Altered serum metabolic profile in patients with IgA nephropathy.

BACKGROUND: We investigated alterations in the serum metabolomic profile of IgA nephropathy (IgAN) patients and screen biomarkers of IgA nephropathy based on ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). METHODS: Serum samples from 65 IgAN patients and 31 healthy controls were analyzed by ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). Univariate and multivariate analysis were performed to screen the differential metabolites. Differential metabolites should meet both the following two criteria: adjusted P < 0.05 in the univariate analysis and VIP value > 1 in the multivariate model. Pathway analysis was performed to reveal the metabolic pathways that were significantly influenced in IgAN. Spearman correlation analysis was applied to explore the correlation between metabolites and between the metabolites and clinicopathological features of IgAN. A random forest model and Logistics regression analysis were conducted to evaluate the predictive ability of the metabolites. RESULTS: The metabolic profile was significantly altered in IgAN patients compared with healthy controls. Thirty-nine metabolites were identified, including glycerophospholipids, sphingolipids, vitamin K1, vitamin K2, bile acids and amino acids. Sphingolipid metabolism, ubiquinone and other terpenoid-quinone biosynthesis, and glycerophospholipid metabolism were found to be significantly disturbed in the pathway analysis. Differential metabolites were found to be associated with the clinical and pathological features of IgAN patients. Lanosterol, vitamin K1, vitamin K2, and ß-elemonic acid were found to have promising predictive ability for IgAN. CONCLUSIONS: We confirmed the differences in the metabolic profiles of IgAN patients and healthy controls and identified the differential metabolites of IgAN, which may help with the further exploration of the pathogenesis and treatment of IgAN.

Probiotics ameliorate IgA nephropathy by improving gut dysbiosis and blunting NLRP3 signaling.

BACKGROUND: Recently, a few studies have indicated a relationship between the gut microbiota and IgA nephropathy (IgAN). Whether the gut microbiota participates in the pathogenesis of IgAN and whether probiotics are effective in treating IgAN are still controversial. Therefore, this study aimed to identify the differences in the structure of the gut microbiota between IgAN and controls and to evaluate the efficacy and mechanism of probiotics in the treatment of IgAN. METHODS: To address this question, 35 IgAN patients and 25 healthy volunteers were enrolled, and a mouse IgAN model was also constructed. The stool microbes were analyzed by 16S rRNA high-throughput sequencing to identify the differential strains between IgAN and healthy controls. The impact of probiotics on the structure of the intestinal flora and the efficacy of the probiotics in the treatment of IgAN were evaluated. RESULTS: Although the microflora structure of mice and humans was not the same, both patients and mice with IgAN exhibited gut microbiota dysbiosis, with all subjects presenting an evident decrease in Bifidobacterium levels. The Bifidobacterium proportion was negatively correlated with proteinuria and hematuria levels, indicating that the decreased Bifidobacterium abundance could be related to IgAN severity. Probiotic treatment containing Bifidobacterium in IgAN mice could significantly alleviate gut dysbiosis, specifically by increasing the proportion of beneficial bacteria and reducing the abundance of potentially pathogenic bacteria. Moreover, both probiotics and their metabolites, short-chain fatty acids (SCFAs), could attenuate IgAN clinicopathological manifestations by inhibiting the NLRP3/ASC/Caspase 1 signaling pathway. CONCLUSIONS: Supplementation with probiotics mainly containing Bifidobacterium could markedly improve gut dysbiosis in IgAN. Moreover, both probiotics and their SCFA metabolites could attenuate the clinicopathological manifestations of IgAN by inhibiting the NLRP3/ASC/Caspase 1 signaling pathway. Therefore, probiotics have potential as an adjunctive therapy for IgAN.

Case Report: Adolescent-Onset Isolated Nephronophthisis Caused by a Novel Homozygous Inversin Mutation.

Objective: Nephronophthisis (NPHP) is a rare autosomal recessive inherited kidney disease that can cause cystic enlargement of the kidneys, and lead to end-stage renal disease (ESRD) before the age of 30 years. Herein we describe a case of adolescent-onset NPHP with a novel homozygous mutation in the inversin gene (INVS). Methods: The patient was a 15-year-old Chinese boy who presented with ESRD. Genetic testing was performed via whole exome sequencing and validated via Sanger sequencing. A novel homozygous INVS mutation was identified (c. 1909C > T; p. Gln637Ter). Results: The results of laboratory examinations included urinary protein 1.05 g/24 h, urine erythrocyte count 5/high-power field, serum creatinine 1,026.2 µmol/L, and estimated glomerular filtration rate 5.8 ml/min/1.73 mm2. Extrarenal features included hypertension and moderate anemia, and his parents were consanguineous (first cousins). A homozygous 1-bp substitution resulting in a nonsense mutation (c. 1909C > T; p. Gln637Ter) in exon 15 of INVS was detected via whole exome sequencing, and validated via Sanger sequencing. According to the classification system of the American College of Medical Genetics and Genomics, the mutated gene in INVS is strongly pathogenic (PVS1+PM2+PP3+PP5). His parents and a younger brother were heterozygous carriers. Based on the above results he was diagnosed with juvenile type 2 NPHP. He underwent hemodialysis, and received a kidney transplant after 2 months. He is currently recovering well, with a serum creatinine level of 117 µmol/L and an estimated glomerular filtration rate of 79.6 ml/min/1.73 mm2. Conclusion: Here we have described an extremely rare case of adolescent-onset type 2 NPHP caused by a homozygous INVS mutation. The patient had progressed to ESRD by the age of 15 years. The current report will deepen our understanding of the clinical and genetic basis of this disease.

Intestinal dysbiosis featuring abundance of Streptococcus associates with Henoch-Schönlein purpura nephritis (IgA vasculitis with nephritis) in adult.

BACKGROUND: The pathogenesis of Henoch-Schönlein purpura nephritis (HSPN) is closely associated with mucosal infection. But whether intestinal microbiota dysbiosis plays a role in it is not clear. METHODS: A total of 52 participants including 26 HSPN patients and 26 healthy controls were included. By using 16S ribosomal RNA gene sequencing, the intestinal microbiota composition between HSPN and healthy controls was compared. The diagnostic potency was evaluated by Receiver operating characteristic (ROC) with area under curves (AUC). Meanwhile, correlation analysis was also performed. RESULTS: The lower community richness and diversity of fecal microbiota was displayed in HSPN patients and the structure of gut microbiota was remarkedly different. A genus-level comparison indicated a significant increase in the proportions of g-Bacteroides, g-Escherichia-Shigella and g-Streptococcus, and a marked reduction of g-Prevotella_9 in HSPN patients, suggesting that the overrepresentation of potential pathogens and reduction of profitable strains were the main feature of the dysbiosis. The differential taxonomic abundance might make sense for distinguishing HSPN from healthy controls, with AUC of 0.86. The relative abundance of the differential bacteria was also concerned with clinical indices. Among them, Streptococcus spp. was positively associated with the severity of HSPN (P < 0.050). It was found that HSPN patients with higher level of Streptococcus spp. were more likely to suffering from hematuria and hypoalbuminemia (P < 0.050). CONCLUSIONS: The dysbiosis of gut microbiota was obvious in HSPN patients, and the intestinal mucosal streptococcal infection was distinctive, which was closely related to its severity.

Arterial-Arteriolar Sclerosis Is Independently Associated With Poor Renal Outcome in IgA Nephropathy Patients.

Aim: This study aimed to investigate the clinicopathological features and prognosis of immunoglobulin A nephropathy (IgAN) with arterial-arteriolar sclerosis (AS). Methods: Patients with biopsy-proven IgAN from the West China Hospital of Sichuan University were retrospectively enrolled. Clinicopathological features were collected. Patients were categorized based on the presence and the severity of the AS. All the patients were regularly followed-up until a composite end point. The correlation between AS and prognosis of IgAN was assessed. Results: A total of 1,424 patients were recruited and followed for 60.0 ± 28.7 months. Patients with AS tended to have older age, higher blood pressure, heavier proteinuria, higher serum creatinine, uric acid, and total triglyceride (TG). Meanwhile, they were more likely to have a lower estimated glomerular filtration rate (eGFR), hemoglobin, and albumin. At the end of follow-up, 126 patients in the AS group and 47 patients in the non-AS group had reached the composite end point (p < 0.001). AS was associated with the renal outcome (log-rank p < 0.001) and was an independent risk factor for the progression of IgAN (p = 0.049). The severity of AS was associated with renal outcomes (log-rank p < 0.001) and there was a trend that it might serve as an independent risk marker for progression of IgAN. In the subgroup analysis, patients presenting with AS and lower eGFR, albumin, and hemoglobin or higher proteinuria, uric acid, and TG had a significant trend for a shorter time to reach the end point (log-rank p < 0.001). Conclusion: AS was commonly seen in patients with IgAN and was independently associated with the poor prognosis.

The Influences of COVID-19 on Patients With Chronic Kidney Disease: A Multicenter Cross-Sectional Study.

Background: The outbreak of coronavirus disease 2019 (COVID-19) has attracted global attention. During the lockdown period of COVID-19, follow-up of many patients with chronic disease had been interrupted, which brought severe challenges to better management of their disease. This study aimed at exploring the change of illness, daily life, and psychological responses during the COVID-19 pandemic among chronic kidney disease (CKD) patients. Methods: A total of 612 patients were enrolled in this study; 282 patients were categorized into the CKD stage 1-2 group and 330 patients were categorized into the CKD stage 3-5 group. Among two groups, 168 (27.5%) and 177 (28.9%) patients were female with a median age of 42 and 45, respectively. The study was conducted by collecting the questionnaires in five nephrology centers. The questionnaire consisted of assessment of anxiety by using the Self-Rating Anxiety Scale and the influences of COVID-19, which included basic demographic data, the influences of COVID-19 on illness and daily life, as well as the patients' psychological responses during the epidemic. Results: A total of 612 patients were included and divided into two groups according to eGFR. Ninety-six patients (34%) in the CKD stage 1-2 group and 141 patients (42.7%) in the CKD stage 3-5 group had reduced their follow-up frequency (p = 0.031). More patients with CKD stages 1-2 consulted online (25.9%), p = 0.005. Besides, patients in the CKD stage 3-5 group tended to be more anxious about follow-up (p = 0.002), fearful of being infected with COVID-19 (p = 0.009), and more likely to feel symptoms getting worse (p = 0.006). The standard scores of SAS were 48.58 ± 7.082 and 51.19 ± 5.944 in the CKD stage 1-2 group and the CKD stage 3-5 group, respectively (p < 0.001). There were significant differences in the severity of anxiety (p = 0.004). Conclusion: COVID-19 had a greater impact on patients with CKD stages 3-5 than those with stages 1-2 in terms of illness, daily life, and psychological disorder. Patients with CKD stages 3-5 were more anxious during the COVID-19 pandemic.

Serum Bilirubin Is Correlated With the Progression of IgA Vasculitis With Nephritis.

Background: Bilirubin has been identified as an endogenous antioxidant and cellular protectant. The present study was performed to clarify the potential influence of serum bilirubin on IgA vasculitis with nephritis (IgAV-N). Methods: One hundred and eighty-nine IgAV-N patients over 14 years old were enrolled. The patients were divided into two groups by the optimum cut-off value calculated by ROC curve. The composite endpoints were defined as a 60% decline in estimate glomerular filtration rate (e-GFR), end-stage renal disease (ESRD) and/or death. Kaplan-Meier (K-M) analysis and multivariate Cox analysis were carried out to determine the predictors for renal outcomes. In order to eliminate the influence of different baseline data, a 1:2 propensity score (PS) match was performed to make the results comparable and convictive. Results: The baseline data suggested that patients in low serum bilirubin group had significantly higher levels of systolic blood pressure, proteinuria, serum creatinine and crescent formation ratio and lower levels of serum albumin and hemoglobin. Renal survival analysis indicated that lower serum bilirubin levels were significantly correlated with a poorer prognosis. Multivariate Cox analysis demonstrated that the higher level of serum bilirubin was an independent protective factor for renal survival (HR, 0.172; 95% CI, 0.030-0.991; P = 0.049). After PS matching, the baseline characters of two groups had no statistical differences. Similar outcomes were demonstrated in K-M curve and the multivariate Cox analysis. Conclusion: Elevated bilirubin levels might be related to the favorable renal outcomes.

Mesangial IgM deposition predicts renal outcome in patients with IgA nephropathy: a multicenter, observational study.

Mesangial IgM deposition is found in patients with immunoglobulin A nephropathy (IgAN). This study aims to investigate the relationships between mesangial IgM deposition and disease progression in IgAN patients. A total of 1239 patients with biopsy-proven primary IgAN were enrolled in this multicenter, observational study between January 2013 and August 2017. According to the degree of IgM deposition, 1239 patients were divided into three groups: Grade 0 (no or trace; n = 713, 57.55%), Grade 1 (mild; n = 414, 33.41%), Grades 2 + 3 (moderate and marked; n = 112, 9.04%). Using a 1:1 propensity score matching (PSM) method identifying age, gender and treatment modality to minimize confounding factors, 1042 matched patients (out of 1239) with different degrees of IgM deposition were enrolled to evaluate the severity of baseline clinicopathological features and renal outcome: Grade 0 (n = 521, 50.00%), Grade 1 (n = 409, 39.25%), Grades 2 + 3 (n = 112, 10.75%). Kaplan-Meier and Cox proportional hazards analyses were performed to determine whether different degrees of mesangial IgM deposition are associated with varying renal outcomes in IgAN. During a mean follow-up of 48.90 ± 23.86 and 49.01 ± 23.73 months, before and after adjusting for propensity scores, respectively, the rate of complete remission (CR) was progressively lower with increased IgM deposition in both unmatched (63.39%, 46.14%, 45.54%) and matched cohort (61.80%, 46.45%, 45.54%), whereas the proportion of patients progressing to end-stage renal disease (ESRD) showed reverse correlation (P < 0.001). Kaplan-Meier analysis indicated negative correlation between the intensity of mesangial IgM deposits and cumulative renal survival (all P < 0.05). Moreover, Cox regression analysis revealed that the degree of mesangial IgM deposition predicted renal outcome independent of MESTC score and clinical variables in the unmatched (Grade 1, HR, 1.59; 95% CI, 1.11-2.29; P = 0.01; Grades 2 + 3, HR, 1.69; 95% CI, 1.02-2.08; P = 0.04) and matched cohort (Grade 1, HR, 1.84; 95% CI, 1.19-2.85; P = 0.01; Grades 2 + 3, HR, 1.91; 95% CI, 1.01-3.24; P = 0.04). Mesangial IgM deposition is associated with histological activity, clinical severity and renal outcome and is an independent risk factor for poor renal prognosis in IgAN. TRIAL REGISTRATION: TCTR, TCTR20140515001. Registered May 15, 2014, http://www.clinicaltrials.in.th/index.php?tp=regtrials&menu=trialsearch&smenu=fulltext&task=search&task2=view1&id=1074 .

A multicenter, prospective, observational study to determine association of mesangial C1q deposition with renal outcomes in IgA nephropathy.

It was reported that histopathologic lesions are risk factors for the progression of IgA Nephropathy (IgAN). The aim of this study was to investigate the relationships between mesangial deposition of C1q and renal outcomes in IgAN. 1071 patients with primary IgAN diagnosed by renal biopsy were enrolled in multiple study centers form January 2013 to January 2017. Patients were divided into two groups: C1q-positive and C1q-negative. Using a 1: 4 propensity score matching (PSM) method identifying age, gender, and treatment modality to minimize confounding factors, 580 matched (out of 926) C1q-negative patients were compared with 145 C1q-positive patients to evaluate severity of baseline clinicopathological features and renal outcome. Kaplan-Meier and Cox proportional hazards analyses were performed to determine whether mesangial C1q deposition is associated with renal outcomes in IgAN. During the follow-up period (41.89 ± 22.85 months), 54 (9.31%) patients in the C1q negative group and 23 (15.86%) patients in C1q positive group reached the endpoint (50% decline of eGFR and/or ESRD or death) respectively (p = 0.01) in the matched cohort. Significantly more patients in C1q negative group achieved complete or partial remission during the follow up period (P = 0.003) both before and after PSM. Three, 5 and 7-year renal survival rates in C1q-positive patients were significantly lower than C1q-negative patients in either unmatched cohort or matched cohort (all p < 0.05). Furthermore, multivariate Cox regression analysis showed that independent risk factors influencing renal survival included Scr, urinary protein, T1-T2 lesion and C1q deposition. Mesangial C1q deposition is a predictor of poor renal survival in IgA nephropathy.Trial registration TCTR, TCTR20140515001. Registered May 15, 2014, http://www.clinicaltrials.in.th/index.php?tp=regtrials&menu=trialsearch&smenu=fulltext&task=search&task2=view1&id=1074 .

Corticosteroids could improve the renal outcome of IgA nephropathy with moderate proteinuria.

BACKGROUND: The specific treatment regimens of IgA nephropathy (IgAN) patients with moderate proteinuria (1.0-3.5 g/day) remain controversial. The purpose of this study was to explore the optimized therapeutic regimen for IgAN patients through analyzing the clinical data. METHODS: A retrospective study was conducted, 449 patients with biopsy-proven IgAN were enrolled. Patients were divided into three groups according to proteinuria levels: urine protein 1.0-1.5 g/day (UP1, n = 111), urine protein 1.5-2.5 g/day (UP2, n = 213), urine protein 2.5-3.5 g/day (UP3, n = 125). Clinical pathological features, treatment regimens and renal outcome were compared. Responses to therapy included complete remission (CR), partial remission (PR), no response (NR) and end-stage renal disease (ESRD). The composite endpoints of renal outcome were defined as 50% decline in eGFR and/or progressing into end-stage renal disease. RESULTS: During the average follow-up of 44.27 months, 71 (63.9%), 150 (70.4%) and 68 (54.4%) patients achieved CR + PR among three groups, respectively. Whereas 15 (13.5%), 28 (13.1%) and 39 (31.2%) patients progressed to the primary endpoint (P < 0.001). Patients who received corticosteroids (CS) treatment had better remission rate than those with supportive care (SC) or combined corticosteroid plus immunosuppressant (CS + IT) therapy (P < 0.05). Kaplan-Meier survival analysis revealed that patients received CS and CS + IT treatments had better renal prognosis compared with SC therapy in UP2 and UP3 groups (P < 0.05). However, no statistical difference was found among three treatment regimens in UP1 group (P = 0.358). CONCLUSION: Corticosteroids therapy might better improve renal prognosis compared with supportive care alone or corticosteroids plus immunosuppressant in IgAN patients with moderate proteinuria (1.5-3.5 g/day).

Corticosteroids Improve Renal Survival: A Retrospective Analysis From Chinese Patients With Early-Stage IgA Nephropathy.

Background: The efficacy and safety of corticosteroids and immunosuppressive therapy remain controversial for the treatment of immunoglobulin A nephropathy (IgAN). This study aimed to evaluate the effects of corticosteroid and immunosuppressant therapy in Chinese patients with early-stage IgAN whose estimated glomerular filtration rate (eGFR) was ≥45 ml/min/1.73 m2 and proteinuria was ≥1 g/24 h at biopsy. Methods: Patients with biopsy-proven IgAN were retrospectively enrolled from four study centers between 2007 and 2016. Patients were regularly followed up for at least 1 year or until the study end point. Patients were categorized into three treatment groups: supportive care (SC), steroids alone (CS), and steroids plus immunosuppressants (IT). The observed responses to therapy included complete remission (CR), partial remission (PR), no response (NR), and end-stage renal disease (ESRD). The primary end point of the current study was defined as a 50% decline in eGFR and/or ESRD. Results: A total of 715 patients (male 47% and female 53%) were recruited and followed up for 44.69 ± 24.13 months. The observed CR rate was 81.8% with corticosteroids alone (CS), 62.7% with corticosteroids + immunosuppresants (IT), and 37% with supportive care alone (SC). Renal outcomes were remarkably better in the CS group compared with the SC and IT groups (the percentage of patients reaching the end point in each group was 4.6 vs. 14.4 vs. 11.5%, respectively; p = 0.001). Moreover, 36 and 80-month renal survival were significantly better for the CS group (98.3 and 86.4%) than for the IT (94.2 and 82.4%) and SC (94.0 and 51.6%) groups. Early CKD stage also presented with better kidney survival (p < 0.001). Renal survival of CKD stage 1 patients was relatively good regardless of the specific treatment regimen. CS and IT treatment significantly improved renal survival for CKD stage 2 patients when compared with the SC group (p < 0.001 and 0.007, respectively). However, renal survival of CKD stage 3a patients was not impacted by any of the three treatment regimens. Subgroup analysis also showed that renal survival of patients with proteinuria >3.5 g, M1, E0, S1, T0, and C0 was significantly better in the CS group than in the SC and IT groups. A multivariate model showed that hypertension, serum creatinine, E1 lesion, and T1/T2 lesion remained independent predictors of poor renal survival. Conclusions: Immunosuppressive therapy does not have further benefit beyond that provided by steroids. Corticosteroids plus optimal supportive care may further be beneficial in treating early-stage IgAN patients in that it could significantly improve the short-term renal outcome.

Global Glomerulosclerosis and Segmental Glomerulosclerosis Could Serve as Effective Markers for Prognosis and Treatment of IgA Vasculitis With Nephritis.

Background: This study was aimed at investigating the clinical significance and curative effect of global glomerulosclerosis (GS) and segmental glomerulosclerosis (S) in adult-onset IgA vasculitis with nephritis (IgAV-N) patients since there was no consensus pathological grading method for adult IgAV-N. Methods: A total of 188 biopsy-proven IgAV-N patients were prospectively identified. Patients were separately assigned to GS0/GS1/GS2 group and S0/S1/S2 based on the scores of global glomerulosclerosis and segmental glomerulosclerosis (0% /0-15% />15%, respectively). Results: GS0, GS1, and GS2 occurred in 56.4, 29.2, and 14.4% of the adult-onset IgAV-N, respectively. Patients in GS2 group tended to have the most serious renal deterioration and the highest levels of blood pressure. IgAV-N patients were also divided into S0 group (64.4%), S1 group (20.7%), and S2 group (14.9%), where no obvious differences in baseline data were noted. K-M curves indicated that GS2 group had the worst renal outcome (P = 0.05) while there seemed to be no significant differences between GS0 group and GS1 group. In addition, no remarkable differences in primary outcome were found among S0 group, S1 group, and S2 group though the prognosis of S2 group tended to be the worst. However, the prognosis of S0/S1 group was markedly better than that of S2 (P = 0.04). The discrimination of poor prognosis could be improved by adding the pathological indicators of global glomerulosclerosis and segmental glomerulosclerosis. Most importantly, immunosuppressive treatment might be a superior alternative in IgAV-N patients without sclerosis scores or with lower level of sclerosis scores. But addition of immunosuppression was not recommended in patients with higher sclerosis scores. Conclusions: Global glomerulosclerosis and segmental sclerosis might be used for management and treatment of adult-onset IgAV-N.

Modifications of gut microbiota are associated with the severity of IgA nephropathy in the Chinese population.

Immunoglobulin A nephropathy (IgAN) is a common glomerular disease. The pathogenesis of IgAN is associated with dysregulated intestinal mucosal immunity. However, whether gut microbial modifications play a role in IgAN remains unclear. Blood and faecal samples were collected from 52 patients with IgAN and 25 healthy controls (HCs). The gut microbiome was analysed using the 16S ribosomal RNA gene. The levels of galactose-deficient IgA1 (Gd-IgA1), soluble cluster of differentiation 14 (sCD14), lipopolysaccharide binding protein (LBP), intercellular adhesion molecule-1 (ICAM-1), tumour necrosis factor α (TNF-α), interleukin-1, and C-reactive protein were quantified. Substantial differences in the gut microbiota were identified between patients with IgAN and HCs (P < 0.05). Bacteroides and Escherichia-Shigella levels were significantly higher in patients with IgAN than in HCs, while Bifidobacterium and Blautia spp. Levels were lower. Higher proportions of Escherichia-Shigella and lower proportions of Bifidobacterium spp. were observed in patients with IgAN with high urine RBC count (≥10/HP) and proteinuria (≥1 g/24 h) levels. Correlation analysis was used to assess the association between gut microbiota and biomarkers in patients with IgAN. The results showed that Prevotella 7 levels were negatively correlated with Gd-IgA1, LBP, sCD14, ICAM-1, and TNF-α levels, while Bifidobacterium spp. Levels presented a significant inverse relationship with LBP and Gd-IgA1. Additionally, Escherichia-Shigella levels were negatively correlated with Prevotella 7. In patients with IgAN, gut modifications were characterised by an increase in the number of pathogenic bacteria and a reduction in the levels of beneficial bacteria, suggesting that the disturbance of intestinal microflora might be important in the severity of IgAN.

Goodpasture syndrome manifesting as nephrotic-range proteinuria with anti-glomerular basement membrane antibody seronegativity: A case report.

RATIONALE: The Goodpasture syndrome is an extremely rare disease, with renal and pulmonary manifestations, and is mediated by anti-glomerular basement membrane (anti-GBM) antibodies. Renal pathological changes are mainly characterized by glomerular crescent formation and linear immunofluorescent staining for immunoglobulin G on the GBM. There are few reports on the atypical course of the syndrome involving serum-negative anti-GBM antibodies. Therefore, we present a case of Goodpasture syndrome that presented with nephrotic-range proteinuria and was seronegative for anti-GBM antibodies. PATIENT CONCERNS: A 38-year-old Chinese man presented with a lung lesion that was discovered by physical examination a month prior to presentation. The chief concern was occasional hemoptysis without fever, cough, chest pain, and edema. DIAGNOSES: Laboratory testing revealed that the urinary protein level and urine erythrocyte count were 7.4 g/24 hours and 144/high-power field (HPF), respectively. Serological testing for anti-GBM antibodies was negative. Chest computed tomography revealed multiple exudative lesions in both lungs, indicating alveolar infiltration and hemorrhage. Electronic bronchoscopy and pathological examination of the alveolar lavage fluid indicated no abnormalities. However, kidney biopsy suggested cellular crescent formation and segmental necrosis of the globuli, with linear IgG and complement C3 deposition on the GBM. These findings were consistent with the diagnosis of anti-GBM antibody nephritis. INTERVENTIONS: The patient underwent 7 sessions of double filtration plasmapheresis. He was also administered with intravenous methylprednisolone and cyclophosphamide. After renal function stabilization, he was discharged under an immunosuppressive regimen comprising of glucocorticoids and cyclophosphamides. OUTCOMES: Three months later, follow-up examination revealed that the 24-hour urine protein had increased to 13 g. Furthermore, the urine erythrocyte count was 243/HPF. After a 6-month follow-up, the patient achieved partial remission, with a proteinuria level of 3.9 g/24 hours and a urine erythrocyte count of 187/HPF. LESSONS: This extremely rare case of Goodpasture syndrome manifested with seronegativity for anti-GBM antibodies and nephrotic-range proteinuria. Our findings emphasize the importance of renal biopsy for the clinical diagnosis of atypical cases. Furthermore, because renal involvement achieved only partial remission despite therapy, early detection and active treatment of the Goodpasture syndrome is necessary to improve the prognosis of patients.

Corticosteroids or immunosuppressants were not superior to supportive care in IgA nephropathy patients with mild proteinuria.

BACKGROUND: We aimed to evaluate the effect of immunosuppressant therapy for immunoglobulin A nephropathy (IgAN) patients with mild proteinuria (<1 g/d). METHODS: We recruited patients with biopsy-proven IgAN from 4 study centers. Patients were followed for more than 1 year or up to the study end point. Clinical indexes, renal pathological data, and treatment information were collected during the follow-up period. IgAN patients with mild proteinuria (<1 g/d at biopsy) were included. Patients were divided into a supportive care group (SC) and an immunosuppressant group (IT). Patients in the SC group received the optimal dose of renin angiotensin system inhibitors (RASi). Patients in the IT group received corticosteroids or immunosuppressant therapy plus RASi. Responses to therapy included complete remission (CR), partial remission (PR), no response (NR), and end stage renal disease (ESRD). A 50% decline in estimated glomerular filtration rate (eGFR) and/or ESRD was the primary end point of this study. RESULTS: 295 patients (36.3% male and 63.7% female) were included in this study and were followed for 49.46 ±â€Š24.35 months. We found a significant difference in estimated glomerular filtration rate, urine protein, mesangial hypercellularity, segmental glomerulosclerosis, cellular or fibrocellular crescents, and glomerulosclerosis between the 2 treatment groups at baseline. At the final follow-up, 224 patients (75.9%) achieved CR, 7 patients (2.4%) achieved PR, 55 patients (18.6%) had NR, and 9 patients (3.1%) reached ESRD. However, no significant differences were observed between the SC and IT groups with respect to CR (76.4% vs 73.5%, P = .659), PR (2.0% vs 4.1%, P = .329), NR (18.3% vs 20.4%, P = .728), and ESRD (3.3% vs 2.0%, P = 1.000). Kidney survival rates were also comparable between the SC and IT groups (93.7% vs 94.1%, P = .808). We observed similar results after subgroup analysis according to chronic kidney disease stages or pathological manifestations. A multivariate model showed that segmental sclerosis (HR 9.55, 95% CI 1.04-88.16, P = .047) and glomerulosclerosis (HR 21.09, 95% CI 1.39-320.53, P = .028) were independent predictors of poor renal survival. CONCLUSIONS: Corticosteroids or immunosuppressants were not superior to supportive care in IgA nephropathy patients with mild proteinuria.

The efficacy and safety of immunosuppressive therapies in the treatment of IgA nephropathy: A network meta-analysis.

Immunoglobulin A nephropathy (IgAN) is a common autoimmune glomerulonephritis that can result in end-stage renal disease (ESRD). Whether immunosuppressants are superior or equivalent to supportive care is still controversial. A network meta-analysis was conducted to compare the efficacy and safety of immunosuppressive treatment for IgAN. Medline, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, and EMBASE were searched on December 30, 2018. We used a random-effects model with a Bayesian approach to appraise both renal outcomes and serious adverse effects. Relative risks (RRs) with 95% confidence intervals (CIs) were calculated to present the relative effects. The ranking probabilities were calculated by the surface under the cumulative ranking curve (SUCRA). In total, 24 RCTs comprising 6 interventions were analyzed. Steroids significantly delayed the progression of renal deterioration with acceptable serious adverse effects, compared with supportive care (RR = 0.28, 95% CI = 0.13-0.51, SUCRA = 48.7%). AZA combined with steroids might be an alternative immunosuppressive therapy. Tacrolimus might decrease the proteinuria level (RR = 3.1, 95% CI = 1.2-9.4, SUCRA = 66.5%) but cannot improve renal function, and the side effects of tacrolimus should not be neglected. MMF and CYC showed no superiority in the treatment of IgAN. In summary, steroids might be recommended as the first-line immunosuppressive therapy for IgAN.

The Clinicopathological Characteristics of Henoch-Schönlein Purpura Nephritis with Presentation of Nephrotic Syndrome.

BACKGROUND: Henoch-Schönlein purpura nephritis (HSPN) is a common vasculitis involving the kidneys, with a lower incidence in adults. Meanwhile, nephrotic syndrome (NS) can appear in HSPN. However, the clinicopathological features and renal outcome of adult-onset HSPN presenting with NS (NS-HSPN) have not been well clarified. METHODS: A total of 191 HSPN patients were prospectively analyzed and comparisons were made between NS-HSPN and non-NS-HSPN. Multivariate Cox regression analysis was carried out to find the unfavorable factors of renal outcome of NS-HSPN. RESULTS: Among the 191 patients, 44 (23.0%) had NS-HSPN. Apart from edema and abdominal pain, patients with NS-HSPN tended to have lower levels of erythrocytes and hemoglobulin in blood as well as a greater number of erythrocytes in urine (p < 0.05). Mesangial proliferation was the most common pathological lesion in HSPN and the rates of crescent formation were significantly different, with 54.5% in NS-HSPN and 33.3% in non-NS-HSPN (p < 0.05). Notably, 18.2 and 4.8% of patients reached the composite endpoints in the NS-HSPN and non-NS-HSPN groups, respectively (p < 0.05), demonstrating that NS-HSPN patients were more likely to progress to end-stage renal disease and had a worse outcome. We also found that hypertension, estimated glomerular filtration rate (eGFR), cystatin, and tubular atrophy/interstitial fibrosis (HR > 1, p < 0.05) at onset were correlated with adverse outcome in NS-HSPN. CONCLUSION: NS-HSPN had more severe clinicopathological manifestations and poorer prognosis. The adverse predictors of NS-HSPN principally depend on clinicopathological presentation rather than on different therapies, and hypertension, eGFR, cystatin, and tubular atrophy/interstitial fibrosis can serve as independent risk factors in NS-HSPN.

Crescent lesions are not a predictive factor in adult-onset Henoch-Schönlein purpura nephritis.

Henoch-Schönlein purpura nephritis (HSPN) is a common secondary glomerulonephritis, and its prognosis mainly depends on the severity of renal impairment. To date, the significance of crescent lesions in adult-onset HSPN is still unclear. Therefore, the purpose of this research was to assess whether crescents could predict the renal outcomes in adult HSPN patients. A total of 188 adult patients with HSPN proven by renal biopsy were enrolled in this prospective study. Patients were divided into three groups based on the proportion of crescents: non-crescent group (C0, n = 110), crescent ≤ 25% group (C1, n = 50) and crescent > 25% group (C2, n = 28). The composited endpoint was defined as eGFR decreased > 50% of baseline level, reached end-stage renal disease and/or death. Among three groups, clinical pathological features, treatment regimens and renal outcomes were compared. During a mean follow-up of 26 months, 78 (42.5%) patients had crescent lesions. A total of ten (9.1%) patients in C0 group and five (17.9%) patients in C2 group reached the combined endpoint, but no patients in C1 group reached endpoint. Renal survival analysis indicated patients in C1 group tended to have the best renal outcome, while patients in C2 group had the poorest renal survival. Moreover, Cox regression analysis revealed crescents were not a predictor of poor developing to renal outcome after adjusting potential confounders [hazard ratio (HR) = 0.28, 95% confidence interval (CI) 0.07-1.18, P = 0.083]. Crescent formation is not necessarily a predictive factor of poor renal survival in adult HSPN patients who had small proportions of crescents (crescent ≤ 25%).

The efficacy and safety of immunosuppressive agents plus steroids compared with steroids alone in the treatment of Henoch-Schönlein purpura nephritis: A meta-analysis.

BACKGROUND: Henoch-Schönlein purpura nephritis (HSPN) is the most severe symptom of Henoch-Schönlein purpura. The role of immunosuppressive agents combined with steroids is controversial in treating HSPN. Our meta-analysis was performed to assess the efficacy and safety of the combined therapy in the treatment of HSPN compared with steroids alone. METHODS: Cochrane Library, Pubmed, Embase, and Web of Science were searched and Newcastle-Ottawa Scale was used to assess the quality of the literatures. Odds ratios (OR) and standard mean difference (SMD) with a 95% confidence interval (CI) were used for dichotomous and continuous variables. A random-effect model or fixed-effect analysis was applied according to heterogeneity. RESULTS: A total of 9 articles were selected in our study. HSPN patients treated with combined therapy demonstrated a significant increase in complete remission rates (OR = 1.95; 95% CI 1.17-3.23, P = 0.010) and total remission rates (OR = 2.30 95% CI 1.33-3.98, P = 0.003) when compared with steroids alone. Children seemed to benefit more from combined treatment (OR = 2.45; CI 1.20-5.02, P = 0.014) than adults (OR = 1.56; CI 0.76-3.20, P = 0.225). Additionally, immunosuppressants plus steroids had an advantage on decreasing proteinuria (SMD = 0.28; CI 0.05-0.52, P = 0.019) and increasing the level of serum albumin (SMD = 0.98; CI 0.35-1.60, P = 0.002). However, significant differences were not found in the estimated glomerular filtration rate (eGFR) and rates of side-effects. CONCLUSION: Administration of immunosuppressive agents combined with steroids may be a superior alternative for HSPN. Nevertheless, long-term, high-quality, large-sample, and multicenter RCTs are required to make the results more convincing.