Ritsuko Katafuchi

Controlled, prospective trial of steroid treatment in IgA nephropathy: a limitation of low-dose prednisolone therapy

BACKGROUND No accepted therapy has been established for progressive immunoglobulin A (IgA) nephropathy. METHODS A prospective, randomized, controlled trial of low-dose prednisolone therapy was performed in patients with IgA nephropathy with moderate histological characteristics. Forty-three patients in the steroid group and 47 patients in the control group were included in the study. The initial dose of prednisolone was 20 mg/d, gradually tapered to 5 mg/d during 2 years. RESULTS Baseline urine protein-creatinine ratio (UP-UCR) was significantly greater in the steroid group than in controls. Follow-up duration was 65 +/- 25 months in the steroid group and 64 +/- 23 months in controls. Changes in UP-UCR from baseline, ie, UP-UCR at last follow-up minus UP-UCR at baseline, were significantly lower in the steroid group than in controls (steroid group, -0.84 +/- 1.78; controls, 0.26 +/- 1.65; P = 0.0034). Kidney survival was similar in both groups. Patients were divided into two subgroups according to clinical course. There were 28 improved patients and 15 unimproved patients in the steroid group and 27 improved patients and 20 unimproved patients in the control group. In the steroid group, UP-UCR was significantly greater in the unimproved than improved subgroup (3.1 +/- 2.6 versus 1.8 +/- 1.5). CONCLUSION These data suggest that our protocol had an antiproteinuric effect, but could not improve kidney survival. Because the effect of steroid therapy to prevent the progression of IgA nephropathy is believed to be linked closely to reduction in urinary protein, an insufficient dose of prednisolone in our protocol may be the reason for the discrepancy between the effect on proteinuria and kidney survival.

Membranous Glomerulonephritis Development with Th2-Type Immune Deviations in MRL/lpr Mice Deficient for IL-27 Receptor (WSX-1)

MRL/lpr mice develop spontaneous glomerulonephritis that is essentially identical with diffuse proliferative glomerulonephritis (World Health Organization class IV) in human lupus nephritis. Lupus nephritis is one of the most serious complications of systemic lupus erythematosus. Diffuse proliferative glomerulonephritis is associated with autoimmune responses dominated by Th1 cells producing high levels of IFN-γ. The initial mounting of Th1 responses depends on the function of the WSX-1 gene, which encodes a subunit of the IL-27R with homology to IL-12R. In mice deficient for the WSX-1 gene, proper Th1 differentiation was impaired and abnormal Th2 skewing was observed during infection with some intracellular pathogens. Disruption of the WSX-1 gene dramatically changed the pathophysiology of glomerulonephritis developing in MRL/lpr mice. WSX-1−/− MRL/lpr mice developed disease resembling human membranous glomerulonephritis (World Health Organization class V) with a predominance of IgG1 in glomerular deposits, accompanied by increased IgG1 and IgE in the sera. T cells in WSX-1−/− MRL/lpr mice displayed significantly reduced IFN-γ production along with elevated IL-4 expression. Loss of WSX-1 thus favors Th2-type autoimmune responses, suggesting that the Th1/Th2 balance may be a pivotal determinant of human lupus nephritis development.

An important role of glomerular segmental lesions on progression of IgA nephropathy : a multivariate analysis

The independent predictors of progression of IgA nephropathy (IgAN) were investigated by multivariate life table analysis, using Coxs proportional hazard model, in 225 patients with IgAN diagnosed by renal biopsy (Bx). There were 105 men and 120 women. Mean age at Bx was 32.5 years. The follow-up period following Bx was 4.0 +/- 2.6 yrs, ranging from 5 months to 11 yrs. The clinical parameters analyzed were age at the time of discovery of the disease, age at Bx, intervals from discovery to Bx, presence or absence of macrohematuria, and clinical data at Bx such as presence or absence of hypertension, the degree of hematuria, the amount of urinary protein excretion, serum creatinine and serum IgA concentration. The following immunopathological parameters were also examined; glomerular hypercellularity index, percentage of glomeruli associated with segmental lesions such as tuft adhesions, crescents and segmental sclerosis, percentage of obliterated glomeruli by global sclerosis, severity of interstitial infiltration, fibrosis, arterial wall thickening, arterial hyaline changes, and intensity of the depositions of IgG, IgA, IgM, C3, C1q and fibrinogen by immunofluorescent study. Among all clinical and pathologic parameters examined, the following parameters were proved to be significant independent predictors of progression of IgAN: serum creatinine exceeding 1.5 mg/dl in men and 1.3 mg/dl in women, proteinuria over 2 g/day, segmental lesions involving more than 25% of glomeruli and interstitial fibrosis occupying more than 25% of cortical area.(ABSTRACT TRUNCATED AT 250 WORDS)

Validation Study of Oxford Classification of IgA Nephropathy: The Significance of Extracapillary Proliferation

UNLABELLED BACKGROUND AND OBJECTIVES The Oxford classification of IgA nephropathy (IgAN) includes mesangial hypercellularity, endocapillary hypercellularity, segmental glomerulosclerosis (S), and tubular atrophy/interstitial fibrosis (T) as prognosticators. The value of extracapillary proliferation (Ex) was not addressed. Because the Oxford classification excludes patients with urinary protein <0.5 g/d and eGFR <30 ml/min per 1.73 m(2) at biopsy, the significance of Ex should be confirmed by validation cohorts that include more rapidly progressive cases. We present such a study. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The significance of pathologic features for development end-stage renal failure (ESRF) was examined by multivariate analysis in 702 patients with IgAN. The association of Ex with kidney survival was examined by univariate analysis in 416 patients who met the Oxford criteria and 286 who did not, separately. RESULTS In a multivariate model, S and T were significantly associated with ESRF. With addition of Ex, not S but Ex was significant for ESRF. In univariate analysis, kidney survival was significantly lower in patients with Ex than in those without, in patients who did not meet the Oxford criteria, but such a difference was not found in patients who met it. CONCLUSIONS The prognostic significance of Ex was evident in our cohort. It seems that Ex did not emerge from the Oxford classification as a prognosticator because of exclusion of severe cases (eGFR <30 ml/min per 1.73 m(2)). We suggest that extracapillary proliferation be included in the next version of the Oxford classification of IgAN to widen the scope of the classification.

Oxford Classification of IgA nephropathy 2016: an update from the IgA Nephropathy Classification Working Group

Since the Oxford Classification of IgA nephropathy (IgAN) was published in 2009, MEST scores have been increasingly used in clinical practice. Further retrospective cohort studies have confirmed that in biopsy specimens with a minimum of 8 glomeruli, mesangial hypercellularity (M), segmental sclerosis (S), and interstitial fibrosis/tubular atrophy (T) lesions predict clinical outcome. In a larger, more broadly based cohort than in the original Oxford study, crescents (C) are predictive of outcome, and we now recommend that C be added to the MEST score, and biopsy reporting should provide a MEST-C score. Inconsistencies in the reporting of M and endocapillary cellularity (E) lesions have been reported, so a web-based educational tool to assist pathologists has been developed. A large study showed E lesions are predictive of outcome in children and adults, but only in those without immunosuppression. A review of S lesions suggests there may be clinical utility in the subclassification of segmental sclerosis, identifying those cases with evidence of podocyte damage. It has now been shown that combining the MEST score with clinical data at biopsy provides the same predictive power as monitoring clinical data for 2 years; this requires further evaluation to assess earlier effective treatment intervention. The IgAN Classification Working Group has established a well-characterized dataset from a large cohort of adults and children with IgAN that will provide a substrate for further studies to refine risk prediction and clinical utility, including the MEST-C score and other factors.

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.

Diffuse proliferative glomerulonephritis after bone marrow transplantation.

A 15-year-old boy developed nephrotic syndrome and acute renal failure 4 years after allogenic bone marrow transplantation (BMT) for lymphoid crisis of chronic myelocytic leukemia. On admission, he presented with clinical features of chronic GVHD including transient exacerbation of cholestatic liver injury. Renal biopsy showed diffuse proliferative glomerulonephritis with cellular crescents. The patient was treated with methylprednisolone pulse therapy (1 g/day, for 3 days) followed by oral prednisolone. Renal function gradually improved but nephrotic state was persistent. A second renal biopsy showed improvement of acute tubular necrosis and endocapillary proliferation and transformation of crescents into a fibrous form. After tapering of oral prednisolone, cyclophosphamide was started, which resulted in a gradual improvement of proteinuria. Several cases of nephrotic syndrome occurring after BMT have already been reported, but most cases had membranous nephropathy. In our case, renal biopsy revealed diffuse proliferative glomerulonephritis with findings of active cellular immunity, and aggressive treatment resulted in attenuation of these findings. Moreover, chronic GVHD-related liver injury was noted at the time of this episode. Our findings suggest that chronic GVHD may be complicated with diffuse proliferative glomerulonephritis through unknown cellular immune mechanism.

Development and Validation of a Prediction Rule Using the Oxford Classification in IgA Nephropathy

BACKGROUND AND OBJECTIVES The risk assessment for developing ESRD remains limited in patients with IgA nephropathy (IgAN). The aim of this study was to develop and validate a prediction rule for estimating the individual risk of ESRD in patients with IgAN. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A total of 698 patients with IgAN diagnosed by renal biopsy at Kyushu University Hospital (derivation cohort) between 1982 and 2010 were retrospectively followed. The Oxford classification was used to evaluate the pathologic lesions. The risk factors for developing ESRD were evaluated using a Cox proportional hazard model with a stepwise backward elimination method. The prediction rule was verified using data from 702 patients diagnosed at Japanese Red Cross Fukuoka Hospital (validation cohort) between 1979 and 2002. RESULTS In the derivation cohort, 73 patients developed ESRD during the median 4.7-year follow-up. The final prediction model included proteinuria (hazard ratio [HR], 1.30; 95% confidence interval [95% CI], 1.16 to 1.45, every 1 g/24 hours), estimated GFR (HR, 0.84; 95% CI, 0.74 to 0.96, every 10 ml/min per 1.73 m(2)), mesangial proliferation (HR, 1.85; 95% CI, 1.10 to 3.11), segmental sclerosis (HR, 3.21; 95% CI, 1.37 to 7.51), and interstitial fibrosis/tubular atrophy (T1: HR, 5.30; 95% CI, 2.63 to 10.7; T2: HR, 20.5; 95% CI, 9.05 to 46.5) as independent risk factors for developing ESRD. To create a prediction rule, the score for each variable was weighted by the regression coefficients calculated using the relevant Cox model. The incidence of ESRD increased linearly with increases in the total risk scores (P for trend <0.001). Furthermore, the prediction rule demonstrated good discrimination (c-statistic=0.89) and calibration (Hosmer-Lemeshow test, P=0.78) in the validation cohort. CONCLUSIONS This study developed and validated a new prediction rule using clinical measures and the Oxford classification for developing ESRD in patients with IgAN.

The improvement of renal survival with steroid pulse therapy in IgA nephropathy

Background. The benefits of steroid therapy in immunoglobulin A nephropathy (IgAN) have not been established. Methods. The effect of steroids on kidney survival was retrospectively investigated in 702 patients with IgAN by multivariate analyses. Results. There were 295 men and 407 women. The median follow-up period was 62 months. One hundred and ninety-four patients were treated with oral steroids (oral steroid group). Thirty-four patients were treated with methylprednisolone (mPSL) pulse therapy (pulse steroid group) followed by oral prednisolone (PSL). In 474 patients, no steroid was used (no steroid group). The urinary protein-creatinine ratio and histological grade were significantly different among treatment groups and were highest in the pulse steroid group followed by the oral steroid group and lowest in the no steroid patients. Serum creatinine was significantly higher in the pulse steroid group than in other two groups. Eighty-five patients developed end-stage renal failure (ESRF) requiring haemodialysis. In multivariate analysis, steroid pulse therapy significantly decreased the risk of ESRF while oral steroid treatment did not improve renal survival in this cohort. Conclusion. We found that pulse steroid therapy improved kidney survivals in IgAN. Since the clinical findings and histological grade were the most severe in patients treated with mPSL pulse therapy, such therapy may prevent progression of IgAN.

Low-dose prednisolone ameliorates acute renal failure caused by cholesterol crystal embolism.

AIMS The prognosis of renal cholesterol crystal embolism (CCE) is poor. Although various treatments for CCE have been attempted, there is no optimal therapy. We tested the effect of low-dose prednisolone (PS) on CCE-related acute renal failure (ARF). PATIENTS AND METHODS 7 patients (mean age 69 years) diagnosed with CCE-related ARF were treated with oral PS at 15-20 mg/day for 2-4 weeks, which was then tapered at 5 mg/day over 2-4 weeks, followed by 5 mg/day maintenance dose. Recurrent ARF during PS tapering was treated with a larger dose of PS. RESULTS Inciting factors were identified in four patients: coronary angiography (n=3) and cerebral angiography (n=1). On admission, serum creatinine (SCr) was 2.1 +/- 0.3 mg/dl (mean +/- SEM). SCr and eosinophil count before treatment were 4.2 +/- 0.4 mg/dl and 682 +/- 73/microl, respectively. PS therapy improved ARF in all cases at week 2 (SCr 3.8 +/- 0.5 mg/dl) parallel to a decrease in eosinophilia (116 +/- 30/microl), and at week 4 (3.1 +/- 0.4 mg/dl and 134 +/- 20/microl, respectively). At last follow-up, renal function was improved or maintained in 5 patients compared with that at week 4 post-treatment. One patient died of lung cancer. Another required LDL apheresis and hemodialysis but died due to CCE-related multi-organ failure. A third patient had recurrent ARF and was re-treated with a larger dose of PS, which resulted in an immediate decrease in SCr. However, the patient developed acute renal dysfunction due to congestive heart failure, and required hemodialysis. CONCLUSIONS Low-dose PS improved CCE-related ARF, probably through amelioration of inflammatory reaction surrounding affected renal vessels.