The correlation between anti-phospholipase A2 receptor antibodies and hypercoagulability in patients with idiopathic membranous nephropathy.

BACKGROUND: Patients with idiopathic membranous nephropathy (IMN) are more likely to be complicated by venous thromboembolism (VTE). The aim of the study was to investigate the potential association between anti-phospholipase A2 receptor (PLA2R) antibodies and hypercoagulability in patients with IMN. METHODS: A total of 168 patients with biopsy-proven IMN and 36 patients with biopsy-proven minimal change disease (MCD) were enrolled in this study. The clinical data, serum anti-PLA2R antibodies and coagulation-related indices of the patients were retrospectively analyzed. RESULTS: Patients with IMN were categorized into glomerular PLA2R staining-positive (GAg+) IMN group and glomerular PLA2R staining-negative (GAg-) IMN group in the study. Patients with IMN who were GAg + had lower PT, APTT and R time than patients with IMN who were GAg-, while the CI value was higher in patients with IMN who were GAg+. Patients with IMN who were GAg + were divided into the SAb+/GAg + group and the SAb-/GAg + group. Patients with IMN who were SAb+/GAg + had higher Fib and MA values than patients with IMN who were SAb-/GAg+. Correlation analysis showed that serum anti-PLA2R antibodies were positively correlated with fibrinogen, D-dimer, K time, CI value, α-angle, and MA value. Multiple linear regression analysis indicated that anti-PLA2R antibodies were independently correlated with fibrinogen and MA value. CONCLUSION: Our study provides a new perspective on the underlying mechanisms of hypercoagulability in patients with IMN. Anti-PLA2R antibodies are associated with hypercoagulability in patients with IMN and may affect coagulation in patients with IMN by affecting platelet aggregation function and fibrinogen counts.

Clinicopathological Characteristics of Light and Heavy Chain Deposition Disease: A Case Series.

RATIONALE & OBJECTIVE: Light and heavy chain deposition disease (LHCDD) is a rare form of monoclonal immunoglobulin (Ig) deposition disease, and limited clinical data are available characterizing this condition. Here we describe the clinicopathological characteristics and outcomes of LHCDD. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: 13 patients with biopsy-proven LHCDD diagnosed between January 2008 and December 2022 at one of 2 Chinese medical centers. FINDINGS: Among the 13 patients described, 6 were men and 7 were women, with a mean age of 52.6±8.0 years. Patients presented with hypertension (76.9%), anemia (84.6%), increased serum creatinine concentrations (84.6%; median, 1.7mg/dL), proteinuria (100%; average urine protein, 3.0g/24h), nephrotic syndrome (30.8%), and microscopic hematuria (76.9%). Serum immunofixation electrophoresis showed monoclonal Ig for 11 patients (84.6%). Serum free light chain ratios were abnormal in 11 patients (84.6%), and heavy/light chain ratios were abnormal in 9 of 10 patients (90%) with available data. Five patients were diagnosed with multiple myeloma. A histological diagnosis of nodular mesangial sclerosis was made in 10 patients (76.9%). Immunofluorescence demonstrated deposits of IgG subclass in 7 patients (γ-κ, n=4; γ-λ, n=3) and IgA in 5 patients (α-κ, n=2; α-λ, n=3). Six patients underwent IgG subclass staining (γ1, n=3; γ2, n=2; γ3, n=1). The deposits of IgD-κ were confirmed by mass spectrometry in 1 patient. Among 12 patients for whom data were available during a median of 26.5 months, 11 received chemotherapy and 1 received conservative treatment. One patient died, and disease progressed to kidney failure in 3 (25%). Among the 9 patients evaluable for hematological and kidney disease progression, 5 (56%) had a hematologic response and 1 (11%) exhibited improvement in kidney disease. LIMITATIONS: Retrospective descriptive study, limited number of patients, urine protein electrophoresis or immunofixation electrophoresis test results missing for most patients. CONCLUSIONS: In this case series of LHCDD, light and heavy chain deposition in kidney tissues were most frequent with monoclonal IgG1-κ. Among patients with evaluable data, more than half had a hematologic response, but a kidney response was uncommon.

Clinical features of anemia in membranous nephropathy patients: a Chinese cohort study.

BACKGROUND: Anemia is a common complication in patients with progressive chronic kidney disease. This cohort study evaluated the prevalence, clinical features and prognosis of membranous nephropathy (MN) with anemia. METHODS: We retrospectively analyzed a cohort of MN patients diagnosed using renal biopsy between February 2012 and February 2018. The clinical and pathological characteristics at baseline were recorded, and the outcomes (hemoglobin, proteinuria and renal function) during follow-ups were also evaluated. Univariate and multivariate logistic regression analyses were performed to identify the independent risk factors for anemia in MN patients. The MN patients were divided according to the therapeutic effect they experienced as follows: without-anemia, completely corrected anemia, standard anemia treatment and nonstandard anemia treatment groups. We compared the rate of complete remission of MN and renal end-point events among the four groups. RESULTS: The median age of 483 patients was 42.43 (26.59, 50.20) years at the time of MN diagnosis. The prevalence of anemia at baseline was 23.81%, and the cumulative prevalence was 50.72%. There were 133 cases of mild anemia, 103 cases of moderate anemia and 9 cases of severe anemia; in addition, there were 228 cases of normocytic anemia and 17 cases of microcytic hypochromic anemia. Multivariate logistic regression indicated that acute renal tubule injury >5% (OR = 1.634, 95% CI 1.034, 2.581; p = 0.035), total protein level (OR = 0.949, 95% CI 0.923, 0.975; p < 0.001), cholesterol level (OR = 0.833, 95% CI 0.749, 0.926, p = 0.001), hypokalemia (OR = 2.612, 95% CI 1.227, 5.560, p = 0.013) and hypophosphatemia (OR = 2.653, 95% CI 1.303, 5.403, p = 0.007) were independent risk factors for anemia in MN patients. The complete remission rate of MN patients without anemia was significantly higher than that of anemia patients who exhibited treatment failure. The incidence of renal endpoint events was different among the four groups. CONCLUSION: The anemia experienced by MN patients is mainly mild and moderate, normocytic anemia. The pathological features of acute renal tubular injury and clinical nutritional status are independent risk factors for anemia. There were differences in renal prognosis among anemia patients with different treatment outcomes.

Secondary Oxalate Nephropathy: Causes and Clinicopathological Characteristics of a Case Series.

INTRODUCTION: Secondary oxalate nephropathy (OxN) is associated with a variety of causes and has not been well characterized in Chinese population. To investigate the etiology, clinicopathological features, and outcomes of secondary OxN, we report a case series from a single center in China. METHODS: A retrospective analysis of 68 patients diagnosed with secondary OxN by renal biopsy from January 2013 to February 2019 in Jinling Hospital was performed. RESULTS: Secondary OxN accounted for 0.23% of the renal biopsies and 2.31% of patients who received renal biopsies due to acute kidney injury (AKI). A total of 49 men and 19 women with an average age of 51.6 ± 11.8 years were enrolled. The most common cause was iatrogenic medication, followed by oxalate-rich diet and industry exposure. Stage 1, 2, and 3 AKI and AKI on chronic kidney disease (ACKD) were found in 4.4, 8.8, 69.1, and 17.6% of the patients, respectively. The peak serum creatinine during hospitalization was 8.62 ± 4.67 mg/dL. The median urinary oxalate excretion was 51.5 (23.2-147.1) mg/24 h. Kidney biopsy showed extensive calcium oxalate crystal deposits with acute tubulointerstitial nephritis. Thirty-four patients (50.0%) required renal replacement therapy. At the end of a follow-up that lasted 8.7 (0.1-72.1) months, 81.0% of patients achieved renal function recovery in 50 (14-432) days. Patients with renal function recovery had a lower rate of ACKD, a higher level of hemoglobin, a lower level of urine lysozyme, and a lower degree of interstitial fibrosis/tubular atrophy, interstitial inflammation, and global glomerulosclerosis than those in the nonrecovery group. CONCLUSIONS: In this case series of secondary OxN, the most common cause was iatrogenic medication, and it presented with AKI or ACKD. Half of the patients required renal replacement therapy, and in most of them, the renal function was reversible. Renal biopsy played an important role in diagnosis and prognosis evaluation.

Clinicopathological characteristics and outcome of patients with fibrillary glomerulonephritis: DNAJB9 is a valuable histologic marker.

BACKGROUND: Fibrillary glomerulonephritis (FGN) is a rare glomerular disease. DNAJB9 as a new reliable diagnostic marker for the diagnosis of FGN was discovered recently. To investigate the clinicopathological features and prognosis of DNAJB9-positive FGN, we report on a case series in a single center in China. METHODS: DNAJB9 immunohistochemistry was performed on renal biopsy samples from patients with FGN (n = 7), and non-FGN glomerular diseases (n = 27) were used as controls. The patients with DNAJB9-positive FGN were retrospectively analyzed. RESULTS: Strong DNAJB9 staining of glomerular extracellular deposits was observed in 6 cases of originally diagnosed FGN. One man and 5 women with a median age of 26 years were studied. The patients presented with renal insufficiency in 1 case, proteinuria in 6 cases, nephrotic syndrome in 3 cases, and microscopic hematuria in 2 cases. The histologic pattern was mesangial proliferative glomerulonephritis in 1 case and membranoproliferative glomerulonephritis in 5 cases. The glomerular deposits stained for polytypic IgG and both kappa and lambda in 3 cases, polytypic IgG without kappa or lambda in 1, monotypic IgG1-kappa in 1 and IgG1-lambda in 1. Extraglomerular deposits were identified in all cases. Congo red positivity was observed in 3 cases. All of the patients received renin-angiotensin-aldosterone system blockade and 5 of them received glucocorticoid and/or immunosuppression. At a median time of 36.2 months after biopsy, 2 cases had partial remission, 3 cases displayed no remission, and 1 case progressed to end-stage renal disease. CONCLUSIONS: Extraglomerular deposits in the FGN were common. Monotypic FGN was found in young patients with a favorable renal outcome.

Features of phospholipase A2 receptor and thrombospondin type-1 domain-containing 7A in malignancy-associated membranous nephropathy.

AIMS: Phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing 7A (THSD7A) were identified as pathogenic antigens in patients with membranous nephropathy (MN). Notably, PLA2R is detected in few patients with malignancy-associated MN, and a high incidence of cancer is reported in patients with THSD7A-associated MN. Therefore, the roles of PLA2R and THSD7A in malignancy-associated MN must be clarified. METHODS: Serum anti-PLA2R antibodies and glomerular PLA2R staining were assessed in 36 patients with malignancy-associated MN, followed by examination of serum anti-THSD7A antibodies and glomerular THSD7A. THSD7A staining in cancer tissues was also assessed in 9 of the 36 patients. RESULTS: Twelve (33%) of 36 patients were positive for both glomerular PLA2R and serum anti-PLA2R antibodies, one of whom had enhanced glomerular THSD7A staining. Two patients were positive for either glomerular PLA2R or serum anti-PLA2R antibody. All these patients had IgG4-dominant deposits in glomeruli. Among the 22 (61%) patients who were double negative for glomerular PLA2R and serum anti-PLA2R antibodies, 17 of 20 (85%) had IgG1-dominant deposits in glomeruli, and 2 (9.1%) were positive for glomerular THSD7A staining. Serum anti-THSD7A antibody was not detected in any of the 36 patients. Among the nine patients with available cancer tissues, positive staining of THSD7A in the cancer tissues was observed in five (56%) patients, and one showed enhanced glomerular staining of THSD7A. CONCLUSIONS: Screening of glomerular PLA2R antigen and serum anti-PLA2R antibodies is necessary in patients with malignancy-associated MN, whereas the incidence of glomerular THSD7A antigen or circulating anti-THSD7A antibodies is uncommon.

Phosphorus is an independent risk factor for the progression of diabetic nephropathy.

BACKGROUND: Serum phosphorus is thought to be an important risk factor for the progression of chronic kidney disease (CKD). However, the association of serum phosphorus with disease progression in patients with different causes of kidney diseases remains to be elucidated. OBJECTIVES: The aim of this study was to estimate the effect of serum phosphorus on disease progression in 2 cohorts of CKD with different causes. MATERIAL AND METHODS: A total of 591 patients with diabetic nephropathy and 957 patients with IgA nephropathy from the National Clinical Research Center of Kidney Diseases, Nanjing, China, with biopsy-proven kidney disease, stage 1-4 CKD and a follow-up of at least 1 year were recruited. We evaluated the relationship between the baseline phosphorus category and the disease progression in the 2 cohorts. RESULTS: Multivariate Cox regression analyses indicated that the risk of the endpoint event was 1.68-fold higher (95% confidence interval (CI): 0.95-2.91) in IgA nephropathy patients and 2.88-fold higher (95% CI: 1.12-5.04) in diabetic nephropathy patients with the highest quartile of serum phosphorus compared with the risk of those with the lowest quartile. CONCLUSIONS: The association of serum phosphorus with the progression of CKD may vary in specific CKD patient subgroups. Serum phosphorus is independently associated with the progression of kidney disease in patients with diabetic nephropathy.

PLA2R antibodies and PLA2R glomerular deposits in psoriasis patients with membranous nephropathy.

BACKGROUND: The association between psoriasis and membranous nephropathy (MN) remains largely unclear. We examined the prevalence of serum PLA2R antibody and characterized the expression of PLA2R and THSD7A in glomeruli in patients with MN and psoriasis. METHODS: A total of 24 patients with MN without evidence of a secondary cause except psoriasis were enrolled. The clinical and pathological features were retrospectively analyzed. Serum anti-PLA2R antibody was measured using IFA Mosaic. Renal tissue samples stored in the laboratory bio-bank were used for PLA2R staining under immunofluorescence microscopy and THSD7A immunohistochemical analysis. RESULTS: Twenty-four patients (21 male and 3 female) with a mean age of 43.6 ± 15.7 years old were enrolled. Serum anti-PLA2R antibody was positive in 7 patients, which was significantly lower than the positivity observed in idiopathic MN (29.2% vs. 81.7%, P < 0.001). Glomerular PLA2R staining was positive in 7 patients with positive serum anti-PLA2R antibody. THSD7A staining was negative in all 24 patients. During the follow-up visits, 13 patients with negative serum PLA2R antibody achieved CR. In contrast, CR was only achieved in 1 patient with positive serum PLA2R antibody, PR was achieved in 2 patients. CONCLUSIONS: The prevalence of serum anti-PLA2R antibody and glomerular expression of PLA2R was significantly lower in patients with psoriasis and MN than in those with idiopathic MN, and THSD7A staining was negative, suggesting that MN is associated with psoriasis in the majority of patients. However, idiopathic MN might also accompany psoriasis in a minority of psoriatic patients with positive serum anti-PLA2R antibody.

Combined Assessment of Phospholipase A2 Receptor Autoantibodies and Glomerular Deposits in Membranous Nephropathy.

Serum phospholipase A2 receptor antibodies (SAbs) and glomerular phospholipase A2 receptor antigen (GAg) deposits have been observed in idiopathic membranous nephropathy (IMN). However, the clinical application of these two biomarkers, particularly GAg deposition, needs to be further evaluated. We measured SAb concentration by ELISA and GAg deposition by immunofluorescence in 572 patients with biopsy-proven IMN. Overall, 68.5% of patients (392 of 572) had detectable SAb (SAb+), and 98.7% of patients who were SAb+ (387 of 392) and 70.6% of patients who were SAb- (127 of 180) had GAg deposition (GAg+). Compared with patients who were SAb-/GAg+, patients who were SAb+/GAg+ exhibited higher levels of proteinuria (P<0.001) and a lower chance of proteinuria remission (P<0.001). In 52 patients who underwent repeat biopsies, patients who did not achieve remission had a higher SAb+ rate on the first biopsy than patients who went into remission (P=0.001). Furthermore, SAb+ levels persisted in patients who did not achieve remission but significantly decreased in patients who achieved remission by the second biopsy. Patients who did not achieve remission also had a higher GAg+ rate on the first biopsy than patients who achieved remission (P<0.01). Sustained GAg+ deposits correlated with disease relapse. In conclusion, combining the measurements of SAb levels and detection of GAg deposition may provide additional information regarding diagnoses, treatment response, and disease relapse in patients with IMN.

A non-invasive laboratory panel as a diagnostic and prognostic biomarker for thrombotic microangiopathy: development and application in a Chinese cohort study.

BACKGROUND: Thrombotic microangiopathy (TMA) in the kidney is a histopathologic lesion that occurs in a number of clinical settings and is often associated with poor renal prognosis. The standard test for the diagnosis of TMA is the renal biopsy; noninvasive parameters such as potential biomarkers have not been developed. METHODS: We analyzed routine parameters in a cohort of 220 patients with suspected TMA and developed a diagnostic laboratory panel by logistic regression. The levels of candidate markers were validated using an independent cohort (n = 46), a cohort of systemic lupus erythematosus (SLE) (n = 157) and an expanded cohort (n = 113), as well as 9 patients with repeat biopsies. RESULTS: Of the 220 patients in the derivation cohort, 51 patients with biopsy-proven TMA presented with a worse renal prognosis than those with no TMA (P = 0.002). Platelet and L-lactate dehydrogenase (LDH) levels showed an acceptable diagnostic value of TMA (AUC = 0.739 and 0.756, respectively). A panel of 4 variables - creatinine, platelets, ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats 13) activity and LDH - can effectively discriminate patients with TMA (AUC = 0.800). In the validation cohort, the platelet and LDH levels and the 4-variable panel signature robustly distinguished patients with TMA. The discrimination effects of these three markers were confirmed in patients with SLE. Moreover, LDH levels and the 4-variable panel signature also showed discrimination values in an expanded set. Among patients undergoing repeat biopsy, increased LDH levels and panel signatures were associated with TMA status when paired evaluations were performed. Importantly, only the 4-variable panel was an independent prognostic marker for renal outcome (hazard ratio = 3.549; P<0.001). CONCLUSIONS: The noninvasive laboratory diagnostic panel is better for the early detection and prognosis of TMA compared with a single parameter, and may provide a promising biomarker for clinical application.