on light microscopy, immunofluorescence, electron microscopy and immunostaining for LRP2 (LDL receptor related protein 2), also known as megalin. Method We report the case of a 47-year-old Caucasian man admitted in January 2023 for oedema and acute kidney injury (creatinine 3 mg/dl). Biology revealed nephrotic syndrome with hypoalbuminemia (12 g/L) and albuminuria (13 g/g). Haematuria was also noted (75/mm3). His medical history was notable for myasthenia gravis and epithelial Gougerot. Serological tests were negative for HIV, hepatitis B and hepatitis C. Anti-GBM and anti-PLA2R were negative, antinuclear antibodies and antineutrophil cytoplasmic antibodies were both positive at 1/80 without specificity. Serum complement (C3 and C4) and protein electrophoresis were normal. Renal biopsy showed membranous nephropathy, anti-PLA2R, anti-THSD7A, NELL1 and EXT1/2 negative. There was also IgG staining along Bowman's capsule and along part of the tubular basement membrane (TBM). The acute tubular injury was severe. Morphological studies with thoracic tomodensitometry, thoracic MRI and PET scan revealed a thymoma. The patient underwent surgery in May. It was a stage 3 thymoma with pulmonary and pericardial invasion. In June 2023, the patient started haemodialysis due to progression of chronic renal failure. We performed a second renal biopsy, which confirmed the atypical membranous nephropathy with glomerular and tubular deposits and 10% interstitial sclerosis. The patient received two injections of RITUXIMAB (30 June and 14 July 2023). Results In October 2023, we performed a third renal biopsy due to dialysis dependency three months after RITUXIMAB. The glomerular lesions were similar to the previous biopsy, with minimal extra-membranous deposits. However, tubulointerstitial lesions were more pronounced than before. There was 25% tubular atrophy and 25% interstitial sclerosis associated with interstitial inflammation. We also identified anti-LRP2 immune deposits along the TBM. All these histopathological features lead to the diagnosis of ABBA. Conclusion Anti-LRP2 nephropathy is an orphan disease. It's caused by autoantibodies directed against the proximal tubular brush border, leading to a progressive decline in kidney function. The largest recently published cohort includes 67 patients. Many patients may be misdiagnosed due to the insidious onset and atypical presentation with concomitant glomerular or tubulointerstitial disease. In the cohort, 30% of patients had cancer, including solid organ malignancies (including 1 thymoma). It seems that combined treatment with corticosteroids and another immunosuppressive therapy (cyclophosphamide or rituximab) has better results. In our case, despite his thymoma surgery and rituximab perfusions, the patient is still on dialysis. The immunosuppressive treatment will be discussed with the oncologist soon.

Diagnostic value of renal biopsy in anti-phospholipase A2 receptor antibody-positive patients with proteinuria in China

Renal biopsy remains the gold standard for diagnosing membranous nephropathy (MN). Recent studies have suggested that renal biopsy can be replaced with the serum phospholipase A2 receptor (PLA2R) antibody test for MN diagnosis in patients with nephrotic syndrome. However, this test has not been validated in the Chinese population. In this study, we investigated whether renal biopsy provides additional diagnostic information on patients with proteinuria who are seropositive for PLA2R antibodies (SAb +). We retrospectively reviewed the clinicopathological characteristics of SAb + adult patients (aged ≥ 18 years) with proteinuria (≥ 0.5 g/24 h) assessed at the Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, from June 2021 to March 2022. Among a total of 801 SAb + patients who received renal biopsy, those with incomplete pathological data, diabetes or any potential cause of secondary MN were excluded. Among the 491 remaining patients, 474 had primary MN (PMN), 16 had atypical MN (AMN, 9 patients with “full house” and 2 patients with HBsAg + /HBcAg + immunofluorescence results), and 1 had focal segmental glomerulosclerosis. In patients with an eGFR of ≥ 60 mL/min/1.73 m2 (n = 451), 436 had PMN, and 71 (16.3%) exhibited additional biopsy findings, with obesity-related glomerulopathy being the most common. In patients with an impaired eGFR (n = 40), 38 had PMN, and 31 (81.6%) showed additional findings, with acute tubular injury being the most common. In conclusion, anti-PLA2R antibody positivity is highly predictive of PMN in Chinese adults but often coexists with other pathological diagnoses. The advantages of renal biopsy for detecting other pathologies should be weighed against the potential risks of the biopsy procedure.

The Safety and Efficacy of Rituximab-Based Regimen in Atypical Membranous Nephropathy: A Single Center Retrospective Cohort Study.

There are increasing reports of atypical membranous nephropathy (AMN) cases with similar pathological characteristics to secondary membranous nephropathy (SMN) without definite underlying causes. Although rituximab has become a first-line option in treating idiopathic membranous nephropathy (IMN), the efficacy and safety of rituximab-based regimen for AMN is not clear. This is a retrospective, single-center study. AMN patients who received rituximab-based therapy were included. IMN patients treated with rituximab during the same period were selected as the control group matched by gender, sex, baseline urinary protein and albumin levels. Baseline data and follow-up data were collected. A total of 20 AMN patients and 40 IMN patients were included. The baseline levels of urinary protein were comparable between the two groups [6.77 (IQR 3.34, 11.49) g/24 h vs 6.47 (IQR 3.4, 10.76) g/24 h, P=0.944]. The baseline levels of serum albumin were 26.15±6.71 g/L and 26.8±5.54 g/L (P=0.689) respectively. The cumulative remission rate for rituximab-based treatment at the 12th month was lower in AMN group than IMN group [13 (65%) vs 36 (90%), P=0.045]. In AMN group, non-responders showed a higher level of proteinuria and a worse renal function at baseline than those of responders. There was no significant difference in the overall adverse events or serious adverse events between the two groups. In our study, AMN patients obtained proteinuria remission in a lower percentage compared with IMN patients. In general, rituximab-based therapy is effective in AMN patients with an acceptable safety profile.

MO252: Complement 3 Deposits on Renal Tubule and Glomeruli in Phospholipase A2 Receptor-Related Idiopathic Membranous Nephropathy

Abstract BACKGROUND AND AIMS Evidence shows galactose-deficient IgG4 is able to act complement system via lectin pathway in phospholipase A2 receptor (PLA2R) related idiopathic membranous nephropathy (IMN). However, the severity of PLA2R-related IMN runs parallel with neither the electron microscope stage nor the complement density in situ. We find positive complement factor 3 (C3) deposition on renal proximal tubule in some IMN patients and manage to analysis the relationship between it and the severity of the disease. METHOD We retrospectively involved 113 PLA2R related IMN patients from March 2017 to October 2019. The inclusion criteria were diagnosed by kidney biopsy with complete clinical and pathological data. The exclusion criteria were with any secondary causes such as lupus nephritis type V, Sjogren's syndrome, hepatitis B associated glomerulonephritis and atypical membranous nephropathy. We divided total patients into four subgroups according to the C3 deposition site. We defined no C3 deposition subgroup (40,35%) as C3 appeared in neither glomeruli nor tubule, C3 glomeruli deposition subgroup (32, 28%) as C3 deposited on glomeruli only, C3 tubule deposition subgroup (12, 11%) as C3 deposited on tubule only, C3 extensive deposition subgroup (29, 26%) as C3 deposited on both glomeruli and tubule. RESULTS Clinical data of four groups were as follows: Male/female ratio were 22/18, 23/9, 5/7, 16/13, P = .252; The median of age were 50 (33, 57), 51 (42, 57), 57 (49, 61), 51 (33, 57), P = .412; The median of were 24-h urine protein were 4.4 (2.0, 6.9), 5.0 (2.7, 8.3), 4.9 (2.5, 11.2), 5.5 (2.4, 10.2) g/L, P = .427. The average serum albumin were 28.6 ± 6.8, 27.2 ± 6.7, 24.6 ± 2.7, 25.5 ± 6.0 g/L, P = .046. The median of serum creatinine were 70 (57, 82), 77 (65, 92), 68 (57, 89), 69 (58, 80) μmol/L, P = .255. The median of serum C3 were 1.14 (1.0, 1.33), 1.17 (1.04, 1.36), 1.22 (1.0, 1.34), 1.11 (0.99, 1.23) g/L, P = .291. The median of anti-PLA2R antibody were 0 (0, 55), 29 (25, 33), 12 (0, 136), 35 (19, 131) RU/mL, P = .049. CONCLUSION There were differences in serum anti-PLA2R antibody and Alb in patients with different C3 deposition. Patients with extensive C3 deposition showed higher PLA2R antibody.

Association of serum mannose-binding lectin, anti-phospholipase A2 receptor antibody and renal outcomes in idiopathic membranous nephropathy and atypical membranous nephropathy: a single center retrospective cohort study

Objectives Idiopathic membranous nephropathy (iMN) is a major cause of nephrotic syndrome. Atypical membranous nephropathy (aMN) is a new type of nephropathy in China, characterized by a ‘full-house’ on immunofluorescent examination, that is IgG, IgA, IgM, C3, C1q positive, but without clinical evidence of a secondary cause. Phospholipase A2 receptor (PLA2R) was the major target antigens in iMN patients. Activation of the mannose-binding lectin (MBL) pathway plays a vital role in the development of MN. Our objective was to investigate the role of PLA2R and MBL in the pathogenesis of iMN and aMN. Methods We conducted a retrospective observational study using propensity score matching by age, gender, and eGFR. All clinical, laboratory data, and follow-up data of the patients were collected. Serum levels of anti-PLA2R antibodies and MBL were tested. Results Finally, 30 iMN patients and 30 aMN patients were included, and 20 healthy controls were retrospectively collected in this study. The 24 h proteinuria level was higher and serum albumin was lower in anti-PLA2R (+) patients than in anti-PLA2R (−) patients in both iMN and aMN groups. In aMN patients, MBL levels were significantly higher in anti-PLA2R (+) patients than in anti-PLA2R (−) patients (p = .045). The serum level of anti-PLA2R positively correlated with no-remission in both iMN and aMN groups. Conclusions The complement lectin pathway has an association with the development of MN, especially in patients with positive anti-PLA2R antibodies. Serum MBL cannot differentiate between the two diseases. Serum MBL levels are not associated with clinical manifestations, nor with prognosis.

A case report of IgG4-related kidney disease with cirrhosis as the first manifestation

Abstract Introduction: Immunoglobulin G4-related kidney disease (IgG4-RKD) is a recently identified inflammatory disorder most often classified as IgG4-related tubulointerstitial nephritis or IgG4-related membranous nephropathy based on the predominant renal pathology. However, almost all the cases are complicated by extrarenal organ involvement that includes lymph nodes, pancreas, lacrimal glands, salivary glands, and/or retroperitoneum. IgG4-RKD with cirrhosis as the initial presentation followed by massive proteinuria and renal dysfunction is very rare. Patient concerns: A 35-year-old Chinese male presented to a local hospital with abdominal distension, edema, and black tarry stool 5 years before. Abdominal color ultrasonography at that time suggested cirrhosis, and the diagnosis was upper gastrointestinal hemorrhage with decompensated cirrhosis. About two weeks before, edema was aggravated, and massive proteinuria and renal impairment were detected with significantly elevated serum IgG. Abdominal computed tomography indicated cirrhosis and diffuse renal enlargement with multiple low-density foci, while light microscopy of renal biopsy tissue indicated atypical membranous nephropathy with interstitial nephritis. Immunohistochemistry revealed 20–50 IgG-positive plasma cells per high-power field among interstitial infiltrating cells, accounting for ∼40% of all IgG-positive plasma cells. Diagnoses: According to clinical manifestations and immunohistochemical findings, the diagnosis was IgG4-RD/IgG4-RKD featuring atypical membranous nephropathy, interstitial nephritis, and decompensated cirrhosis. Interventions: Methylprednisolone 40 mg/day was administered for IgG4 related kidney disease. Other symptomatic therapies were also administered. Outcomes: Half a month following the treatment, 24-hour proteinuria decreased from 10.67 g/d to 2.16 g/d and serum creatinine decreased significantly. Conclusion: IgG4-RKD with cirrhosis as the first manifestation followed by renal dysfunction is very rare. Simultaneous occurrence of these two conditions which improved after the treatment indicates that there may be an association between IgG4 related kidney disease and cirrhosis.

Renal outcomes of idiopathic and atypical membranous nephropathy in adult Chinese patients: a single center retrospective cohort study

BackgroundMembranous nephropathy (MN) is mainly classified into idiopathic MN (iMN) and secondary MN in etiology. In recent years, a new kind of membranous nephropathy, atypical membranous nephropathy (aMN) which shows “full house” in immunofluorescence but without definite etiology was paid more attention. In a single center cohort, the renal outcomes of iMN and aMN were compared.MethodsiMN and aMN patients were selected from renal pathology databank from January 2006 to December 2015. Patients’ demographics, laboratory values, induction regimens and patients’ responses were recorded. Specially, creatinine, eGFR, albumin and 24 h urinary protein excretion were recorded at 6th month after the induction of immunosuppressive (IS) treatment and at the end of follow up. Complete proteinuria remission was defined as urinary protein < 0.3 g/d, partial proteinuria remission was defined as urinary protein between 0.3 g/d ~ 3.5 g/d and decreased > 50 % from the baseline. The primary outcome was worsening renal function, defined as a 30 % or more decrease in eGFR or end-stage renal disease (eGFR < 15ml/min/1.73m2). COX proportional hazard models were used to test if aMN was a risk factor of worsening renal function compared with iMN.ResultsThere were 298 patients diagnosed with MN and followed in our center for 1 year or more, including 145 iMN patients with an average follow-up time of 4.5 ± 2.6 years, and 153 aMN patients with 4.1 ± 2.0 years (p = 0.109). The average age of iMN patients was older than aMN patients (56.1 ± 12.2 versus 47.2 ± 16.2 years old, p < 0.001). There were 99 iMN patients and 105 aMN patients with nephrotic range proteinuria and without previous immunosuppressive treatment. 93 (93.9 %) and 95 (90.5 %) patients underwent immunosuppressive treatment in iMN and aMN group, and there was no significant difference of the overall proteinuria remission rates at 6th month (59.1 % vs. 52.0 %, p = 0.334) and endpoint (73.7 % vs. 69.5 %, p = 0.505) between the two groups. 25 (25.3 %) patients in iMN group and 21 (20.0 %) patients in aMN group reached primary endpoint (X2 = 0.056, p = 0.812). Multivariate COX regression showed that after demographics, baseline laboratory values and remission status at 6th month were adjusted, aMN group had similar renal outcome compared with iMN group, the HR of primary outcome was 0.735 (95 % CI 0.360 ~ 1.503, p = 0.399).ConclusionsThe proteinuria remission rates and renal outcomes were similar in iMN and aMN patients after covariables were adjusted.

12 A Rare Case of Atypical Hemolytic Uremic Syndrome and Primary Membranous Nephropathy With Novel Findings

12 A Rare Case of Atypical Hemolytic Uremic Syndrome and Primary Membranous Nephropathy With Novel Findings

Value of immunofluorescence-mediated detection of Ig, C1q, C3, and FRA for the identification and diagnosis of atypical membranous nephropathy.

The present study was to investigate the value of immunofluorescence-mediated detection of Ig, C1q, C3, and FRA for the identification and diagnosis of atypical membranous nephropathy (AMN). Fifty-five patients with AMN and 135 patients with idiopathic membranous nephropathy (IMN) diagnosed by renal biopsy in our hospital were consecutively selected. The positive expressions of Ig, C1q, C3, and FRA by immunofluorescence were analyzed. We compared the levels of blood urea nitrogen, creatinine, cystatin C, and 24 h urine protein, and the levels of serum IgA, IgG, IgM, and C3. The differences were not significant (p>0.05). Proportionate increases in glomerular spiky projection formations in patients with AMN were observed by light microscopy, without observation of other pathologic changes. By immunofluorescence, AMN patients showed higher positive rates of deposition of IgA, IgM, C1q, and FRA compared with IMN patients. Comparison of the positive rates of deposition of IgG and C3 showed no differences. By electron microscopy, AMN patients showed higher percentages of mesangial cell and mesangial matrix proliferation. Deposition of electron dense granules was mostly found in subepithelium, inside basement membranes, and in the mesangial area. The comparisons between the two groups showed no differences. Immunofluorescence-mediated detection of Ig, C1q, C3, and FRA have important application value for the identification and diagnosis of AMN.

Pathology and treatment of idiopathic membranous nephropathy in children

Objective To study features of clinical manifestation, pathology and treatment effects of idiopathic membranous nephropathy(IMN). Methods A retrospective study was performed in patients with membranous nephropathy through renal biopsy diagnosis in Beijing Children's Hospital Affiliated to Capital Medical University from November 2009 to February 2013.Patients were diagnosed according to renal biopsy apart from hepatitis B virus-associated glomerulonephritis, Henoch-Schonlein purpura nephritis, lupus nephritis, tumor and drug associated nephritis.The study summed the clinical and pathological features of IMN and evaluated the effect of treatment according the follow up. Results (1)There were 13 patients, with the ratio of male and female being 1.0: 1.6, among them 1 patient was younger than 6 years old, 3 cases were between 6 and 12 years old, and 9 cases were elder than 12 years old.Nine patients were nephrotic syndrome, and 3 patients had renal insufficiency.(2)Ten patients had infection, among them 5 cases were upper respiratory infection with agent unfound, 4 patients were mcoplasma infection, 1 patient was influenza B virus infection, 1 patient had positive result of Hepatitis B surface antibody(HBsAb) and Hepatitis B core antibody(HBcAb), and 2 patients had positive result of purified protein derivative(PPD). (3)Pathological feature of IMN was atypical membranous nephropathy.Atypical membranous nephropathy was characterized by an irregular, thickened glomerular basement membrane(GBM), mesangial cells, and a mesangial matrix with mild to moderate hyperplasia.Immune complexes were stained in the subepithelial region, GBM, and mesangial region under light microscopy.Electron microscopy showed various sizes, density, and shapes of electron-dense deposits in multiple regions.The cases of immunofluorescence were 13 for IgG, 10 for C3, 9 for IgM, 9 for C1q, 5 for IgA, 2 for C4, and 0 for fibrinogen.Seven patients were strongly positive(3+ and above) for IgG and one patient was strongly positive for C3.(4)Seven patients had complete remission, three patients had partial remission, and three patients had non-remission. Conclusions (1) In this study, children with IMN were mainly girls, and the age distribution was beyond 12 years.Nephrotic syndrome was the most common clinical manifestation.(2)Atypical membranous nephropathy was the most common pathological feature in children with IMN, which should be distinguished from hepatitis B virus-associated glomerulonephritis by testing HBV antigen in renal biopsy.(3) Prednisone was effective for IMN children, but it was suggested to give enough and long course of application.Effect of prednisone combined with cyclophosphamide was still undefined. Key words: Idiopathic membranous nephropathy; Atypical membranous nephropathy; Pathology; Treatment; Child

Clinical and pathological analysis of hepatitis B virus-related membranous nephropathy and idiopathic membranous nephropathy

The Hepatitis B virus infection rate is high in the Chinese population. The implications of HBV infection are widely recognized, and membranous glomerulonephritis is the most common renal lesion associated with HBV infection. We compared the clinicopathologic features of 119 HBV-related membranous nephropathy (HBV-MN) and 143 idiopathic membranous nephropathy (IMN) patients to identify those factors that facilitate their discrimination. Cohort analysis of demographic information, clinical manifestations, laboratory parameters, renal pathology and prognostic features of the two groups. Most HBV-MN patients were young or middle-aged; the onset age in the HBVMN group was younger than the IMN group (p < 0.05). A male predominance was found in both groups. And the two groups both presented with heavy proteinuria or nephrotic syndrome. In contrast to IMN patients, the HBV-MN group was presented with a high occurrence of microscopic hematuria (73.95 vs. 35.66%) and renal insufficiency (47.06 vs. 24.48%). Plasma complement C3 and C4 in HBV-MN patients were significantly lower than in IMN patients (p < 0.05). The hyperlipidemia was more severe in IMN patients (p < 0.05). The occurrences of segmental glomerular damage, mesangial cell proliferation and tubulointerstitial damage were more common in the HBV-MN group (p < 0.05). Immunofluorescence staining of polyclonal immunoglobulin and polytypic complement immunoglobulin were more frequent in the HBV-MN group. The followup data showed there were no statistic differences in the prognosis between HBV-MN and IMN. HBV-MN patients commonly showed nephrotic syndrome accompanied with renal and hepatic dysfunction which was different from IMN patients. The primary pathological feature of HBVMN was atypical membranous nephropathy, which is usually associated with the inflammatory changes in HBV infection. The renal survival rates did not differ between HBVMN patients and IMN patients.

A case of adefovir-induced membranous nephropathy related to hepatitis B caused by lamivudine-resistant virus after liver transplant due to Byler’s disease

We report on how adefovir-induced membranous nephropathy related to hepatitis B was caused by lamivudine-resistant virus after a liver transplant due to Byler's disease. In 1980, a 2-year-old girl was diagnosed with Byler's disease (familial progressive familial intrahepatic cholestasis). In 1994 (at the age of 14 years) she underwent a liver transplant with her father as the donor. In 2003, hematuria and proteinuria appeared and shortly afterwards her renal function rapidly decreased. A renal biopsy showed atypical membranous nephropathy, which suggested the possibility of a secondary renal disease. The patient had suffered from chronic hepatitis type B (HBV). In 2001 she was administered lamivudine which is an antiviral drug; it was around this time that hematuria and proteinuria appeared as well as an increase of the virus titer. We believed the HBV-related membranous nephropathy was the cause of the virus titer and the renal histology. We concluded that the patient's condition had become resistant to lamivudine medication. Therefore, in February 2004 we administered adefovir, a new drug at the time, to treat the HBV. In April 2004, the HB virus titer decreased and the hematuria and proteinuria decreased. The patient's renal function also showed improvement. HBV-associated nephropathy is caused by HBV antigen deposition in the glomeruli. Generally the first choice of treatment is antivirus therapy. There are many reports demonstrating that administration of interferon and lamivudine are effective; however, there are few reports that show adefovir as an effective treatment for HBV-associated nephropathy.

Ichthyosiform mycosis fungoides with alopecia and atypical membranous nephropathy

We describe here a rare case of variant of mycosis fungoides (MF): ichthyosiform MF with alopecia and atypical membranous nephropathy. The diagnosis was made based on the following findings: generalized ichthyosis-like eruption, alopecia, enlarged superficial lymph nodes, proteinuria, and hematuria, the histological features of the skin biopsy from both ichthyotic and alopecic lesions with immunohistochemical staining, and the renal biopsy examination with immunofluorescence. The histological examination of ichthyotic and alopecic lesions displayed a predominant infiltration of atypical lymphocytes in the upper dermis with the characteristics of epidermotropism and folliculotropism. Immunohistochemical studies demonstrated that most infiltrated atypical lymphocytes were CD3, CD4, and CD45RO positive, whereas negative for CD5, CD7, CD20, CD30, and CD56. A renal biopsy examination revealed atypical membranous nephropathy with deposition of immunoglobulin G (IgG), IgM, IgA, C1q, and C3. In this case atypical membranous nephropathy was involved, which is very uncommon and has never been presented in the literature to date. Although ichthyosiform MF usually features a relatively favorable course, diffuse alopecia and the renal involvement in this case might indicate aggressive disease and poor prognosis.