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Objective Lipoprotein glomerulopathy (LPG) is a rare disorder characterized by the development of glomerular lipoprotein thrombosis. LPG exhibits familial aggregation, with mutations in the apolipoprotein E (APOE) gene identified as the leading cause of this disease. This study aimed to investigate APOE gene mutations and the clinicopathological features in eleven LPG patients.Methods Clinicopathological and follow-up data were obtained by extracting DNA, followed by APOE coding region sequencing analysis. This study analyzed clinical and pathological manifestations, gene mutations, treatment and prognosis.Results The mean age of the eleven patients was 33.82 years. Among them, five had a positive family history for LPG, ten presented with proteinuria, four exhibited nephrotic syndrome, and six presented with microscopic hematuria. Dyslipidemia was identified in ten patients. In all renal specimens, there was evident dilation of glomerular capillary lumens containing lipoprotein thrombi, and positive oil red O staining was observed in frozen sections of all samples. APOE gene testing revealed that one patient had no mutations, while the remaining ten patients exhibited mutations in the APOE gene, with three patients presenting with multiple mutations simultaneously. Following the confirmation of LPG diagnosis, treatment with angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) was initiated, and the disease progressed slowly.Conclusion LPG is histologically characterized by lamellated lipoprotein thrombi in glomeruli, and kidney biopsy is essential for diagnosis. Mutations in the APOE gene are the leading cause of LPG. This study revealed clinicopathological characteristics and APOE gene mutations in patients with LPG, which helps us better understand the disease.

Background Light-chain proximal tubulopathy (LCPT) is a rare disease characterized by the accumulation of monoclonal light chains within proximal tubular cells. This study aimed to investigate the clinical characteristics of LCPT from a single Chinese nephrology referral center.Methods Patients with kidney biopsy-proven isolated LCPT between 2016 and 2022 at Peking University First Hospital were retrospectively included. Clinical data, kidney pathological type, treatment, and prognosis were analyzed.Results Nineteen patients were enrolled, the mean age at diagnosis was 57 ± 11 and the sex ratio was 6/13 (female/male). Mean proteinuria was 2.44 ± 1.89 g/24 hr and the mean estimated glomerular filtration rate (eGFR) at the point of biopsy was 59.640 ± 27.449 ml/min/1.73 m2. κ-restriction (84%) was dominant among LCPTs. An abnormal free light chain ratio was observed in 86% of the patients. Proximal tubulopathy with cytoplasmic inclusions accounted for the majority (53%), followed by tubulopathy associated with interstitial inflammation reaction (26%), proximal tubulopathy without cytoplasmic inclusions (16%), and proximal tubulopathy with lysosomal indigestion/constipation (5%). One patient presented with acute kidney injury and 16 patients presented with chronic kidney disease. Regarding follow-up, patients received bortezomib-based or R-CHOP chemotherapy or supportive treatment only. The mean follow-up time was 22 ± 16 months, and the mean eGFR was 63.098 ± 27.439 ml/min/1.73 m2 at the end of follow-up. These patients showed improved or stable kidney function.Conclusions This is the first case series report of LCPT in four different pathological types in northern China. Clone-targeted chemotherapy may help preserve the kidney function in these patients.

Abstract Background The phospholipase A2 receptor (PLA2R) associated with membranous nephropathy (MN) is an organ-specific autoimmune disease associated with PLA2R and human leukocyte antigen (HLA) genes. Familial PLA2R-related MN is rarely reported. The combination of anti-GBM disease and MN has been well documented, though the mechanism behind it remains unclear. Case presentation We describe two siblings diagnosed with pathology-confirmed PLA2R-related MN 1 year apart. And one of the two siblings developed an anti-GBM disease. The high-resolution HLA typing showed identical alleles in both siblings, specifically heterozygotes of DRB1*15:01/*03:01. Conclusion We describe a familial case of PLA2R-related MN supporting the role of genetic factors that HLA-DRB1*15:01 and DRB1*03:01 predispose patients in the development of PLA2R-related MN in the Han Chinese population. The combination of MN and anti-GBM disease may also partially be associated with the same susceptible HLA allele DRB1*15:01.

AbstractObjectives This study was initiated to establish a renal thrombotic microangiopathy (TMA) scoring system based on clinical needs and investigate its predictive value for patients’ long-term outcomes.Methods Kidney biopsy-proven Complement-mediated TMA (C-TMA) patients from January 2000 to December 2017 in Peking University First Hospital were retrospectively studied. Both acute and chronic TMA-related lesions, including 15 pathologic indices, were semiquantitatively scored. The interobserver and intraobserver reproducibility and correlation between the pathologic indices and clinical parameters were analyzed. Furthermore, the patients were divided into 2 groups by dialysis use at baseline, and the association of these pathologic indices with their prognostic outcomes was assessed between the two groups.Results Ninety-two patients with renal biopsy-proven C-TMA were enrolled. All fifteen included pathology indices showed good or moderate interobserver and intraobserver reproducibility and correlated well with several clinical parameters. Several clinicopathological indices were worse in the dialysis group than in the nondialysis group, such as serum creatinine, hemoglobin, platelet count, and estimated glomerular filtration rate. Moreover, morphologic features in the dialysis group presented with more severe vascular lesions. Interstitial fibrosis and chronic tubulointerstitial lesions were related to a trend of high risk of continuous dialysis in the dialysis group. Based on univariate and multivariable Cox regression analysis, more severe glomerular lesions, including glomerular mesangiolysis, glomerular basement membrane double contours and glomerular mesangial proliferation, were identified as risk factors predicting worse prognosis.Conclusions Our renal C-TMA semiquantitative scoring system is reliable with good reproducibility and prognostic value in clinical practice, which needs further validation.

Abstract Background The renal risk score (RRS) is a useful tool to predict end-stage renal disease (ESRD) in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The current study aimed to validate the predictive performance of RRS and to further modify this model in Chinese AAV patients. Methods Two hundred and seventy-two patients diagnosed with AAV confirmed by renal biopsies were retrospectively enrolled from a single center. The RRS was calculated based on 3 categorical variables, i.e., the proportion of normal glomeruli, the proportion of interstitial fibrosis and tubular atrophy (IF/TA), and eGFR at biopsy, classifying these patients into low-, medium-, and high-risk groups. In addition, a modified model was developed based on the RRS and was further validated in another independent cohort of 117 AAV patients. The predictive performance of each model was evaluated according to discrimination and calibration. Results Patients were classified by the RRS into low- (26.5%), medium- (46.7%), and high-risk (26.8%) groups, with 120-month renal survival rates of 93.3%, 57.2%, and 18.4%, respectively (P 50%) included. Internal and external validation of the modified model were performed. Finally, an online risk prediction tool was developed based on the modified model. Conclusions The RRS was an independent predictor of ESRD of AAV patients. The modified model could predict the probability of ESRD for AAV patients with improved performance in Chinese AAV patients.

Background Anti-glomerular basement membrane (anti-GBM) disease is a rare but severe autoantibody-mediated immune disorder. The typical clinical presentation includes rapidly progressive glomerulonephritis and often concurrent pulmonary hemorrhage. The present study is aimed to investigate the therapeutic effects of rituximab either used alone or with other immunosuppressants.Methods Eight patients diagnosed with anti-GBM disease and treated with rituximab from 2014 to 2020 were retrospectively reviewed.Results Eight patients included 5 males and 3 females with a median age of 58.5 years. They all presented severe kidney injuries and 1 patient had lung hemorrhage. At diagnosis, the median of serum creatinine was 246 µmol/L (ranging from 91 to 850 µmol/L), with 3 patients requiring dialysis. All of them received corticosteroids and plasmapheresis. Rituximab was given as either standard four weekly doses or one pulse ranging from 100 to 600 mg. After a median follow-up of 34.5 months, kidney function was partially recovered or stabilized in 5/8 (62.5%) patients, free of dialysis. Anti-GBM antibodies remained undetected in all patients during follow-up. No severe adverse effect associated with rituximab was observed.Conclusion Rituximab may be an alternative therapy in the treatment of patient with severe or refractory anti-GBM disease.

Abstract Background Although extensive efforts have been paid to identify reliable predictors for renal outcomes of diabetic kidney disease (DKD) patients in type 2 diabetes mellitus (T2DM), there are still only a limited number of predictive factors for DKD progression. Increasing evidence reported the role of the overactivated complement system in the pathogenesis of DKD. Whether renal complement depositions are associated with renal outcomes of DKD in T2DM is of interest. Methods A total of 213 biopsy‐proven DKD patients with T2DM were retrospectively recruited. Clinical and pathological data of the patients were analyzed. Kaplan‐Meier analysis and Cox regression analysis were performed to explore predictors of end‐stage renal disease (ESRD). Results During a median follow‐up of 23.0 (12.0, 39.0) months, 100/213 (46.9%) patients progressed to ESRD. C3c and C1q deposition were observed in 133/213 (62.4%) and 45/213 (21.1%) patients, respectively. Kaplan‐Meier analysis revealed patients with C3c or C1q deposition had significantly worse renal outcomes compared with those without C3c or C1q deposition (p = .001 and p

Background: Cryoglobulinemic glomerulonephritis (Cryo-GN), caused by circulating cryoglobulins, has varied etiology and clinical-pathologic manifestations. This study aimed to investigate the clinicopathological spectrum and outcome of patients with various Cryo-GN in China. Methods: A retrospective review of 74 Chinese patients with biopsy-proven cryoglobulin-related renal lesions in Peking University First Hospital from 2010 to 2020 was performed. Results: The mean age at diagnosis was 52.9 ± 15.0 years, and the female-to-male ratio was about 2/5. For the etiology screening, serum/urine monoclonal immunoglobulin could be detected on immunofixation electrophoresis in 34% of patients, including 6 patients who had hematological malignancies. Fifty-seven percent of patients had HBV infection, far more than HCV infection (5%). Ten percent of patients had other infections, and 27% of patients were classified as essential or idiopathic. Eleven out of the 15 patients with type II cryoglobulinemia had a consistent monotype of serum monoclonal immunoglobulins and monoclonal cryoprecipitate. The clinical manifestations were similar between various types of cryoglobulinemia. Hematuria, proteinuria, hypertension, anemia, and chronic renal insufficiency were the most common features. Fifty-three percent of patients presented with nephrotic syndrome, and 32% experienced acute kidney injury. Hypocomplementemia, serum-positive rheumatoid factor activity, and skin lesions were reported in 45%, 29%, and 28% of patients, respectively. After a median of 24 months follow-up, 18 patients reached end-stage kidney disease. The clone-targeted treatment could retard the renal deterioration compared with immunosuppressive therapy. Conclusions: This was the largest single-center, clinicopathological retrospective study of Cryo-GN in China. Our data strongly support the association between monoclonal gammopathy and type II Cryo-GN. The renal responsive rate of immunosuppressant therapy is still suboptimal. The clone-targeted treatment shows promising effects in patients with type I or II Cryo-GN.

Autosomal dominant tubulointerstitial kidney disease due to UMOD mutations (ADTKD-UMOD) is a rare condition associated with high variability in the age of end-stage kidney disease (ESKD). An autosomal dominant inheritance is the general rule, but de novo UMOD mutations have been reported. It was reported that the median age of ESKD was 47 years (18–87 years) and men were at a much higher risk of progression to ESKD. Here, we reported a 13-year-old young girl with unexplained chronic kidney disease (CKD) (elevated serum creatine) and no positive family history. Non-specific clinical and histological manifestations and the absence of evidence for kidney disease of other etiology raised strong suspicion for ADTKD. Trio whole-exome sequencing confirmed that she carried a de novo heterozygous mutation c.280T > C (p.Cys94Arg) in the UMOD gene. The functional significance of the novel mutation was supported by a structural biology approach. With no targeted therapy, she was treated as CKD and followed up regularly. The case underscores the clinical importance of a gene-based unifying terminology help to identify under-recognized causes of CKD, and it demonstrates the value of whole-exome sequencing in unsolved CKD.

Leukocyte chemotactic factor 2-associated (ALECT2) amyloidosis is one of the recently reported types of amyloidosis, which is caused by the extracellular deposition of leukocyte chemotactic factor 2 (LECT2). There have not been any reports involving the concurrence of ALECT2 amyloidosis with Sjögren’s syndrome (SS) or systemic lupus erythematosus (SLE)s. Herein, we report a case of a 68-year-old Chinese woman presenting with long duration of sicca symptoms. The clinical evaluation and laboratory findings showed that she had SS overlapped with SLE. Kidney biopsy revealed a membranoproliferative glomerulonephritis (MPGN) with glomerular deposition of dominant IgG3-kappa by immunofluorescene, which was related to SS/SLE. Furthermore, patchy congophilic amyloid deposits in the tubulointerstitium were detected, which were positive for LECT2 protein by immunohistochemical staining and immunoelectron microscopy. This is the first case of ALECT2 amyloidosis that coexisted with SS/SLE, and the causal relationship between ALECT2 amyloidosis and autoimmune diseases remain unclear.

Abstract Background Multiple myeloma (MM) is a plasma-cell derived hematologic malignant disease. The malignant proliferating plasma cells secrete massive monoclonal immunoglobulins which lead to various pathologic types of renal injury. Myeloma cast nephropathy (MCN) is the most common histopathologic lesion with the worst renal prognosis. Rarely, the free light chains in the protein casts can form amyloid fibrils. Here, we reported two rare cases of MCN with diffuse amyloid casts. Case presentation Case 1: A 54-year-old Chinese man presented with a 4-year history of multiple myeloma, proteinuria and hematuria. He had monoclonal IgAλ plus free λ spike in both serum and urine. He had been on chemotherapy for 4 years and maintained normal serum creatinine until 11 months ago. Then, his renal function deteriorated and he went on hemodialysis 4 months before admission. Renal biopsy showed diffuse amyloid casts in the tubular lumens, without any obvious amyloid deposits in other kidney compartments or signs of extra-renal amyloidosis. The amyloid fibrils formed around mononuclear cells which were CD68 negative. According to the morphology and location, these mononuclear cells were considered as tubular epithelial cells. The patient was maintained on chemotherapy and hemodialysis. He died 8 months after renal biopsy. Case 2: A 58-year-old Chinese man presented with a one-and-a-half-year history of proteinuria and slowly rising serum creatinine. He had monoclonal IgDλ spike in both serum and urine. Amyloid casts were observed in the tubular lumens and mononuclear cells could be identified in the center of some casts. There were no amyloid deposits in other kidney compartments and no sign of systemic amyloidosis. The patient also had fine granular deposits along the tubular basement membrane with λ linear staining along tubular basement membrane suggesting light chain deposition disease. He was treated with bortezomib-based chemotherapy followed by lenalidomide-based chemotherapy and achieved very good partial remission (VGPR). After 27 months of follow-up, the patient still showed no signs of systemic amyloidosis. Conclusions These 2 cases of MCN with diffuse amyloid casts have different histopathologic characteristics from the usual myeloma casts and tubular epithelial cells might play important roles in the pathogenesis.

Objective To investigate the demographic and clinicopathological features and renal outcomes of Chinese patients with C3 glomerulonephritis in the setting of monoclonal gammopathy. Methods Patients with renal biopsy-proven C3 glomerulonephritis and detectable serum and/or urine monoclonal immunoglobulin from 2006 to 2018 in Peking University First Hospital were included, their clinical data, renal pathology type, treatment, and prognosis were collected and analyzed. Results Nineteen patients were enrolled, accounting for 24% of C3GN patients in the study period. The mean age of onset was 55 years old and the gender ratio was 4/15 (female/male). The mean eGFR at biopsy was 49.55 ± 29.81 ml/min/1.73m2. The prominent clinical manifestations included nephrotic syndrome (58%), anemia (68%), microscopic hematuria and leukocyturia (58%), and hypocomplementemia (13, 68%). The IgG was the most common isotype of monoclonal Ig on immunofixation electrophoresis. Kidney biopsies revealed a relatively prominent MPGN pattern. Only two patients had direct evidence of monocle immunoglobulins acting as C3GN pathogenic factors. Two patients had concurrent TMA-like renal injuries. The median renal survival was 12 and 15 months, respectively in patients receiving conservative therapy and immunosuppressant therapy, without statistical significance. The efficacy of clone-targeted therapy needed further investigation. Plasma exchange therapy only improved one patient’s renal outcome. Conclusions This is the first case series report of C3GN combined with monoclonal Ig in northern China. The renal prognosis of these patients is poor, and immunosuppressant therapies show no advantage over supportive therapy in renal prognosis, while the benefit of clone-targeted chemotherapy is still requiring investigation.

ObjectivesFibrinogen A alpha-chain amyloidosis (AFib amyloidosis) is the most common form of hereditary renal amyloidosis in the United Kingdom and Europe, but has rarely been reported in Asia. In this study, we reported two AFib amyloidosis patients in China, reviewing the literature and summarizing main characteristics of AFib amyloidosis in Asia.MethodsTwo unrelated Chinese patients were diagnosed with AFib amyloidosis by clinical presentation, renal biopsy, mass spectrometry and DNA sequencing in Peking University First Hospital of China from 2014 to 2016.ResultsBoth of the patients presented with proteinuria, edema and hypertension. Renal biopsies of two patients showed extensive amyloid deposits (Congo red positive) in glomeruli, and focal tubulointerstitial amyloid deposits was also found in patient 1. Besides, hepatic involvement of amyloidosis has been detected by liver biopsy in patient 1. By electron microscopy, randomly arranged fibrils in a diameter of 8–12 nm was identified in mesangial matrix and subendothelial area of glomeruli. Immunohistochemistry demonstrated amyloid deposits were strongly positive for fibrinogen Aα in glomeruli and positive for LECT2 in the interstitium of renal medulla and the liver in Patient 1. Unevenly positive staining for both fibrinogen Aα and ApoA-I were found in Patient 2. Fibrinogen Aα was the most abundant amyloidogenic protein in both patients identified by laser microdissection and mass spectrometry-based proteomic analysis. Genetic analysis revealed the fibrinogen A a-chain gene (FGA) mutation in both patients, including a new deletion mutation [c.1639delA (p.Arg547Glyfs*21; NM_000508)] in Patient 2. Genetic analysis of the LECT2 gene in patient 1 revealed a codon change from ATC to GTC at position 172 [c.172A>G (p.Ile58Val; NM_002302)], which is a common polymorphism (SNP rs31517) in all ALECT2 amyloidosis patients.ConclusionsWe reported two AFib amyloidosis patients in China, one of them coexisted with ALECT2 amyloidosis simultaneously.

Introduction: Long-term exposure to mercury can cause minimal change disease. However, the current understanding of mercury-associated minimal change disease (M-MCD) is inadequate. To improve the understanding of M-MCD, this study retrospectively analyzed the clinicopathological, ultrastructural, and prognostic features of M-MCD, in comparison with primary minimal change disease (P-MCD). Methods: We retrospectively analyzed the clinicopathological data of 21 M-MCD patients and 21 P-MCD patients. Electron micrographs of glomerular capillaries were taken, and the foot process width (FPW) was measured. A receiver operating characteristics (ROC) curve analysis was performed to determine the optimum cutoff value of FPW that can differentiate the M-MCD from P-MCD. Results: M-MCD patients presented similar clinical and routine pathological characteristics with P-MCD patients but had lower levels of FPW (935.0 [interquartile range (IQR) 853.7–1,176.7] nm vs. 1,403.2 [IQR 1,089.2–1,841.8] nm, p = 0.002). ROC curve analysis showed that FPW value below 1,385 nm might help to differentiate M-MCD from P-MCD (area under the curve of 0.787, sensitivity of 94.7%, and specificity of 52.4%). For patients with M-MCD, 77.8% achieved complete remission after mercury detoxification monotherapy. Patients with M-MCD had a lower relapse rate than patients with P-MCD (0 vs. 47.1%, p = 0.003). In addition, there was no significant difference in remission time between M-MCD patients treated with mercury detoxification monotherapy and those initially treated with immunosuppressive therapy (2.0 [IQR 1.0–6.0] months vs. 2.0 [IQR 1.5–2.5] months, p = 0.606). Conclusions: M-MCD patients showed similar clinicopathological features with P-MCD patients, but with less severe foot process effacement, suggesting different pathogenesis of these 2 disease entities. The treatment of mercury detoxification was highly effective for patients with M-MCD and can be considered as a primary choice in clinical practice.

A new Escherichia coli-produced human papillomavirus (HPV)-16/18 vaccine has been shown to be safe and highly efficacious and was recently licensed in China. As a post hoc analysis of the phase III trial, this study aimed to assess the impact of vaccination time deviations on the specific antibody response and guide the better usage of this vaccine in the real world. A total of 3689 healthy women aged 18–45 years old were randomly assigned to receive the bivalent HPV-16/18 vaccine according to a 0-, 1- and 6-month schedule with a wide vaccination interval. The first vaccination interval between the 1st and 2nd doses (the 1st interval) was divided into three groups: 28–40 d, 41–50 d and 51–60 d. The second vaccination interval between the 2nd and 3rd doses (the 2nd interval) was divided into three groups: 103–139 d, 140–160 d and 161–198 d. The reverse cumulative curves for the IgG of the three groups with different 1st vaccination intervals or with different 2nd vaccination intervals at month 7 almost overlapped for both HPV-16 and HPV-18. Compared with the standard vaccination schedule (a 1st interval of 28–40 d and a 2nd interval of 140–160 d) subgroup, all the subgroups had GMC ratios greater than 0.83, with the lower limit of 95% CIs higher than 0.64. In conclusion, a slight deviation in the vaccination time of the 2nd and 3rd doses has only a minor, insignificant impact on the immune response induced by the Escherichia coli-produced HPV-16/18 vaccine.

Abstract Amyloid light‐chain (AL) is characterized by the presence of small, poorly proliferating plasma cell clones with the production and deposition of light chains into tissues. T cell changes within the tumour microenvironment in AL are poorly understood. By sequencing at a single‐cell level of CD3+ T cells purified from bone marrow (BM) and blood of newly diagnosed AL patients before and after a combination of daratumumab with cyclophosphamide, bortezomib, and dexamethasone (Dara‐BCD), we analysed the transcriptomic features of T cells and found an expansion, activation and type I cytokine upregulation in BM and circulating T cells after the treatment. More prominent changes were shown in CD8+ T cells. In particular, we found the presence of CD8+ BM resident memory T cells (TRM) with high expression of inhibitory molecules in AL patients at diagnosis. After Dara‐BCD, these TRM cells were quickly activated with downregulation of suppressive molecules and upregulation of IFNG expression. These data collectively demonstrate that Dara‐based therapy in patients with AL amyloidosis promotes anti‐tumour T cell responses. The similar transcriptomic features of BM and circulating T cells before and after therapy further provide a less invasive approach for molecular monitoring of T cell response in AL amyloidosis.

Background: Light-chain deposition disease (LCDD) is a rare systemic disorder characterized by the deposition of monoclonal light chains in organs. The kidney is a prominent target of light-chain deposition, with a median time to end-stage renal disease (ESRD) of 2.7 years and 5-year ESRD-free survival of 37%. The therapeutic management of LCDD remains ill-defined. In addition to bortezomib-based therapy as first-line therapy, the effect of lenalidomide on LCDD is rarely reported.Case Presentation: This study describes two male LCDD patients in their 60s with nephrotic syndrome and moderately impaired renal function. One patient had monoclonal IgGλ with underlying MGRS, and another had monoclonal IgGκ with underlying monoclonal gammopathy that developed into symptomatic MM during follow-up. The hallmarks of this disease were consistent with previous reports. Both patients initially received BCD therapy, but no hematological response was observed. Consequently, the nephrotic syndrome was refractory. Sequential Rd therapy was initiated, and partial hematological response and nephrotic remission were observed in the IgGλ patient but absent in the IgGκ patient.Conclusion: Limited reports have demonstrated the effect of lenalidomide in LCDD. We report the outcome of lenalidomide in two cases of bortezomib-resistant LCDD. This treatment might be a beneficial supplement for those unresponsive or intolerant to bortezomib in LCDD, but the effect should be prospectively investigated.

IntroductionAs the most common complication of diabetes mellitus (DM), diabetic nephropathy (DN) was initially considered to begin with proteinuria preceding the progression of renal insufficiency. This clinical paradigm has been questioned in the late decades, as many DM patients without proteinuria have progressive renal insufficiency. However, the characteristics of nonproteinuric DN were not fully clear yet.Patients and MethodsA total of 390 patients with renal biopsy-proven DN in our center were retrospectively recruited in the current study. Clinical and histopathological data of the patients were analyzed. We used propensity score-matching methods to address the imbalance of age, sex, and diabetes duration for comparative analyses.ResultsAmong all the renal biopsy-proven DN patients with renal biopsy proven DN, 18 patients were classified as nonproteinuric DN. Compared with 36 propensity score-matched proteinuric DN patients, diabetic retinopathy (DR) was less frequent in nonproteinuric DN patients (38.9% vs. 66.4%, p

Abstract Background C3 glomerulonephritis (C3GN) is a rare disease caused by inherited or acquired complement alternative pathway (CAP) dysregulation, which could also be secondary to monoclonal gammopathy of undetermined significance (MGUS). Herein, we described a patient presenting with C3GN and monoclonal gammopathy, and the pathogenic association between the two diseases was further explored in vitro. Case presentation A 76-year-old Chinese man presented with low serum C3 level, haematuria and nephrotic syndrome, and experienced rapid worsening of renal function over a period of 10 months. His serum and urine immunofixation electrophoresis both revealed a monoclonal IgGλ. A bone marrow puncture showed plasma cell dyscrasias with the highest plasma cell count of 5.25%. Kidney biopsy showed the presence of C3 glomerulonephritis, with exclusive deposits of C3 visible on immunofluorescence, a membranoproliferative pattern on light microscopy and electron dense deposits in sub-epithelial, intramembranous, sub-endothelial and mesangial regions by electron microscopy. The patient was positive for C3 nephritic factor (C3NeF) activity and anti-CFH autoantibodies, and all became negative during disease remission. The anti-CFH autoantibodies purified from the patient’s plasma exchange fluids were proven to be a monoclonal IgGλ, and could inhibit CFH binding to C3b and accelerate the formation of C3 convertase indirectly by interfering with the formation-impeding activity of CFH. No deficiency of candidate genes, especially variants in CFH, was detected in our patient. Based on the pathological and laboratory findings, the diagnosis of monoclonal gammopathy of renal significance (MGRS)-associated C3GN was finally made. Conclusions This is the first demonstration that intact monoclonal immunoglobulin (IgGλ) could act as an anti-CFH antibody and lead to MGRS-associated C3GN by activating the CAP.

Abstract Background The commonly used methods for amyloid typing include immunofluorescence or immunohistochemistry (IHC), which sometimes may come with diagnostic pitfalls. Mass spectrometry (MS)-based proteomics has been recognized as a reliable technique in amyloid typing. Case presentation We reported two middle-aged patients who presented with proteinuria, hypertension and normal renal function, and both had a family history of renal diseases. The renal biopsies of both patients revealed renal amyloidosis with the similar pattern by massive exclusively glomerular amyloid deposition. The IHC was performed by using a panel of antibodies against the common types of systemic amyloidosis, and demonstrated co-deposition of fibrinogen Aα chain and apolipoprotein A-I in the glomerular amyloid deposits of each patient. Then the MS on amyloid deposits captured by laser microdissection (LMD/MS) and genetic study of gene mutations were investigated. The large spectra corresponding to ApoA-I in case 1, and fibrinogen Aα chain in case 2 were identified by LMD/MS respectively. Further analysis of genomic DNA mutations demonstrated a heterozygous mutation of p. Trp74Arg in ApoA-I in case 1, and a heterozygous mutation of p. Arg547GlyfsTer21 in fibrinogen Aα chain in case 2. Conclusions The current study revealed that IHC was not reliable for accurate amyloid typing, and that MS-based proteomics and genetic analysis were essential for typing of hereditary amyloidosis.

Background: C3 glomerulonephritis is a rare, chronic disease characterized by C3c-dominant staining on renal biopsy and is caused by inherited or acquired alternative complement pathway dysregulation. Case presentation: Here, we reported a 36-year-old man presenting with nephritic syndrome and normal renal function. Secondary causes were excluded by detailed clinical history and laboratory tests. His renal biopsy was consistent with C3 glomerulonephritis with a membranoproliferative glomerulonephritis pattern. To identify the etiology, we carried out genetic and autoantibody screening tests. The results showed he was negative for autoantibodies, while the next-generation sequencing revealed common variants of complement factor H (c.1204T>C; p.Tyr402His), (c.184G>A; p.Val62Ile) and thrombomodulin (c.1418C>T; p.Ala473Val), which have previously been reported to increase susceptibility to complement-mediated diseases. He also carried complement factor H (c.2808G>T; p.Glu936Asp) and mannose-binding lectin (c.161G>A; p.Gly54Asp), putting the patient at an increased risk of infections, which was an important trigger for C3 glomerulonephritis. A novel variant of complement 2 (c.53A>G; p.His18Arg) that might contribute to the occurrence of C3 glomerulonephritis when combined with these susceptibility variants was further identified. The patient was treated with ramipril and regular fresh frozen plasma infusion. He had a good response to treatment with well-controlled proteinuria, stable renal function and an increasing serum C3 level. Conclusions: This case adds insight into the pathogenesis of C3 glomerulopathy by showing that a combination of susceptibility variants, genetic mutations and triggers might be responsible for the clinical and pathological phenotypes. Resumen: Antecedentes: La glomerulonefritis C3 es una enfermedad rara y crónica caracterizada por tinción dominante en C3c en la biopsia renal y es causada por una desregulación de la ruta alternativa del complemento heredada o adquirida. Presentación del caso: Informamos sobre un varón de 36 años que presenta síndrome nefrítico y función renal normal. Las causas secundarias fueron excluidas por la historia clínica detallada y las pruebas de laboratorio. Su biopsia renal fue consistente con glomerulonefritis C3, con un patrón de glomerulonefritis membranoproliferativa. Para identificar la etiología realizamos pruebas de cribado genéticas y de autoanticuerpos. Los resultados mostraron que era negativo para autoanticuerpos, mientras que la secuenciación de próxima generación reveló variantes comunes del factor del complemento H (c.1204T>C; p.Tyr402His), (c.184G>A; p.Val62Ile) y trombomodulina (c.1418C>T; p.Ala473Val), que previamente se había informado que aumentaban la susceptibilidad a las enfermedades mediadas por el complemento. También tuvo factor del complemento H (c.2808G>T; p.Glu936Asp) y lectina de unión a manosa (c.161G>A; p.Gly54Asp), que aumentaba el riesgo de infección para el paciente, y que fue un desencadenante importante para glomerulonefritis C3. Una nueva variante del complemento 2 (c.53A>G; p.His18Arg) que podría contribuir a la aparición de glomerulonefritis C3 cuando se combina con estas variantes de susceptibilidad fue identificado. El paciente fue tratado con ramipril e infusión regular de plasma fresco congelado. Tuvo una buena reacción al tratamiento con proteinuria bien controlada, función renal estable y un aumento de suero del nivel C3. Conclusiones: Este caso agrega una idea de la patogénesis de la glomerulopatía C3 al mostrar que una combinación de variantes de susceptibilidad, mutaciones genéticas y desencadenantes podría ser responsable de los fenotipos clínicos y patológicos. Keywords: C3 glomerulonephritis, Membranoproliferative glomerulonephritis, Alternative pathway, Complement 2, Susceptibility variants, Palabras clave: Glomerulonefritis C3, Glomerulonefritis membranoproliferativa, Ruta alternativa, Complemento 2, Variantes de susceptibilidad

Abstract Background Proliferative glomerulonephritis with monoclonal Immunoglobulin (G) deposits (PGNMID) is a rare kind of MGRS with intact monoclonal IgG deposition. Seventy percent of PGNMID patients were negative for M-spike. Case presentation A 51-year-old Chinese woman presented with 16-month history of chronic nephritic syndrome. Her first biopsy showed a MPGN pattern, and the IF showed polyclonal IgG deposition but with IgG3λ dominance, MGRS was highly suspected. But the serum/urine IFE and bone marrow examination was negative for monoclonal gammopathy. She was treated with RAS inhibitors, and monitored carefully in the outpatient clinic. When the proteinuria was not controlled by RAS inhibitors, immunosuppressive agents were initiated. The second biopsy was done due to her acute kidney injury 9 months later, showing a MPGN pattern with acute tubulointerstitial disease, but the IF showed monoclonal IgG3λ deposition. The κ light chain, IgG1, IgG2 and IgG4 were absent. Electron microscopic examination revealed electron-dense deposits in the mesangial, subendothelial and subepithelial area which is the same as the first renal biopsy. The final diagnose of this patient was PGNMID (IgG3λ) with non-organized deposits. Repeated serum/urine IFE and free light chain still failed to identify monoclonal gammopathy. The patient was treated with steroid and cyclophosphamide, and her serum creatinine decreased. Conclusions Some of the PGNMID patients may be derived from polyclonal immune complex mediated glomerulonephritis.

Proliferative glomerulonephritis with monoclonal immunoglobulin G (IgG) deposits is a rare monoclonal gammopathy of renal significance with dense deposits on electron microscopy similar to polyclonal immune complex–mediated glomerulonephritis. 70% of patients with proliferative glomerulonephritis with monoclonal IgG are negative for a monoclonal (M) spike, and patients with this condition rarely develop an M spike during follow-up. We report a Chinese man in his 50s who presented with nephrotic syndrome and normal glomerular filtration rate. His first kidney biopsy showed masked IgG3 deposition, such that IgG3 staining was apparent only after digestion by enzyme on paraffin tissue, with a membranoproliferative pattern. During follow-up, his glomerular filtration rate worsened and proteinuria increased. 18 months after the first biopsy, the patient developed an M spike; a second kidney biopsy showed proliferative glomerulonephritis with monoclonal IgG deposits with unmasked IgG3λ deposition. The patient was successfully treated with bortezomib and dexamethasone, followed by lenalidomide and dexamethasone maintenance therapy. Index Words: MPGN, monoclonal gammopathy, monoclonal gammopathy of renal significance, proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID)

Isolated or dominant tubulointerstitial lupus nephritis is rare. Here, we reported a 67-year-old man diagnosed with systemic lupus erythematosus (SLE) based on clinical and laboratory criteria, who was showing impaired renal function and non-nephrotic range proteinuria in the past 2 years. Renal biopsy showed almost normal glomeruli, but the tubulointerstitium showed “storiform” pattern with interstitial infiltration of IgG3 predominant plasma cells. Immunofluorescence showed linear and granular staining of IgG and C1q along TBM and interstitium. He started on medium dose of oral steroids and mycophenolate mofetil, which were gradually tapered. As a result, his renal function improved over a few days. Now, he continued on low dose steroids and mycophenolate mofetil with no evidence of relapse.

Background: Atypical cases of anti-glomerular basement membrane (GBM) disease had absent circulating antibodies but linear IgG deposits along GBM in the kidneys. Herein, we reported the clinical-pathological features and outcome of these rare cases.Methods: Linear IgG deposit along GBM were examined by immunofluorescence on renal specimens, with exclusion of diabetic kidney disease. Circulating anti-GBM antibodies were tested by commercial ELISA assay. Clinical, pathological and follow-up data were retrospectively analyzed.Results: From 2013 to 2018, a total of 60 patients were diagnosed as atypical anti-GBM disease. They had a male predominance, with an average age of 51.7 ± 15.6 years. Three (5.0%) patients had alveolar hemorrhage. Forty five percent of them presented with acute kidney disease. All patients had linear IgG deposit along GBM, some in addition on tubular basement membrane and/or Bowmans' capsules. C3 deposition was found in 65.0% of the patients. 41.7% (25/60) of the patients showed crescent formation and the percentage of crescent was (34.7 ± 23.5)% in those patients. They had higher prevalence of hematuria and C3 deposit, higher levels of serum creatinine, worse renal and patient survival than those without crescent (P < 0.05). During the follow-up of 35.7 ± 21.4 months, 14 (23.3%) patients progressed to ESRD. The serum creatinine on diagnosis [per 200 μmol/L increase, HR (95% CI): 2.663 (1.372, 5.172), P = 0.004], serum C3 [per 0.1 g/L increase, HR (95% CI): 0.689(0.483, 0.984), P = 0.040] and the intensity of kidney C3 staining [per 1+ increase, HR (95% CI): 2.770 (1.115, 6.877), P = 0.028] were independent predictive factors for kidney outcome. Nine (15.0%) patients died of all causes.Conclusions: Atypical anti-GBM disease manifested milder kidney injury and scarce pulmonary hemorrhage compared to the classical cases. Though heterogeneous, a substantial number of the patients had complement activation and crescent formation. Patients having crescents presented with more severe clinical course and worse outcomes. The poor kidney and patient prognosis emphasize prompt interventions from physicians. The immunosuppressive intervention was not associated with kidney or patient outcome. Further studies are needed to address the optimal therapeutic regimen.

Abstract Background Monoclonal gammopathy of renal significance (MGRS) is a recently defined group of renal diseases caused by monoclonal immunoglobulin secreted by nonmalignant proliferative B cell or plasma cell. Monoclonal immunoglobulin can form different types of structures deposited in renal tissue, including fibrils, granules, microtubules, crystals and casts, and has mostly been reported in multiple myeloma patients. Here we report a rare case with κ light chain crystals in both podocytes and tubular epithelial cells associated with MGRS, which adds more information to the spectrum of MGRS-related renal diseases. Case presentation A 53-year old woman presented with albumin–predominant moderate proteinuria and renal failure. She had monoclonal IgGκ in the serum and monoclonal IgGκ plus free κ in the urine. Multiple myeloma and lymphoproliferative disorders were excluded. Renal biopsy confirmed κ-restricted crystal-storing renal disease involving the podocytes and proximal tubular epithelial cells. The patient was treated with bortezomib followed by lenalidomide-based chemotherapy, and renal function was stable after 1 year of follow-up. Conclusions This is a rare case of combined crystalline podocytopathy and tubulopathy associated with MGRS, in which diagnosis was dependent on electron and immuno-electron microscopy.

Background. Pigment epithelium-derived factor (PEDF) is demonstrated to be elevated in diabetes patients. However, no reports have emerged in pregnant women with gestational diabetes mellitus (GDM). This study was undertaken to investigate serum PEDF levels in GDM women and to evaluate PEDF as a biomarker to predict diabetes postpartum. Methods. Serum PEDF concentration and clinical characteristics were detected in the pregnant women with GDM (n = 120) and without GDM (control group, n = 120). Results. PEDF levels were elevated in subjects with GDM versus controls. Univariate correlations showed that serum PEDF levels were positively correlated with fasting glucose and fasting insulin levels, respectively, and negatively correlated with adiponectin. Receiver operating characteristic (ROC) analysis demonstrated that the AUC of serum PEDF for diabetes mellitus in women postpartum was 0.893. Conclusion. Serum PEDF was elevated in pregnant women with GDM, which is probably an early detection marker for predicting development of GDM to diabetes mellitus.

Objective. The current study aimed to investigate the spectrum of etiologies and associated disorders of renal biopsy-proven thrombotic microangiopathy (TMA) patients. Methods. The clinical, laboratory, and renal histopathological data of patients with renal TMA from 2000 to 2012 in our institute were collected and reviewed. Results. One hundred and nine TMA patients were enrolled in this study. The mean age was 34.0 ± 11.1 years. Seventy patients (64.2%) were male and thirty-nine patients (35.8%) were female. There were eight patients (7.3%) with hemolytic uremic syndrome (HUS). Sixty-one patients (56.0%) were secondary to malignant hypertension. Fourteen patients (12.8%) were pregnancy-associated TMA. Other associated disorders included 17 patients with connective tissue disorders, 2 patients with hematopoietic stem cell transplantation, 4 patients with Castleman’s disease, 1 patient with cryoglobulinemia, and 2 patients with glomerulopathy. During followup, 8 patients died due to severe infection, 17 patients had doubling of serum creatinine, and 44 had end-stage renal disease. In multivariate analysis, male, elevated serum creatinine, and decreased hemoglobin were independently associated with poor renal outcomes. Conclusions. Renal TMA changes consisted of different disorders with various etiologies. aHUS, pregnancy-associated TMA, and malignant hypertension accounted for the majority of patients in our cohort.