Long-term Prognosis Of IgA Nephropathy Research Articles

#968 Impact of the presence of acute kidney injury at the time of renal biopsy on long-term prognosis of IgA nephropathy

Abstract Background and Aims IgA nephropathy is the most common primary glomerular disease and an important cause of end-stage renal disease. Factors such as decreased renal function, persistent proteinuria, hypertension, and older age predict a poor prognosis in IgA nephropathy. Current international prediction tools for IgA nephropathy determine prognosis based on renal function using estimated glomerular filtration rate (eGFR) at the time of kidney biopsy. However, we observed differences in prognosis between patients with and without concurrent acute kidney injury (AKI) at the time of kidney biopsy. Therefore, we aimed to investigate whether renal function at the time of renal biopsy is a suitable indicator for assessing the long-term prognosis of patients with IgA nephropathy with AKI. Method We retrospectively analyzed a total of 185 patients who were diagnosed with IgA nephropathy between 2009 and 2016 at the Gyeongsang National University Hospital. Clinical data, including pathological, demographic, and laboratory findings of patients, were used. We divided the patients into two groups based on the progression rate of kidney function per year, ‘Progression’ or ‘Non-progression group’. AKI was defined according to the KDIGO Clinical Practice Guidelines. Results Among a total of 185 patients, 113 showed a sustained decline in eGFR of more than 1 ml/min/1.73 m2 per year. The mean eGFR level of the non-progression group was significantly lower than that of the progression group (p = 0.027). The percentage of patients with AKI in the non-progression group was 25%, which was higher than that in the progression group (p < 0.001). The two groups had no significant differences in comorbid disease, medications at kidney biopsy, and treatment. In sub-analysis, the mean eGFR at kidney biopsy was significantly lower than that in the non-AKI group (p < 0.001). The mean estimated risk, calculated by the international prediction tool, was significantly lower in the AKI group. On the other hand, the mean rate of actual GFR decline per year was higher in the non-AKI group (p < 0.001). Conclusion We confirmed a discrepancy between the predicted prognosis and the actual decline in GFR, particularly in the AKI group. We found that AKI at the time of renal biopsy was a good long-term prognostic factor. There is a need to conduct further research to confirm whether this is due to early detection of AKI and early active treatment.

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

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. 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 105months 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. 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.

Glomerular Density in Renal Biopsy Specimens Predicts the Long-Term Prognosis of IgA Nephropathy

An early histopathologic predictor of the renal prognosis, before the occurrence of advanced glomerular sclerosis/interstitial fibrosis and/or apparent renal dysfunction, remains to be established in IgA nephropathy (IgAN). This study aimed to determine whether the glomerular density (GD; nonsclerotic glomerular number per renal cortical area) of biopsy specimens obtained at an early stage of IgAN could predict the long-term renal outcome. The predictive value of the factors at biopsy, including the GD, on the renal outcome was retrospectively analyzed for 98 patients who had IgAN with an estimated GFR of > or =60 ml/min per 1.73 m(2) at biopsy (87 ml/min per 1.73 m(2) on average). The individual value of GD in biopsy ranged from 1.2 to 8.1/mm(2) (i.e., approximately a seven-fold variation), and the GD showed a close inverse correlation with mean glomerular volume. Among the various clinicopathologic factors involved, both a cellular/fibrocellular crescent and the GD were found to be significant predictors of progression in multivariate analyses. A low GD in the biopsy specimens was frequently associated with a steeper slope of the renal function and a synergistically enhanced risk for progression with the presence of cellular/fibrocellular crescent. The renal function, proteinuria, degrees of glomerulosclerosis, and interstitial fibrosis at biopsy were not independent predictors of the prognosis in these patients. A strong predictive relationship of low GD with progression observed in this study suggests that GD may serve as an early histopathologic marker of long-term renal prognosis in IgAN.

Tonsillectomy combined with steroid pulse therapy: A curative therapy for IgA nephropathy

As IgA nephropathy (IgAN) was originally regarded as a benign condition, the indication of corticosteroids has been highly restricted because of their side effects, and has been used for a specific subgroup of IgAN patients with consideration of the risk/benefit ratio. During the last decade, however, with the recognition that the overall long-term prognosis of IgAN is a non-benign condition, more aggressive treatments, including high dose corticosteroids and tonsillectomy, have been used for a wider subgroup of patients with IgAN. Since 1988, we have treated IgAN patients with steroid semi-pulse therapy combined with tonsillectomy. Over 500 patients with IgAN have been treated with this treatment protocol, and a high percentage of patients enter clinical remission, i.e. free from urinary abnormalities if the combination therapy was initiated in its early stage. Through these experiences we think the goal of treatment of IgAN patients should be changed from "slowing the progression of nephropathy" to "clinical remission".

Use of corticosteroids, other immunosuppressive therapies, and tonsillectomy in the treatment of IgA nephropathy

Because IgA nephropathy (IgAN) was originally regarded as a benign condition, the indication of corticosteroids or other immunosuppressive therapies have been highly restricted because of potential side effects, and such drugs have been used for a specific subgroup of patients with IgAN, taking the risk/benefit ratio into consideration. During the last decade, however, with the recognition that the overall long-term prognosis of IgAN is a nonbenign condition, more aggressive treatments, including high-dose corticosteroids, various immunosuppressive agents, and tonsillectomy, have been used for wider subgroups of patients with IgAN. Moreover, recent studies have suggested that clinical remission as well as histopathologic regression of the nephropathy could be obtained by such treatments if treatment is initiated in its relatively early stage. Thus, the possibility has now been raised that the goal of treatment for patients with IgAN will shift from “slowing the progression of nephropathy” to “remission of nephropathy.”

Prognostic indicators of IgA nephropathy in the Chinese--clinical and pathological perspectives.

IgA nephropathy is the most common primary glomerulonephritis in the world. Up to 30% of patients can progress to end-stage renal disease (ESRD) in 10 years. We studied 168 Chinese patients with IgA nephropathy followed for an average of 7.4 years in our hospital and tried to identify the clinical and pathological data that were associated with the prognosis of the disease. Clinical features at the time of renal biopsy were reviewed. Severity of histological involvement was scored semi-quantitatively as grade 1-3. There was a female preponderance in our cohort of patients (male:female ratio 1:1.5). The average age at biopsy was 32.9+/-10.0 years. Forty-seven of the 168 patients (28.0%) were hypertensive and 47 of 136 patients (34.6%) had a family history of hypertension. A high histological grade of IgA nephropathy was associated with hypertension at presentation, family history of hypertension, a higher serum creatinine, total cholesterol and 24-h urine protein excretion, and a lower serum albumin level. During the follow-up period, four patients died and another 24 progressed to ESRD. The renal survival was 92.0% at 1 year, 87.5% at 5 years and 81.8% at 10 years. With univariate analysis, hypertension at presentation, family history of hypertension, renal impairment at presentation (plasma creatinine >120 micromol/l), high cholesterol, proteinuria >1 g/day and high histological grading were associated with poor prognosis. With multivariate analysis, hypertension at presentation, family history of hypertension, renal impairment at presentation, proteinuria >1 g/day and histological grading were independent predictors of renal survival. The relative risks of renal failure for patients were 9.60 (95% confidence interval 4.02-22.92) with hypertension, 1.56 (1.16-2.02) with a family history of hypertension, 15.38 (6.40-36.93) with renal impairment and 5.93 (3.07-11.46) with every increase of one histological grade. Male patients did not show a more adverse outcome compared with females. Our results suggest that renal biopsy remains useful, even in clinically trivial disease, because of its distinct value in prognosis and risk stratification. The long-term prognosis of IgA nephropathy in Chinese patients is guarded. The prognostic importance of family history of hypertension has not been widely recognized and requires further study.

Significance of mesangial expression of alpha-smooth muscle actin in the progression of IgA nephropathy.

To determine whether phenotypic modulation of mesangial and interstitial cells correlated with the long-term prognosis of IgA nephropathy (IgAN), we analyzed retrospectively 27 patients with IgAN whose creatinine clearance at the time of renal biopsy was normal. The patients were subdivided into two groups according to the course of renal function during follow-up. Thirteen patients maintained normal renal function for more than 15 years (stable group), and 14 progressed to end-stage renal disease (ESRD group). The score of mesangial cell cellularity in the ESRD group was significantly higher than in the stable group. Immunohistochemistry localized alpha-smooth muscle actin (alpha-SMA) in renal mesangial cells of approximately half these patients. Macrophages localized predominantly in the mesangial area in patients with mesangial expression of alpha-SMA, which was associated with the expression of macrophage-colony-stimulating factor. Noteworthily, the score of mesangial alpha-SMA expression and the incidence of patients with mesangial expression of alpha-SMA at the time of renal biopsy were markedly higher in the ESRD group than in the stable group. However, there was no significant difference in both the score of interstitial alpha-SMA expression and the incidence of patients with interstitial expression of alpha-SMA between these two groups. These results suggest that macrophages recruited into the mesangium may induce phenotypic modulation of mesangial cells and that mesangial alpha-SMA expression predicts a progressive decline in renal function in patients with IgAN.

Pathogenesis and therapy of IgA nephropathy

IgA nephropathy (IgAN) is the most common chronic glomerulonephritis of unknown cause. Two factors are important in the pathogenesis of IgAN; one is IgA immune complex (IgA-IC) formation and the other is IgA-IC deposition to mesangium. For the formation of IgA-IC, antibody of IgA class, T-cells which help the generation of IgA antibody, and antigen are necessary. The serum IgA level in patients with IgAN is elevated probably due not only to the activation of B-cell but also to the hyperactivity of alpha beta chain positive T-cells. Analysis of the immunoglobulin gene of IgAN patients indicated that the genetic polymorphism could be correlated with the production of IgA antibody. The gamma delta chain positive T-cell may play some role for the formation of IgA-IC. Food, bacteria, viral proteins are reported to be the antigens of IgA-IC. Regarding to IgA-IC deposition, cytokines from T-cells and the molecular weight of IgA-IC are also indispensable factors. Clinically, long-term prognosis of IgAN are not unanimously the same. Approximately 15% patients progress to renal failure over a period of 10 years, and 25% to renal failure within 20 years. Roughly, patients can be classified into three groups in view of clinical course. First group maintains stable renal function for more than 20 years, second exhibits progressive course in more than 20 years and third progresses more rapidly than the second. Although the exact mechanism(s) governing the fate of renal function in IgAN is unclear, non-immunological factors, such as intraglomerular hypertension, are presumed to participate in its progression.(ABSTRACT TRUNCATED AT 250 WORDS)

The Role of HLA-DR4 in the Long-Term Prognosis of IgA Nephropathy

The study was performed to clarify the relationship between the long-term prognosis of IgA nephropathy and the HLA-DR4 antigen. From the 130 patients typed for HLA antigens, stable (n = 42) and progressive (n = 45) patient groups were selected. DR4 frequency was not different in the two groups (stable, 66.7 vs. progressive, 53.3%). However, the frequencies of HLA-DR4 and B35 in the 130 patients were significantly higher than those in the national control (DR4; 60.0 vs. 41.6%; B35:30.0 vs. 15.5%). We concluded that DR4 played no role in the long-term prognosis of IgA nephropathy, but that B35 and DR4 were associated with the disease in the Japanese population.