Successful Treatment with Belimumab in a Patient with Refractory Systemic Lupus Erythematosus after Initiation of Hemodialysis: Considering the Synergistic Effect of Belimumab and Immunological Burn-Out Phenomenon in End-Stage Renal Disease Patients on Hemodialysis.

BACKGROUND: In patients with systemic lupus erythematosus (SLE), disease activity can persist even after initiating dialysis. However, guidelines for the treatment of patients with SLE after dialysis is initiated have not yet been established. CASE PRESENTATION: We describe the case of a 54-year-old Japanese woman who was diagnosed with SLE at age 12, progressed to end-stage renal disease (ESRD), and initiated hemodialysis for lupus nephritis. However, SLE activity persisted after hemodialysis. Cyclophosphamide and mycophenolate mofetil were administered in addition to prednisolone and immunoadsorption, but this treatment strategy was limited by side effects. The patient was subsequently treated with belimumab, and the activity of SLE decreased rapidly. CONCLUSIONS: ESRD patients with SLE show no significant decrease in transitional B cells and have elevated levels of B-cell activating factor (BAFF). Both transitional B cells and BAFF are important therapeutic targets for belimumab, indicating that patients with ESRD may benefit from belimumab therapy. However, the effects of belimumab may be potentiated in patients with uremia, who may be more susceptible to adverse events such as infections. Patients with SLE who receive belimumab after initiation of hemodialysis therefore require careful follow-up. Here, we report the first case of belimumab administration in a patient with SLE after initiation of hemodialysis.

Grading system utilising the total score of Oxford classification for predicting renal prognosis in IgA nephropathy.

The Oxford classification of IgA nephropathy (IgAN) can evaluate each MEST-C score individually. We analysed a new grading system that utilised the total MEST-C score in predicting renal prognosis. Altogether, 871 IgAN patients were classified into three groups using the new Oxford classification system (O-grade) that utilised the total MEST-C score (O-grade I: 0-1, II: 2-4, and III: 5-7 points), and the 10-year renal prognosis was analysed. The clinical findings became significantly severer with increasing O-grades, and the renal survival rate by the Kaplan-Meier method was 94.1%, 86.9%, and 74.1% for O-grades I, II, and III, respectively. The hazard ratios (HRs) for O-grades II and III with reference to O-grade I were 2.8 (95% confidence interval [CI] 1.3-6.0) and 6.3 (95% CI 2.7-14.5), respectively. In the multivariate analysis, mean arterial pressure and eGFR, proteinuria at the time of biopsy, treatment of corticosteroids/immunosuppressors, and O-grade (HR 1.63; 95% CI 1.11-2.38) were the independent factors predicting renal prognosis. Among the nine groups classified using the O-grade and Japanese clinical-grade, the renal prognosis had an HR of 15.2 (95% CI 3.5-67) in the severest group. The O-grade classified by the total score of the Oxford classification was associated with renal prognosis.

Validation of the revised Oxford classification for IgA nephropathy considering treatment with corticosteroids/immunosuppressors.

The Oxford classification for IgA nephropathy (IgAN) was updated in 2017. We have validated the revised Oxford classification considering treatment with corticosteroids/immunosuppressors. In this retrospective analysis, 871 IgAN patients were enrolled. Patients were divided into two groups, those treated with or without corticosteroids/immunosuppressors. The 20-year renal prognosis up to end-stage renal disease was assessed using the Oxford classification. In all patients, the renal survival rate was 87.5% at 10 years and 72.6% at 20 years. The T score alone was significantly related to renal prognosis in the Kaplan-Meier analysis and multivariate Cox regression analysis. In the non-treatment group (n = 445), E, S, T, and C scores were significantly related to renal survival rates, however, in the treatment group (n = 426), T score alone was significantly related to renal prognosis on Kaplan-Meier analysis, indicating that corticosteroids/immunosuppressors improved renal prognosis in E1, S1, and C1. In patients with E1, S1, or C1, the treatment group showed significantly better renal prognosis than the non-treatment group in univariate and multivariate analysis. The Oxford classification and T score were used to determine renal prognosis in IgAN patients. Corticosteroids/immunosuppressors improved renal prognosis, especially E1, S1, and C1 scores.

Long-Term Beneficial Effects of Tonsillectomy on Patients with Immunoglobulin A Nephropathy.

Background: Tonsillectomy may treat IgA nephropathy (IgAN) by reducing the levels of galactose-deficient IgA1. Therefore, we aimed to analyze the long-term effects of tonsillectomy on patients with IgAN, as an initial treatment and as a treatment at any time in their lives. Methods: In this retrospective cohort analysis, 1147 patients with IgAN were grouped according to whether they had undergone tonsillectomy at any time, >1 year after renal biopsy (study 1), or within 1 year after renal biopsy (study 2). The patients were propensity-score matched or divided into four groups according to their proteinuria and renal function. The 20-year renal survival rates were evaluated until serum creatinine levels doubled (primary end point) and ESKD occurred (secondary end point). Results: Patients in both studies had similar background characteristics after propensity score matching. In study 1, the renal survival rates for the primary and secondary end points were significantly higher for patients who underwent tonsillectomy at any time or >1 year after renal biopsy compared with those who did not. In study 2, the renal survival rates for the primary and secondary end points were significantly higher for patients who underwent tonsillectomy soon after renal biopsy compared with those who did not (primary end point, 98% versus 69%, P=0.001; secondary end point, 100% versus 75%, P=0.0001). A stratified analysis showed that significant treatment efficacy was observed for patients with proteinuria >1.0 g/d. Multivariate Cox regression analyses showed that tonsillectomy was associated with disease progression (hazard ratio, 0.27; P=0.04). Complications associated with tonsillectomy occurred in 8% of patients. Conclusions: Among patients with IgAN, tonsillectomy at any time of life, or soon after renal biopsy, prevents disease progression, and the procedure is relatively safe.

A case of Lemierre syndrome combined with a suspected systemic lupus erythematosus flare.

Lemierre syndrome develops in healthy young patients as a result of bacteremia after oral cavity infection. It causes thrombophlebitis in the internal jugular vein. Infection can easily occur during immunosuppressive treatment in patients with systemic lupus erythematosus and become severe. We present a case of Lemierre syndrome in a patient with systemic lupus erythematosus. A 56-year-old woman presented with fever, left lower toothache, and skin symptoms from the left neck to the anterior chest. Clinical presentation and laboratory investigations revealed Lemierre syndrome. The inflammation and thrombus disappeared with antibiotic and anticoagulant therapies. However, transient hypocomplementemia and elevated antinuclear antibody levels were observed during treatment; therefore, a concomitant systemic lupus erythematosus flare was considered. In systemic lupus erythematosus patients with Lemierre syndrome, complement and antinuclear antibody levels are modified, so other indicators should be precisely evaluated, such as levels of urinary protein, sediment, serum creatinine and anti-dsDNA antibody, and systemic lupus erythematosus disease activity index.

Primary IgA Vasculitis with Nephritis in a Patient with Rheumatoid Arthritis Diagnosed by Anti-galactose-deficient IgA1 Immunostaining.

Renal disease is a common complication of rheumatoid arthritis (RA) and can occur secondary to RA or be induced by therapeutic agents. Recently, glomerular deposition of galactose-deficient IgA1 (Gd-IgA1) was identified as a feature of primary IgA vasculitis with nephritis (IgA-VN). We herein report a case of IgA-VN in an RA patient whose disease activity was controlled by treatment with etanercept. To distinguish between primary IgA-VN and secondary IgA-VN caused by RA or etanercept, we performed immunostaining of renal biopsy sections with the Gd-IgA1-specific antibody KM55. Positive KM55 staining confirmed the diagnosis of primary IgA-VN in a patient with RA.

Comparison of the response of frequently relapsing steroid-dependent minimal change nephrotic syndrome to rituximab therapy between childhood-onset and adult-onset disease.

Rituximab has been approved in Japan for the treatment of intractable nephrotic syndrome, but in cases of childhood-onset disease only; its efficacy and safety in adult-onset disease has yet to be established. This study was undertaken to evaluate the efficacy of rituximab and adverse effects in patients with adult-onset minimal change nephrotic syndrome (MCNS).The study involved 32 childhood-onset cases (mean age at onset: 8.6 years) and 19 adult-onset cases (mean age at onset: 30.6 years) of frequently relapsing steroid-dependent MCNS, all of whom received intravenous rituximab drip infusion (375 mg/m body surface area per dose) at 4 time points at 6-month intervals. Relapse frequency, oral dose of immunosuppressants, and adverse effects were compared between the 2 groups.Remission was maintained in all cases in the childhood-onset and adult-onset groups; a significant reduction in relapse frequency was noted during the first 24 months of rituximab therapy (0.3 ±â€Š0.7 times and 0.3 ±â€Š0.6 times in the childhood-onset and adult-onset groups, respectively; P < .001). Oral corticosteroid therapy could be discontinued in 81.3% of cases of the childhood-onset group (26/32 cases) and in 70.6% of cases of the adult-onset group (12/17 cases); the oral corticosteroid dose was reduced significantly to 0.9 ±â€Š2.5 mg/day in the childhood-onset group and to 0.8 ±â€Š1.6 mg/day in the adult-onset group (P < .001). Cyclosporin treatment was also discontinued in 87.5% of cases in the childhood-onset group (21/24 cases) and in 80.0% of cases of the adult-onset group (15/21 cases); the oral cyclosporin dose was reduced significantly to 8.6 ±â€Š27.4 mg/day and 9.2 ±â€Š22.0 mg/day, respectively (P < .001). Regarding adverse reactions, infusion reactions developed at a frequency of 21.1% and 19.7% in both groups, respectively, with no significant inter-group difference (P = .72).Rituximab showed significant efficacy in adult-onset MCNS, with a comparable incidence of adverse reactions to that in childhood-onset cases, suggesting that this drug can also be used safely in adult-onset MCNS.

Rituximab as a Therapeutic Option for Steroid-Sensitive Minimal Change Nephrotic Syndrome in Adults.

Minimal change nephrotic syndrome (MCNS) usually responds to steroids but frequently relapses, requiring additional treatment with immunosuppressive agents. Rituximab is a chimeric murine/human monoclonal immunoglobulin G1 antibody that targets CD20, a B-cell differentiation marker. B-cell recovery begins at approximately 6 months following the completion of treatment. Rituximab has a beneficial effect, with the sustained remission or reduction of proteinuria in patients with steroid-dependent MCNS. Relapses are thought to be associated with an increase in CD19 cells. The mean serum half-life of rituximab was reported to be 10-15 days in patients with steroid-dependent MCNS. Only infusion reactions, such as rash and chills, occurred after single-dose rituximab infusion and can be managed by pre-medication or infusion rate adjustments. Even though severe adverse effects of rituximab are not expected, we must be aware of potentially life-threatening adverse effects. Controlled randomized trials that include adult patients with steroid-dependent MCNS are required to prove the efficacy and safety of rituximab and to evaluate the cost-effectiveness of rituximab treatment. In this review, we highlight recent studies and discuss the effects of these studies on the management of patients with MCNS in adults.

Successful treatment with steroid and cyclosporine A in a patient with immunoglobulin A-proliferative glomerulonephritis with monoclonal immunoglobulin deposits.

We report a case of glomerulonephritis with monoclonal immunoglobulin (Ig) A deposits as a form of monoclonal gammopathy of renal significance (MGRS) caused by monoclonal immunoglobulins without blood disorders in a 41-year-old woman. She developed lower leg oedema and was hospitalized because of nephrotic syndrome. Serum and urine were negative for M protein, and the free light chain κ/λ ratio was within the normal range. Renal histopathological findings included mesangial proliferation, endocapillary cell proliferation, and a double-contour appearance of the capillary walls. Immunofluorescent staining indicated IgA and C3 deposits on the mesangium and capillary walls. Only λ chain and IgA1 deposits were noted. Fine granular sub-endothelial deposits with no specific structure were observed under electron microscopy. The patient was diagnosed with IgA-proliferative glomerulonephritis with monoclonal immunoglobulin deposits (IgA-PGNMID). The patient had decreased urine protein and sediment erythrocytes after she underwent two rounds of steroid pulse therapy and oral steroid therapy, but proteinuria and haematuria still remained. Four months later, the patient was administered 50 mg/day cyclosporine (CsA), and proteinuria and haematuria dramatically decreased. Only a few case reports have been published on IgA-PGNMID. This case is rare in that the patient achieved successful treatment using a combination of steroids and CsA.

[Rituximab therapy in the treatment of anti-neutrophil cytoplasmic antibody (ANCA) -positive interstitial pneumonia: case report].

We report a patient treated with rituximab for interstitial pneumonia (IP) associated with microscopic polyangiitis (MPA) and who was undergoing hemodialysis. A 59-year-old woman who had been treated with tacrolimus for 1 year for rheumatic arthritis was referred to the Department of Nephrology for fatigue, fever, weight loss, and rapidly developing renal dysfunction. On the first admission, severe renal dysfunction, proteinuria, hematuria, and an elevated titer of MPO-ANCA were observed, and the woman was diagnosed with rapidly progressive glomerulonephritis because of MPA. At that point, IP was found to be present but not active. Although steroid semipulse therapy following an initial prednisolone (PSL) administration of 40 mg/day, IVCY, and plasma exchange were administered, renal dysfunction did not recover, and the patient required maintenance hemodialysis. Upon discharge, a high titer of MPO-ANCA was continuously observed. Nine months after the initiation of hemodialysis, respiratory discomfort and desaturation developed. Interstitial shadow and ground glass opacity were seen on a CT scan, and the patient was diagnosed with exacerbation of interstitial pneumonia caused by MPA recurrence. At the second admission, acute findings identified by imaging techniques had improved. However, the high titer of MPO-ANCA continued in spite of the steroid semi-pulse therapy following PSL administration, and rituximab corresponding to 200 mg/weekly for 1 month was also administered. The dose of rituximab was decreased subsequently because the patient was judged to be compromised by the hemodialysis. At the same time, internal administration of sulfamethoxazole/trimethoprim was initiated. After the rituximab treatment, MPO-ANCA antibodies gradually decreased, and the respiratory condition improved. Five months after the rituximab treatment, respiratory dysfunction recurred. Based on the CT findings and a high level of ß-D-glycan, the patient was diagnosed with ARDS due to pneumocystis pneumonia. In this case, rituximab was effective for IP due to MPA, but pneumocystis pneumonia could not be prevented in spite of prophylactic antibiotics. This case suggests that deliberative dose adjustments, careful patient observation, and prophylactic measures for infection are critical in rituximab treatment.

Amelioration of the adverse effects of prednisolone by rituximab treatment in adults with steroid-dependent minimal-change nephrotic syndrome.

BACKGROUND: We previously demonstrated the efficacy of single-dose 6-monthly rituximab infusions in 25 adults with steroid-dependent minimal-change nephrotic syndrome. Herein, we assessed the safety of rituximab treatment and its effect in ameliorating the adverse effects of prednisolone (PRED) in a larger study sample. METHODS: We treated 54 adult patients with four single-dose 6-monthly infusions of rituximab (375 mg/m(2) BSA per dose). We compared the adverse effects of PRED (osteoporosis, hypertension, and diabetes mellitus) between the first rituximab infusion (baseline) and the end of the 24-month observation period. In addition, we examined the adverse effects of rituximab during the same period. RESULTS: The PRED dose was significantly lower at 24 months than at the baseline. The bone density was significantly higher at 24 months as compared to the baseline value (Z score -1.8 vs. -1.1; p < 0.05). Blood pressure at 24 months was significantly lower than that at the baseline (120.9/74.4 vs. 111.8/70.3 mm Hg; p < 0.05). Eight patients with diabetes mellitus showed improved glycemic control at 24 months as compared to that at the baseline. There were no severe adverse effects of rituximab. However, mild infusion reactions occurred in 31 patients (57%). The frequency of the infusion reactions decreased significantly with every successive infusion. CONCLUSION: Rituximab treatment was effective and safe in patients with steroid-dependent nephrotic syndrome, allowed reduction of the PRED dose, and ameliorated the adverse effects of PRED. It may be preferentially used in patients at a risk of the adverse effect of PRED.

High uric acid level is a risk factor for progression of IgA nephropathy with chronic kidney disease stage G3a.

BACKGROUND: High uric acid level is a known risk factor for deterioration of renal function in chronic kidney disease (CKD), but its influence on the progression of IgA nephropathy (IgAN) remains unclear. METHODS: Adult IgAN patients (n = 611) were classified according to CKD stage. Renal survival rates and clinical and histological findings were compared between patients with high (H-UA) and normal (N-UA) uric acid levels in different CKD stages. RESULTS: The proportion of patients with H-UA increased significantly with increasing CKD stage (stage G1, 12.3%; stage G2, 19.0%; stage G3a, 43.7%; stage G3b-4, 69.0%; P < 0.001). The 30-year renal survival rate was similar in patients with H-UA and N-UA in CKD stages G1, G2, and G3b-4, but was significantly lower in patients with H-UA than with N-UA in CKD stage G3a (24.7 vs. 51.9%; P = 0.0205). The clinical findings were similar in patients with H-UA and N-UA, but the interval from onset to biopsy differed between groups. The proportion of patients with global sclerosis was significantly higher in patients with H-UA than with N-UA in CKD stage G3a (33.3 vs. 11.4%; P = 0.0005), but the Oxford classifications were similar between groups. Multivariate Cox regression analysis identified H-UA (HR 1.36, 95% CI 1.07-1.72, P = 0.011) and a large amount of proteinuria (HR 1.38, 95% CI 1.09-1.74, P = 0.0084) as independent predictors of end-stage renal disease. CONCLUSIONS: H-UA induced global glomerular sclerosis and accelerated the progression of IgAN in CKD stage G3a.

Long-term prognosis of adult patients with steroid-dependent minimal change nephrotic syndrome following rituximab treatment.

This study was to evaluate the long-term efficacy and safety of a single-dose rituximab regimen rituximab treatment in adult patients with steroid-dependent minimal change nephrotic syndrome (MCNS). We conducted a prospective cohort study with historical controls to evaluate the effect of single-dose infusions of rituximab at 375 mg/m2 BSA per dose administered at intervals of 6 months for a period of 24 months. At the end of the 24-month period, the patients were divided into the treatment continuation (n = 20) and treatment discontinuation (n = 5) groups according to their intention to continue/discontinue the treatment. A significant reduction in the total number of relapses was observed during the 24-month period after the first rituximab infusion as compared with that during the 24-month period before the first rituximab infusion (108 vs. 8, P < 0.001). Complete remission was induced/maintained in all patients from 12 to 24 months after the first rituximab infusion. In regard to the clinical course after 24 months, 4 of the 20 patients in the treatment continuation group discontinued the rituximab treatment after the fifth infusion and 2 patients discontinued the treatment after the sixth infusion. However, complete remission was maintained in all the 20 patients of this group during the 12-month observation period after the first four single-dose rituximab infusions. On the other hand, 1 of the 5 patients in the treatment discontinuation group developed relapse during the observation period after the first four rituximab infusions, and the rituximab treatment was resumed. In our trial, rituximab therapy was associated with maintenance of complete remission. Complete remission was maintained even in most of the patients who showed B-cell repletion after discontinuation of rituximab therapy. Thus, rituximab may be considered as a radical therapeutic agent for patients with steroid-dependent MCNS.

Relationship between serum fibroblast growth factor-23 level and mortality in chronic hemodialysis patients.

BACKGROUND: Fibroblast growth factor-23 (FGF23) is a phosphate-regulating hormone and is found to be markedly increased in patients with chronic kidney disease. The aim of the present study was to evaluate the relationship between serum FGF23 levels and mortality, including the impact of gender and cardiovascular disease (CVD), in a Japanese cohort of chronic hemodialysis (HD) patients. METHODS: Ninety-two maintenance dialysis patients (58 men; mean age 60.3 years) were included. Serum intact FGF23, calcium, phosphate, albumin, intact parathyroid hormone (PTH), and C-reactive protein were measured at baseline. CVD was defined as clinical symptoms and/or a history of CVD. RESULTS: During a median follow-up time of 53.2 months, 24 patients (26 %) died. Serum FGF23 levels were positively correlated with serum levels of calcium (r = 0.5433, P < 0.0001), phosphate (r = 0.5048, P < 0.0001), calcium × phosphate product (r = 0.6801, P < 0.0001), and intact PTH (r = 0.2710, P = 0.0090) (r = 0.27, P < 0.0001). In Cox proportional hazard models, serum FGF23 level was not associated with increased mortality risk, neither in crude nor in multivariate-adjusted models. However, in a subgroup analysis of women with previous CVD, serum FGF23 level above median was associated with higher cardiovascular event risk in crude models (hazard ratio 9.52, 95 % confidence interval 1.56-86.11, P = 0.0129). Kaplan-Meier analysis stratifying for the presence of CVD demonstrated a significant higher mortality risk in patients with history of CVD and higher serum FGF23 levels (P < 0.0001). CONCLUSION: Serum FGF23 level was not associated with increased mortality risk in this cohort of prevalent HD patients. These results suggest that the impact of FGF23 on mortality may be modified by gender and previous CVD and is blunted in the grade of hyperphosphatemia.

Left ventricular end-diastolic diameter is an independent predictor of mortality in hemodialysis patients.

Left ventricular (LV) function is impaired in most hemodialysis (HD) patients. We conducted an observational cohort study to investigate whether LV end-diastolic diameter (LVDd) could predict all-cause mortality in a cohort of 166 HD patients. The LVDd values (5.06 ± 0.64 cm) of the non-survivor group were significantly greater than in the survivor group (4.78 ± 0.71 cm). The area under the receiver operating characteristic curve for an LVDd cut-off value of 5.01 cm was 0.6145 (P = 0.0234). The sensitivity and specificity of the LVDd threshold of 5.01 cm were 75.7% and 50.4%, respectively. The 4-year survival rate was significantly lower in the group with LVDd ≥ 5.01 cm than in the group with LVDd < 5.01 cm (log-rank test, P = 0.0047). Multivariate analysis with adjustments for clinical and echocardiographic parameters showed that increased LVDd was an independent predictor of all-cause mortality (hazard ratio 2.363, 95% CI 1.320-4.228, P = 0.0013). The results of the present study showed that increased LVDd predicts the all-cause mortality of chronic HD patients better than other echocardiographic parameters. Our findings suggest that LVDd measurements may be helpful for risk stratification and providing therapeutic direction for the management of HD patients.

Elevated E/E' predicts cardiovascular events in hemodialysis patients with preserved systolic function.

OBJECTIVE: We conducted a cohort study to investigate whether diastolic function could predict cardiovascular (CV) events in 161 HD patients with preserved systolic function. MATERIALS AND METHODS: The ratio of early transmitral flow velocity to early mitral annular velocity (E/E') was measured by tissue Doppler imaging. Patients were stratified into two groups based on whether they experienced a CV event. RESULTS: During a 4-year follow-up period, 64 patients experienced a CV event. The E/E' values (15.18 ± 5.78) in the CV-event group were significantly higher than in the group who had not experienced a CV event (12.32 ± 4.23). Kaplan-Meier analysis indicated that the incidence of CV events was significantly higher in the group of patients whose E/E' was >15 than in the group whose E/E' was ≤ 15 (log-rank p=0.0016). Multivariate Cox proportional hazards regression analysis revealed the E/E' ratio to be a significant predictor of CV events in HD patients with preserved LV systolic function. CONCLUSION: The results of this study showed that elevated E/E' ratio in chronic HD patients predicts CV events better than other echocardiographic parameters.

A case of AL amyloidosis with renal rupture.

We report a 59-year-old woman with AL amyloidosis who presented with massive bleeding from the right kidney, in whom emergency surgery proved to be life saving. The patient had been diagnosed as having AL amyloidosis 16 years previously. After 5 years, hemodialysis had been initiated. In 2007, a large right-sided perinephric, intracapsular hematoma was detected. Right nephrectomy was performed and the patient recovered with no sequelae. Histopathological examination revealed a greater degree of amyloid deposition in the resected kidney than that at the time of diagnosis. Amyloid angiopathy may promote bleeding.