Severe glomerular C3 deposition indicates severe renal lesions and a poor prognosis in patients with immunoglobulin A nephropathy.

AIMS: Glomerular complement 3 (C3) deposition is often observed in renal biopsies of patients with IgA nephropathy (IgAN); however, the relationship between the intensity of C3 deposition and the long-term prognosis of IgAN has rarely been reported. In this retrospective study, we aimed to evaluate the prognostic value of glomerular C3 deposition for IgAN progression. METHODS AND RESULTS: From June 2009 to June 2010, a total of 136 adult patients with IgAN were enrolled in the study. According to the intensity of glomerular C3 deposition, patients were divided into a glomerular C3high group (34 patients) and a glomerular C3low group (102 patients). The levels of clinical parameters, glomerular immune complexes, histopathological features, and serum cytokines of the two groups were compared. On the basis of an average of 105 months of follow-up, the predictive value of glomerular C3 deposition for IgAN progression was also investigated. Patients in the C3high group had more severe glomerular IgA, IgG, IgM, and complement factor H deposition, a higher percentage of mesangial hypercellularity (M1), and higher levels of segmental glomerulosclerosis (S1), tubular atrophy/interstitial fibrosis (T2), and crescents (C2) than those in the C3low group. Renal biopsies in the C3high group showed higher densities of interstitial inflammatory cells and higher levels of serum interferon-γ than those in the C3low group. Multivariate Cox regression analysis revealed that a higher intensity of glomerular C3 deposition remained as an independent predictor of serum creatinine doubling and end-stage renal disease. CONCLUSIONS: A high intensity of glomerular C3 deposition is associated with the severity of renal lesions, and predicts long-term poor renal survival for IgAN patients.

Lower serum bilirubin is associated with poor renal outcome in IgA nephropathy patients.

Aims: IgA nephropathy (IgAN) is the most prevalent primary glomerulonephritis worldwide. We conducted this study to explore the relationship between serum bilirubin and renal outcome of patients with IgAN. Methods: A total of 1492 biopsy proven IgAN patients were recruited and divided into two groups according to their median serum bilirubin concentration: the low bilirubin group (serum bilirubin≤9.7umol/L, n=753) and high bilirubin group (serum bilirubin>9.7umol/L, n=739). Basic clinical characteristics were assessed at the time of renal biopsy and the relationships between serum bilirubin and the combined endpoints were analyzed. The combined endpoints were defined as a 50% decline in estimate glomerular filtration rate (e-GFR), end-stage kidney disease (ESKD), renal transplantation and/or death. In addition, propensity score matching (PSM) was then performed to improve balance and simulate randomization between patients in different groups. Kaplan-Meier survival analysis was applied to explore the role of serum bilirubin in the progression of IgAN. Three clinicopathological models of multivariate Cox regression analysis were established to evaluate the association of serum bilirubin and renal prognosis of IgAN. Results: During median 5-year follow-up period, significant differences were shown in Kaplan-Meier analysis. In the unmatched group, 189 (12.7%) patients progressed to the renal combined endpoints. Among this, 122 in 753 patients (16.2%) were in low bilirubin group and 67 in 739 patients (9.1%) were in high bilirubin group (p<0.001). After PSM, there were 134 (11.8%) patients reached the combined endpoints, which included 77 in 566 patients (14.6%) in low bilirubin group and 57 in 566 patients (10.1%) in high bilirubin group (p=0.039). The results of three models (including demographics, pathological, clinical indicators and serum bilirubin) demonstrated that a lower basic serum bilirubin level was significantly associated with a higher risk of reaching combined endpoints in IgAN patients both in unmatched and matched cohort. Conclusion: Serum bilirubin level may be negatively associated with the progression of IgAN.

The prognostic role of heart rate recovery after exercise and metabolic syndrome in IgA nephropathy.

BACKGROUND: Cardiovascular (CV) morbidity and mortality are higher in chronic kidney disease (CKD) than in the general population. Reduced heart rate recovery (HRR) is an independent risk factor for CV disease. The aim of the study was to determine the prognostic role of HRR in a homogenous group of CKD patients. METHODS: One hundred and twenty-five IgA nephropathy patients (82 male, 43 female, age 54.7 ± 13 years) with CKD stage 1-4 were investigated and followed for average 70 months. We performed a graded exercise treadmill stress test. HRR was derived from the difference of the peak heart rate and the heart rate at 1 min after exercise. Patients were divided into two groups by the mean HRR value (22.9 beats/min). The composite (CV and renal) endpoints included all-cause mortality and any CV event such as stroke, myocardial infarction, revascularisation (CV) and end-stage renal disease, renal replacement therapy (renal). RESULTS: Patients with reduced HRR (< 23 bpm) had significantly more end point events (22/62 patients vs. 9/53 patients, p = 0.013) compared to the higher HRR (≥23 bpm). Of the secondary the endpoints (CV or renal separately) rate of the renal endpoint was significantly higher in the lower HRR group (p = 0.029), while there was no significant difference in the CV endpoint between the two HRR groups (p = 0.285). Independent predictors of survival were eGFR and diabetes mellitus by using Cox regression analysis. Kaplan-Meier curves showed significant differences in metabolic syndrome and non-metabolic syndrome when examined at the combined endpoints (cardiovascular and renal) or at each endpoint separately. The primary endpoint rate was increased significantly with the increased number of metabolic syndrome component (Met.sy. comp. 0 vs. Met. sy. comp. 2+, primary endpoints, p = 0.012). CONCLUSION: Our results showed that reduced HRR measured by treadmill exercise test has a predictive value for the prognosis of IgA nephropathy. The presence of metabolic syndrome may worsen the prognosis of IgA nephropathy.

Relationship between blood neutrophil-lymphocyte ratio and renal tubular atrophy/interstitial fibrosis in IgA nephropathy patients.

BACKGROUND: The study aimed to explore the relationship between neutrophil-lymphocyte ratio(NLR) in peripheral blood and renal tubular atrophy/interstitial fibrosis and to evaluate the clinical significance of NLR in IgA nephropathy (IgAN) patients. METHODS: A Total of 263 IgAN patients were included. The participants were categorized into four groups based on quartile of NLR. The clinical data, pathological features, and 2-year renal survival rates were compared among the four groups. The independent factors affecting renal tubular atrophy/interstitial fibrosis in IgAN were determined by multivariate linear regression analysis. RESULTS: The percentage of renal tubular atrophy/interstitial fibrosis increased with the increase of NLR level (p=0.003). The tubular atrophy/interstitial fibrosis score T1 and T2 in Group Q4 was 40%, which was higher than that of other groups, especially Group Q1 (22.73%, p=0.033) and Group Q3 (22.39%, p=0.029). NLR [ß=1.230, 95%CI (0.081, 2.379), p=0.036] might be an independent factor affecting renal tubular atrophy/interstitial fibrosis in IgAN. The area under curve predicted by NLR was 0.596 (95%CI 0.534~0.656, p=0.007) with the specificity 88.24% and the optimal critical value of NLR 3.25. Fourteen patients progressed to end-stage renal disease within 2 years, and the 2-year survival rate of kidney was 93.49%. The renal survival rate in Group Q4 was 87.04%, lower than that in other three groups, especially Group Q1 (98.11%, p=0.029). CONCLUSION: NLR was correlated with the level of renal tubular atrophy/interstitial fibrosis and might be a significant factor for predicting the prognosis in the IgAN. BACKGROUND: IgA nephropathy (IgAN) is an important cause of the end stage renal disease (ESRD). The study aimed to explore the relationship between neutrophil-lymphocyte ratio (NLR) in peripheral blood and renal tubular atrophy/interstitial fibrosis, and to evaluate the clinical significance of NLR in IgA nephropathy (IgAN) patients. METHODS: Total 263 IgAN patients confirmed by renal biopsy pathology were included from January 2013 to May 2018 in Ningbo Hwamei Hospital, University of Chinese Academy of Sciences. The peripheral blood samples were taken from these participants and the NLR was analyzed. The participants were categorized into four groups based on the median and upper and lower quartile of NLR, which were Group Q1 (NLR<1.64), Group Q2 (1.64≤NLR<2.19), Group Q3 (2.19≤NLR<3.00), and Group Q4 (NLR≥3.00), respectively. The clinical data and pathological features were compared among four groups. The independent factors affecting renal tubular atrophy/interstitial fibrosis in IgAN were determined by multivariate linear regression analysis. The diagnostic ability of NLR for renal tubular atrophy/interstitial fibrosis was evaluated by the area under receiver operating characteristic curve (AUC). The 2-year renal survival rates were compared among the four groups. RESULTS: The levels of white blood cell count, neutrophil count, highly sensitive C-reactive protein, and the percentage of renal tubular atrophy/interstitial fibrosis were increased while lymphocyte count and estimated glomerular filtration rate were decreased with the increase of NLR level (P < 0.05). The percentage of tubular atrophy/interstitial fibrosis 26%-50% (T1) and >50% (T2) in Group Q4 was 40%, which was higher than that of other groups, especially Group Q1 (22.73%) and Group Q3 (22.39%), with significant difference (P < 0.05). NLR [ß = 1.230, 95%CI (0.081, 2.379), P = 0.036] might be an independent factor affecting renal tubular atrophy/interstitial fibrosis in IgAN according to multivariate linear regression analysis results. The AUC predicted by NLR was 0.596 (95%CI 0.534~0.656, P = 0.007) with the specificity 88.24%, the sensitivity 30.00% and the optimal critical value of NLR 3.25. Fourteen patients progressed to end-stage renal disease within 2 years; and the 2-year survival rate of kidney was 93.49%. The renal survival rate in Group Q4 was 87.04%, lower than that in other three groups, especially Group Q1 (98.11%), with significant difference (P < 0.05). CONCLUSION: NLR was correlated with the level of renal tubular atrophy/interstitial fibrosis and might be an significant factor for predicting the prognosis in IgAN.

Increased serum uric acid levels are associated to renal arteriolopathy and predict poor outcome in IgA nephropathy.

BACKGROUND AND AIMS: IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide and a leading cause of end stage renal disease (ESRD). In addition to classical progression factors, other atherosclerosis-related factors, including hyperuricemia (HU), have been associated to the renal progression of IgAN. Increased serum uric acid (SUA) levels are well known to be concomitant of cardiovascular and kidney diseases, and have been proposed to be implicated in the development of arteriolar damage (AD). The aim of the present study was to explore the correlation between SUA levels, renal damage and its implication for outcome in IgAN patients. METHODS AND RESULTS: Clinical, laboratory and histologic data of 145 patients with biopsy proven IgAN were collected and retrospectively analyzed to determine the correlation between SUA levels, renal damage and the primary outcome (death or ESRD). Biopsy-proven AD was defined by the presence of arteriolar hyalinosis and/or intimal thickening. HU, defined as the highest SUA gender-specific tertile, was >7.7 mg/dl for males and >6.2 mg/dl for females. The prevalence of AD increased with the increase in the SUA level tertiles (p = 0.02). At logistic regression analysis SUA was independently related to the presence of AD (OR 1.75 [95%CI 1.10-2.93], p = 0.03). HU and AD had a synergic impact on progression of IgAN. Patients having both AD and HU, showed a reduced survival free from the primary outcome as compared to those having only one risk factor or neither (p = 0.01). CONCLUSIONS: SUA levels are independently associated with AD and poor prognosis in patients with IgAN.

Efficacy of corticosteroids in immunoglobulin A nephropathy with less than 25% crescents.

BACKGROUND: Crescent formation in immunoglobulin A nephropathy (IgAN) has been demonstrated to be a risk factor for worse outcomes. For IgAN patients with 0-25% crescentic glomeruli (C1), whether corticosteroids (CS) can improve the prognosis remains unclear. We tried to investigate the need for using CS in IgAN patients with C1 in different proteinuria levels. METHODS: A total of 120 eligible IgAN patients with C1 from two academic medical centers were retrospectively studied, and 57 (47.5%) received CS. Patients were grouped according to with or without CS. The outcomes were the rate of estimated glomerular filtration rate (eGFR) decline (ml/min per 1.73 m2/year) and a composite outcome (50% decrease in eGFR, end stage renal disease (ESRD) or death due to kidney disease). The progression of adverse outcome among them were analyzed in Kaplan-Meier curve. The independent significance of CS on renal outcome or eGFR decline rate were analyzed by multivariable Cox regression or linear regression. RESULTS: Unadjusted Kaplan-Meier showed that the outcome of treated patients was better than that of the untreated patients. Multiple Cox regression and linear regression analysis found that CS independently protected the renal outcome and decreased the eGFR decline rate. In the subgroup analysis, multivariate linear regression showed that CS decreased the eGFR decline rate both in proteinuria ≥ 1 g/day and < 1 g/day. CONCLUSIONS: CS protected the renal outcome and slowed the eGFR decline rate of IgAN patients with C1, it also decreased the eGFR decline rate even in those with initial proteinuria < 1 g/day.

Clinical, pathological characteristics and outcomes of immunoglobulin A nephropathy patients with different ages.

AIM: To determine the clinical and pathological differences in immunoglobulin A (IgA) nephropathy (IgAN) with different ages, and to determine whether age is a risk factor for progression of IgAN. METHODS: This was a single centre retrospective cohort study. Patients with biopsy-diagnosed primary IgAN were stratified into three groups: young-aged (14-29 years), middle-aged (30-49 years) and older-age (≥50 years). The primary outcome was end-stage renal disease (estimated glomerular filtration rate [eGFR] <15 mL/min/1.73 m2 , dialysis or renal transplantation) or doubling of the baseline serum creatinine. RESULTS: A total of 981 patients were enrolled, including 65 (6.6%) patients in older-age group, 517 (52.7%) in middle-aged group and 399 (40.7%) in young-aged group. The older-age group had significantly higher levels of serum IgA, cholesterol, triglycerides and creatinine, and a reduced eGFR. In contrast to the young adults who had a higher percentage of crescent formation in glomeruli, the older-aged patients had more severe chronic pathological changes including global glomerulosclerosis and vascular lesions (p < .01). The cumulative renal survival in the older-age group was slightly shorter than that in the young adult or middle-aged group, but not achieving significant (p > .05). The 3- and 5-year renal survival rates were similar among the three groups. A multivariate Cox regression analysis showed that age was not an independent predictor of an unfavourable prognosis. CONCLUSION: The IgAN patients with aged 50 years or older had different clinical pathological changes as compared with younger patients. However, aging was not found as an independently predictor of renal progression of IgAN. Prolonged follow up is necessary to confirm this trend.

Mortality in IgA Nephropathy: A Nationwide Population-Based Cohort Study.

BACKGROUND: The clinical course of IgA nephropathy (IgAN) varies from asymptomatic nonprogressive to aggressive disease, with up to one in four patients manifesting ESRD within 20 years of diagnosis. Although some studies have suggested that mortality appears to be increased in IgAN, such studies lacked matched controls and did not report absolute risk. METHODS: We conducted a population-based cohort study in Sweden, involving patients with biopsy-verified IgAN diagnosed in 1974-2011; main outcome measures were death and ESRD. Using data from three national registers, we linked 3622 patients with IgAN with 18,041 matched controls; we also conducted a sibling analysis using 2773 patients with IgAN with 6210 siblings and a spousal analysis that included 2234 pairs. RESULTS: During a median follow-up of 13.6 years, 577 (1.1%) patients with IgAN died (10.67 per 1000 person-years) compared with 2066 deaths (0.7%) in the reference population during a median follow-up of 14.1 years (7.45 per 1000 person-years). This corresponded to a 1.53-fold increased risk and an absolute excess mortality of 3.23 per 1000 person-years (equaling one extra death per 310 person-years) and a 6-year reduction in median life expectancy. Similar increases in risk were seen in comparisons with siblings and spouses. IgAN was associated with one extra case of ESRD per 54 person-years. Mortality preceding ESRD was not significantly increased compared with controls, spouses, or siblings. Overall mortality did not differ significantly between patients with IgAN-associated ESRD and patients with ESRD from other causes. CONCLUSIONS: Patients with IgAN have an increased mortality compared with matched controls, with one extra death per 310 person-years and a 6-year reduction in life expectancy.

Glomerular crescents are associated with worse graft outcome in allograft IgA nephropathy.

The prognosis of patients with allograft IgA nephropathy (IgAN) requires further investigation. We performed a bicenter retrospective cohort study on kidney transplant recipients diagnosed with IgAN in allograft biopsy. Recipients without allograft IgAN but with known IgAN before transplantation were included as the control group. We investigated the associations between clinicopathological characteristics, including allograft crescents, and the risk of death-censored graft failure. In total, 1256 IgAN patients in both pre- and posttransplant stages were included. Among them, 559 were diagnosed with allograft IgAN, which was a time-dependent risk factor for worse prognosis (adjusted hazard ratio = 5.009 [3.610-6.951]; P < .001) during a median of 8.1 years of follow-up. Of the patients with allograft IgAN, 88 (15.9%) had glomerular crescents, including 40 patients (7.2%) with >10% crescent formation in the total biopsied glomeruli. The presence of glomerular crescents in IgAN was associated with a worse graft prognosis, and the association was still valid with the C scores of the current Oxford classification. In conclusion, allograft IgAN is a time-dependent event and is associated with worse graft outcomes. The pathological characteristics of allograft, particularly the degree of glomerular crescent formation, may represent important risk factors for a poor prognosis.

CureGN Study Rationale, Design, and Methods: Establishing a Large Prospective Observational Study of Glomerular Disease.

RATIONALE & OBJECTIVES: Glomerular diseases, including minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and immunoglobulin A (IgA) nephropathy, share clinical presentations, yet result from multiple biological mechanisms. Challenges to identifying underlying mechanisms, biomarkers, and new therapies include the rarity of each diagnosis and slow progression, often requiring decades to measure the effectiveness of interventions to prevent end-stage kidney disease (ESKD) or death. STUDY DESIGN: Multicenter prospective cohort study. SETTING & PARTICIPANTS: Cure Glomerulonephropathy (CureGN) will enroll 2,400 children and adults with minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy (including IgA vasculitis) and a first diagnostic kidney biopsy within 5 years. Patients with ESKD and those with secondary causes of glomerular disease are excluded. EXPOSURES: Clinical data, including medical history, medications, family history, and patient-reported outcomes, are obtained, along with a digital archive of kidney biopsy images and blood and urine specimens at study visits aligned with clinical care 1 to 4 times per year. OUTCOMES: Patients are followed up for changes in estimated glomerular filtration rate, disease activity, ESKD, and death and for nonrenal complications of disease and treatment, including infection, malignancy, cardiovascular, and thromboembolic events. ANALYTICAL APPROACH: The study design supports multiple longitudinal analyses leveraging the diverse data domains of CureGN and its ancillary program. At 2,400 patients and an average of 2 years' initial follow-up, CureGN has 80% power to detect an HR of 1.4 to 1.9 for proteinuria remission and a mean difference of 2.1 to 3.0mL/min/1.73m2 in estimated glomerular filtration rate per year. LIMITATIONS: Current follow-up can only detect large differences in ESKD and death outcomes. CONCLUSIONS: Study infrastructure will support a broad range of scientific approaches to identify mechanistically distinct subgroups, identify accurate biomarkers of disease activity and progression, delineate disease-specific treatment targets, and inform future therapeutic trials. CureGN is expected to be among the largest prospective studies of children and adults with glomerular disease, with a broad goal to lessen disease burden and improve outcomes.

High renal DC-SIGN+ cell density is associated with severe renal lesions and poor prognosis in patients with immunoglobulin A nephropathy.

BACKGROUND AND AIMS: In this observational cohort study, we assessed the prognostic value of DC-SIGN+ cells in the pathogenesis and progression of IgA nephropathy (IgAN). METHODS AND RESULTS: A total of 139 adult IgAN patients were enrolled into this study from June 2009 to June 2010. We characterised DC-SIGN+ cells by immunohistochemistry or immunofluorescence in renal biopsy tissue. Correlations between the DC-SIGN, intercellular adhesion molecule 3 (ICAM-3), CD4 and CD8 were evaluated. Patients were classified into the DC-SIGNhigh and DC-SIGNlow groups. Depending on an average of 100-month follow-up, the predictive value of DC-SIGN+ cells in IgAN progression was analysed. DC-SIGN+ cells were found frequently in IgAN kidneys while rarely observed in normal kidneys, and almost all DC-SIGN+ cells expressed MHC-II. We also found that DC-SIGN+ cells were adjacent to ICAM-3-positive CD4+ and CD8+ lymphocytes. The density of DC-SIGN+ cells was positively and linearly correlated with the density of ICAM-3+ cells, CD4+ cells and CD8+ cells in renal biopsy tissues. In the DC-SIGNhigh group, the degree of renal lesion and inflammatory cell infiltration was more severe compared to the DC-SIGNlow group. Patients in the DC-SIGNhigh group also had increased incidences of deteriorating renal function during the follow up compared to patients in the DC-SIGNlow group. CONCLUSIONS: DC-SIGN+ cells probably served as a potential contributor to exacerbate local inflammatory response. The density of DC-SIGN+ cells was associated with the severity of renal lesions of the patients. High renal DC-SIGN+ cell density might be used as a predictor of poor prognosis in patients with IgAN.

Uric Acid as a Predictor of Immunoglobulin A Nephropathy Progression: A Cohort Study of 1965 Cases.

BACKGROUND: The role of serum uric acid (SUA) level in the progression of Immunoglobulin A nephropathy (IgAN) remains controversial. METHODS: In a cohort of 1,965 cases with biopsy-proven IgAN, we examined the associations of SUA concentration with the primary outcome of a composite of all-cause mortality or kidney failure (defined as a reduction of estimated glomerular filtration rate [eGFR] by 40% from baseline, requirements for dialysis and transplantation), or the outcome of kidney failure alone, assessed using Cox and logistic regression models, respectively, with adjustment for confounders. RESULTS: At baseline, the mean age was 33.37 ± 11.07 years, eGFR was 101.30 ± 30.49 mL/min/1.73 m2, and mean uric acid level was 5.32 ± 1.76 mg/dL. During a median of 7-year follow-up, 317 cases reached the composite outcome of all-cause mortality (5 deaths) or kidney failure (36 cases of dialysis, 5 cases of renal transplantation, and 271 cases with reduction of eGFR by 40% from baseline). After adjustment for demographic and IgAN specific covariates and treatments, a higher quartile of uric acid was linearly associated with an increased risk of the primary outcome (highest versus lowest quartile, hazard ratio [HR] 2.39; 95% CI 1.52-3.75) and kidney failure (highest versus lowest quartile, HR 2.55; 95% CI 1.62-4.01) in the Cox proportional hazards regression models. In the continuous analysis, a 1 mg/dL greater uric acid level was associated with 16% increased risk of primary outcome (HR 1.16, 95% CI 1.07-1.25) and 17% increased risk of kidney failure (HR 1.17, 95% CI 1.08-1.27), respectively, in the fully adjusted model. The multivariate -logistic regression analyses for the sensitive analyses drew consistent results. In the subgroup analyses, significant interactions were detected that patients with mean arterial pressure (MAP) < 90 mm Hg or mesangial hypercellularity had a higher association of SUA with the incidence of the primary outcome than those with MAP ≥90 mm Hg or those without mesangial hypercellularity respectively. Hyperuricemia was not significantly associated with the risk of developing the primary outcome in elder patients (≥32 years old), patients with eGFR < 90 mL/min or with tubular atrophy/interstitial fibrosis. CONCLUSIONS: SUA level may be positively associated with the progression of IgAN. It was noticeable that the association of hyperuricemia with IgAN progression was less significant in patients with elder age, lower eGFR, or tubular atrophy/interstitial fibrosis, which may be due to some more confounders in association with the IgA progression in these patients. Future prospective studies are warranted to confirm these findings and to investigate the underlying mechanisms.

Recurrence of IgA nephropathy after kidney transplantation in steroid continuation versus early steroid-withdrawal regimens: a retrospective analysis of the UNOS/OPTN database.

In the past 20 years, there has been an increase in use of steroid-withdrawal regimens in kidney transplantation. However, steroid withdrawal may be associated with an increased risk of recurrent IgA nephropathy (IgAN). Using United Network of (Organ Sharing/Organ Procurement and Transplantation Network) UNOS/OPTN data, we analyzed adult patients with end-stage renal disease (ESRD) due to IgAN who received their first kidney transplant between 2000 and 2014. For the primary outcome, we used a competing risk analysis to compare the cumulative incidence of graft loss due to IgAN recurrence between early steroid-withdrawal (ESW) and steroid continuation groups. The secondary outcomes were patient survival and death-censored graft survival (DCGS). A total of 9690 recipients were included (2831 in ESW group and 6859 in steroid continuation group). In total, 1238 recipients experienced graft loss, of which 191 (15.43%) were due to IgAN recurrence. In multivariable analysis, steroid use was associated with a decreased risk of recurrence (subdistribution hazard ratio 0.666, 95% CI 0.482-0.921; P = 0.014). Patient survival and DCGS were not different between the two groups. In the USA, ESW in transplant for ESRD due to IgAN is associated with a higher risk of graft loss due to disease recurrence. Future prospective studies are warranted to further address which patients with IgAN would benefit from steroid continuation.

Combined Immunosuppressive Treatment May Improve Short-Term Renal Outcomes in Chinese Patients with Advanced IgA Nephropathy.

BACKGROUND/AIMS: Treatment of advanced Immunoglobulin A nephropathy (IgAN) patients with estimated glomerular filtration rate (eGFR) below 45 mL/min per 1.73 m2 remains inconsistent. The aim of this study is to compare the effects of corticosteroid and immunosuppressant therapies among these patients. METHODS: A total of 201 adult patients with advanced IgAN (eGFR < 45 mL/min/1.73 m2 and proteinuria > 1 g/24h at biopsy) grouped into supportive care (SC), steroids alone (CS), and steroids plus immunosuppressant (IT) groups, were investigated between 30th December 2002 and 30th June 2016. The primary endpoint was the combined endpoint of a 50% decline in eGFR and/or end stage renal disease (ESRD: eGFR < 15 mL/min/1.73 m2 or maintenance renal replacement treatment). Responses to therapy included complete remission (CR: urinary protein excretion < 0.5 g/24h, with eGFR decrease less than 10% baseline), partial remission (PR: proteinuria decrease by > 50% baseline, with eGFR decrease less than 10% baseline), no response (NR: proteinuria decrease < 50% baseline, or eGFR decrease > 10% baseline) and ESRD. Kaplan-Meier and Cox proportional hazards analyses were performed. RESULTS: During the follow-up period (37.2 ± 22.7 months), 6.8% patients in SC group, 25.0% in CS group, and 38.0% in IT group achieved CR or PR, while 78.4%, 62.5% and 49.3% patients in these 3 groups reached primary endpoint respectively (p < 0.001). Three-year renal survival rates in SC and combined immunosuppressive treatment groups (CS and IT groups) were 33.8% vs 51.2% (p = 0.02), and 5-year renal survival rates were 12.2% vs 21.3% (p = 0.1) respectively. Multivariate Cox regression analysis showed that hypertension (HR = 2.44, 95% CI 1.51-3.95; p < 0.001), Scr (HR = 1.01, 95% CI 1.00-1.01; p < 0.001), T1-T2 lesion (HR = 1.99, 95% CI 1.35-2.93; p = 0.001) were independent indicators of poor renal outcome. CONCLUSION: Immunosuppressive treatment (CS and IT therapy) may improve short-term renal outcome compared with supportive treatment in advanced IgAN patients.

Long-term outcomes of tonsillectomy for IgA nephropathy patients: A retrospective cohort study, two-centre analysis with the inverse probability therapy weighting method.

AIM: The effect of tonsillectomy on IgA nephropathy remains controversial. The aim of this study was to compare the effect of tonsillectomy on the outcome, end stage kidney disease (ESKD) and all-cause death in IgA nephropathy patients who did and did not undergo tonsillectomy. METHODS: All basic data were retrospectively gathered from patients who had undergone renal biopsies at two Japanese clinical centres. Two hundred and twenty-seven patients were eligible for the study, with a median age of 34 (Interquartile range (IQR): 25-43) years and median follow-up of 92 (IQR: 40-178) months. The primary endpoint was the composite outcome of the onset of ESKD and all-cause death before ESKD. We performed a Cox proportional hazard regression analysis after adjusting for patient characteristics using the inverse probability therapy weighting (IPTW) method and a Cox analysis using the Matching method. Similarly, we analyzed these outcomes in a mild cohort. RESULTS: We were unable to find any significant advantages of tonsillectomy in either analysis (IPTW and matching, HR: 0.40 (0.12-1.36) P = 0.072 and 0.78 (0.13-4.64) P = 0.786). However, in the mild cohort analysis, our data showed that the Tonsillectomy group tended to be less likely to reach the composite outcomes than the Not Tonsillectomy group with statistical significance (hazard ratio (HR), <0.001 [CI <0.001 to <0.001, P = 0.039]). CONCLUSION: In this study, our findings led us to conclude that performing tonsillectomy in an early and timely manner may have predisposition of less poor prognosis.

A Multicenter Study of the Predictive Value of Crescents in IgA Nephropathy.

The Oxford Classification of IgA nephropathy does not account for glomerular crescents. However, studies that reported no independent predictive role of crescents on renal outcomes excluded individuals with severe renal insufficiency. In a large IgA nephropathy cohort pooled from four retrospective studies, we addressed crescents as a predictor of renal outcomes and determined whether the fraction of crescent-containing glomeruli associates with survival from either a ≥50% decline in eGFR or ESRD (combined event) adjusting for covariates used in the original Oxford study. The 3096 subjects studied had an initial mean±SD eGFR of 78±29 ml/min per 1.73 m2 and median (interquartile range) proteinuria of 1.2 (0.7-2.3) g/d, and 36% of subjects had cellular or fibrocellular crescents. Overall, crescents predicted a higher risk of a combined event, although this remained significant only in patients not receiving immunosuppression. Having crescents in at least one sixth or one fourth of glomeruli associated with a hazard ratio (95% confidence interval) for a combined event of 1.63 (1.10 to 2.43) or 2.29 (1.35 to 3.91), respectively, in all individuals. Furthermore, having crescents in at least one fourth of glomeruli independently associated with a combined event in patients receiving and not receiving immunosuppression. We propose adding the following crescent scores to the Oxford Classification: C0 (no crescents); C1 (crescents in less than one fourth of glomeruli), identifying patients at increased risk of poor outcome without immunosuppression; and C2 (crescents in one fourth or more of glomeruli), identifying patients at even greater risk of progression, even with immunosuppression.

Evidence from the Oxford Classification cohort supports the clinical value of subclassification of focal segmental glomerulosclerosis in IgA nephropathy.

Focal segmental glomerulosclerosis (FSGS) is a common finding in IgA nephropathy (IgAN). Here we assessed FSGS lesions in the Oxford Classification patient cohort and correlated histology with clinical presentation and outcome to determine whether subclassification of the S score in IgAN is reproducible and of clinical value. Our subclassification of lesions in 137 individuals with segmental glomerulosclerosis or adhesion (S1) identified 38% with podocyte hypertrophy, 10% with hyalinosis, 9% with resorption droplets within podocytes, 7% with tip lesions, 3% with perihilar sclerosis, and 2% with endocapillary foam cells. Reproducibility was good or excellent for tip lesions, hyalinosis, and perihilar sclerosis; moderate for podocyte hypertrophy; and poor for resorption droplets, adhesion only, and endocapillary foam cells. Podocyte hypertrophy and tip lesions were strongly associated with greater initial proteinuria. During follow-up of patients without immunosuppression, those with these features had more rapid renal function decline and worse survival from a combined event compared to S1 patients without such features and those without FSGS. Also in individuals with podocyte hypertrophy or tip lesions, immunosuppressive therapy was associated with better renal survival. In IgA nephropathy, the presence of podocyte hypertrophy or tip lesions, markers of podocyte injury, were reproducible. These features are strongly associated with proteinuria and, in untreated patients, carry a worse prognosis. Thus, our findings support reporting podocytopathic features alongside the S score of the Oxford Classification.

Increased C4 and decreased C3 levels are associated with a poor prognosis in patients with immunoglobulin A nephropathy: a retrospective study.

BACKGROUND: An association between serum complement levels and poor renal prognosis in patients with immunoglobulin A nephropathy (IgAN) remains controversial. METHODS: We conducted a retrospective study examining the relationship between serum complement levels and prognosis in patients with IgAN. Between 2009 and 2013, patients with biopsy-confirmed IgAN were identified from the Second Affiliated Hospital of Wenzhou Medical College, China, and various parameters were documented during follow-up until 2015. The definition of the primary endpoint was a decrease of estimated glomerular filtration rate (eGFR) more than 30% from their baseline levels. RESULTS: A total of 403 patients (55.3% female, average 33.7 months of follow-up) were identified and enrolled, with the primary endpoint occurring in 39 (9.8%) patients. Among the patients selected, 202 (50.1%) received corticosteroid treatment alone or in combination with another immunosuppressant (GS group), while others did not receive immunosuppressive treatment (non-GS group). The incidence of the primary endpoint was slightly lower in the GS group compared to the non-GS group (7.0% versus 12.6%, p = 0.06). Multivariate Cox proportional-hazard regression analyses, adjusting for age, systolic and diastolic blood pressure, 24-h urine protein, and immunosuppressive therapy, showed that serum complement 4 (C4) levels (hazard ratio [HR] 2.4, 95% confidence interval [CI] 1.6-3.8, p < 0.001) and serum complement 3 (C3) levels (HR 0.6, 95% CI 0.2-0.6, p < 0.001) were significantly associated with a poor prognosis among patients with IgAN. CONCLUSIONS: We demonstrated that an increase in serum C4, as well as a decrease in C3, was an important outcome determinant for patients with IgAN. Testing serum C3 and C4 levels might assist in predicting renal outcomes among these patients.

Long-term outcomes of end-stage kidney disease for patients with IgA nephropathy: A multi-centre registry study.

BACKGROUND: Clinical outcomes of patients with end-stage kidney disease (ESKD) receiving renal replacement therapy (RRT) secondary to IgA nephropathy (IgAN) have not been well described. AIM: To investigate the characteristics, treatments and outcomes of ESKD because of kidney-limited IgAN and Henoch-Schönlein purpura nephritis (HSPN) in the Australian and New Zealand RRT populations. METHODS: All ESKD patients who commenced RRT in Australia and New Zealand between 1971 and 2012 were included. Dialysis and transplant outcomes were evaluated in both a contemporary cohort (1998-2012) and the entire cohort (1971-2012). RESULTS: Of 63 297 ESKD patients, 3721 had kidney-limited IgAN, and 131 had HSPN. For the contemporary cohort of IgAN patients on dialysis (n = 2194), 10-year patient survival was 65%. Of 1368 contemporary IgAN patients who received their first renal allograft, 10-year patient, overall renal allograft and death-censored renal allograft survival were 93%, 82% and 88%, respectively. Using multivariable Cox regression analysis, patients with IgAN had favourable dialysis patient survival (adjusted hazard ratio (HR) 0.63, 95% confidence interval (CI) 0.57-0.69), overall renal allograft survival (HR 0.67, 95% CI 0.57-0.79) and renal transplant patient survival (HR 0.58, 95% CI 0.45-0.74) compared with ESKD controls. Similar results were found in the entire cohort and when using competing-risks models. Compared with kidney-limited IgAN patients, those with HSPN had worse dialysis patient survival (HR 1.94, 95% CI 1.02-3.69), overall renal allograft survival (HR 3.40, 95% CI 1.00-11.55) and renal transplant patient survival (HR 3.50, 95% CI 1.03-11.92). CONCLUSION: IgAN ESKD was associated with better dialysis and renal transplant outcomes compared with other forms of ESKD. The survival outcomes of ESKD patients with HSPN were worse than kidney-limited IgAN.

Addition of eGFR and Age Improves the Prognostic Absolute Renal Risk-Model in 1,134 Norwegian Patients with IgA Nephropathy.

BACKGROUND: Predicting outcome in individual patients with IgA nephropathy (IgAN) is difficult but important. For this purpose, the absolute renal risk (ARR) model has been developed in a French cohort to calculate the risk of end-stage renal disease (ESRD) and death. ARR (0-3) is scored in individual IgAN patients based on the presence of proteinuria ≥1 g/24 h, hypertension, and severe histopathological lesions (1 point per risk factor). We have validated the ARR model in a Norwegian cohort of IgAN patients and tested whether adding data on initial estimated glomerular filtration rate (eGFR) and age improved prediction. METHODS: IgAN patients diagnosed between 1988 and 2012 were identified in the Norwegian Kidney Biopsy Registry, and endpoints were identified by record linkage with the Norwegian Renal Registry (ESRD) and the Population Registry (deaths). RESULTS: We identified 1,134 IgAN patients. The mean duration of follow-up was 10.2 years (range 0.0 to 25.7 years). Two hundred and fifty one patients developed ESRD and there were 69 pre-ESRD deaths. The ARR model significantly stratified the IgAN cohort according to risk of ESRD/death. The inclusion of eGFR and age significantly improved the ARR prognostic model; in the receiver operator characteristics (ROC) analysis, area under the curve (AUC) at 10-years of follow-up increased from 0.79 to 0.89, p < 0.001. CONCLUSIONS: ARR is a suitable prognostic model for stratifying IgAN patients according to the risk of ESRD or death. Including initial eGFR and age in the model substantially improved its accuracy in our nationwide cohort.