Keita Hirano

A multicenter randomized controlled trial of tonsillectomy combined with steroid pulse therapy in patients with immunoglobulin A nephropathy

Background The study aim was, for the first time, to conduct a multicenter randomized controlled trial to evaluate the effect of tonsillectomy in patients with IgA nephropathy (IgAN). Methods Patients with biopsy-proven IgAN, proteinuria and low serum creatinine were randomly allocated to receive tonsillectomy combined with steroid pulses (Group A; n = 33) or steroid pulses alone (Group B; n = 39). The primary end points were urinary protein excretion and the disappearance of proteinuria and/or hematuria. Results During 12 months from baseline, the percentage decrease in urinary protein excretion was significantly larger in Group A than that in Group B (P < 0.05). However, the frequency of the disappearance of proteinuria, hematuria, or both (clinical remission) at 12 months was not statistically different between the groups. Logistic regression analyses revealed the assigned treatment was a significant, independent factor contributing to the disappearance of proteinuria (odds ratio 2.98, 95% CI 1.01–8.83, P = 0.049), but did not identify an independent factor in achieving the disappearance of hematuria or clinical remission. Conclusions The results indicate tonsillectomy combined with steroid pulse therapy has no beneficial effect over steroid pulses alone to attenuate hematuria and to increase the incidence of clinical remission. Although the antiproteinuric effect was significantly greater in combined therapy, the difference was marginal, and its impact on the renal functional outcome remains to be clarified.

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

BACKGROUND AND OBJECTIVES 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. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS 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). RESULTS 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. CONCLUSIONS 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.

Significance of mesangial expression of α-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.

Macrophage‐colony stimulating factor (M‐CSF) enhances proteinuria and recruitment of macrophages into the glomerulus in experimental murine nephritis

In this study, we examined the effects of macrophage‐colony stimulating factor (M‐CSF) on glomerular macrophages in lipopolysaccharide (LPS)‐induced murine nephritis. Mice injected intraperitoneally with either M‐CSF plus LPS, LPS alone, M‐CSF alone or saline every day for 8 days were examined for the degree of urine albumin excretion and lymphocyte‐function associated antigen‐1‐positive (LFA‐1+) cells in peripheral blood as well as renal pathology. From our results, LPS or M‐CSF combined with LPS emphasized the degree of proteinuria, glomerular deposition of immunoglobulins and mesangial proliferation, associated with accumulation of macrophages in the glomeruli. However, in immunohistological examination of kidneys from these nephritic mice, neither intercellular adhesion molecule‐1 (ICAM‐1), which may play an important role in the recruitment of macrophages into glomeruli, M‐CSF receptor nor the number of LFA‐1+ cells in peripheral blood was enhanced by M‐CSF. On the other hand, M‐CSF alone induced neither proteinuria nor any pathological changes and did not increase the number of glomerular Mac‐1+ cells above that in saline‐treated controls. These results indicate that M‐CSF does not directly cause glomerulonephritis but might participate in accelerating the glomerular inflammatory process by stimulating a potent chemoattractant to recruit monocytes‐macrophages into the glomeruli.

Factors related to the glomerular size in renal biopsies of chronic kidney disease patients.

BACKGROUND Glomerular enlargement is an important process that preserves the optimal surface area of glomerular capillaries under both physiological and pathological conditions. However, information is limited regarding how the glomerular size is defined, especially in chronic kidney disease (CKD) patients. METHODS A total of 206 renal biopsy specimens obtained from two different patient cohorts with or without a diagnosis of glomerulonephritis (non-GN group and IgAN group) were examined. The mean glomerular volume was estimated from the outer capillary area of individual glomeruli, and the clinicopathological factors at biopsy that were associated with the mean glomerular volume were analyzed in each group. RESULTS The mean glomerular volume showed maximal 5.8 and 7.9-fold variations between individuals in the non-GN and IgAN groups, respectively. In both groups, the body mass index and glomerular density (non-sclerotic glomerular number per renal cortical area of the biopsy) were consistently identified as independent factors that were associated with the mean glomerular volume. In addition, the multivariate analyses using the glomerular density/body mass index ratio showed a more close association with the mean glomerular volume than the analyses using each measure separately. CONCLUSION These results suggest that factors presumably reflecting both body consumption and nephron number have close relationships with the glomerular size, regardless of mechanism(s) underlying the injury. The most relevant factor affecting glomerular size may be a balance between these two measures.

A Predictive Clinical Grading System for Immunoglobulin A Nephropathy by Combining Proteinuria and Estimated Glomerular Filtration Rate

Background: There is no clinical classification of immunoglobulin A nephropathy (IgAN) in clinical practice. In this study, we used receiver-operating characteristic (ROC) analysis to create accurate clinical grades based on clinical parameters associated with the development of end-stage renal disease (ESRD) in IgAN patients. Methods: We performed a retrospective analysis of 116 patients with IgAN. The association between clinical variables and progression to ESRD was examined. Results: Logistic regression analysis indicated that 24-hour urinary protein excretion (UPE) and the estimated glomerular filtration rate (eGFR) at the time of renal biopsy (RBx) were independently associated with the development of ESRD. When combining UPE and eGFR, the areas under the curve were superior to those for UPE or eGFR alone. Moreover, two-graph ROC analysis indicated that the threshold values for UPE and eGFR in predicting future ESRD were 1.0 g/day and 64.0 ml/min/1.73 m2, respectively. Of note, the patients were classified into 4 grades by levels of UPE and/or eGFR, and the OR for risk of ESRD rose significantly from grade I to grade IV. Conclusion: The combination of UPE and eGFR at the time of RBx can improve the predictive accuracy of risk for subsequent ESRD in IgAN patients.

Possible prevention of dialysis-requiring congestive heart failure by angiotensin-II receptor blockers in non-dialysis Japanese patients with Stage 5 chronic kidney disease

Background: Preventive medications for dialysis-requiring congestive heart failure (CHF) in non-dialysis Japanese patients with Stage 5 chronic kidney disease (CKD) are unknown. Our aim was to explore which CKD medication was associated with a reduced prevalence of dialysis-requiring CHF in non-dialysis Japanese patients with Stage 5 CKD. Methods: The present multicenter, retrospective, cross-sectional study examined the association between CKD medications and the prevalence of dialysis-requiring CHF in non-dialysis Japanese patients with Stage 5 CKD. Results: There were 1536 Japanese Stage 5 CKD patients who satisfied our inclusion criteria. We had 309 (20.1%) patients whom had developed dialysis-requiring CHF and 940 patients (60.8%) whom had been using angiotensin-II receptor blockers (ARBs) before initiating dialysis. In our multivariate analysis, only ARB use was significantly associated with a lower risk of CHF (Odds ratio (OR): 0.680, 95% confidence interval (CI): 0.516–0.897; p = 0.0064), of the CKD treatments examined in this study. Conclusions: We found that ARB use during the pre-dialysis period is associated with a lower prevalence of CHF in the non-dialysis Japanese patients with Stage 5 CKD, suggesting a possible prevention of dialysis-requiring CHF by ARBs, in non-dialysis Japanese patients with Stage 5 CKD.

Bacterial Superantigen Enhances Cytokine Production by T-Helper Lymphocyte Subset-2 Cells and Modifies Glomerular Lesions in Experimental Immunoglobulin A Nephropathy

BackgroundThe purpose of this study was to examine the effects of bacterial suporantigens, which can derange the immune response and contribute to the renal lesions of immunoglobulin A (lgA) nephropathy.MethodsTwenty-five micrograms of a bacterial superantigen, staphylococcal enterotoxin B (SEB), was injected into IgA nephropathy-prone ddY mice intrathymically when they reached 6 weeks of age. Evaluation included measurement of albumin excretion in urine, immunoglobulin concentration, and lymphokine production in vitro, as well as analysis of T-cell receptor expression in splenic T-cell subsets and examination of renal histology by light and fluorescence microscopy.ResultsAt 40 weeks of age, the serum level of IgA in these mice was substantially increased and the number of Vβ8+ CD4+splenic T-cells was significantly decreased compared with measurements in untreated controls. Both control and SEB-treated mice excreted less than 30 μg/mL of urinary albumin. In mice given SEB, the amount of interleukin 2 (IL-2) and tumor necrosis factor-α (T helper 1 [Th1]-type cytokines) produced by the in vitro-stimulated lymphocytes significantly decreased. whereas that of interleukin 4 (IL-4) and interleukin 6 (IL-6) (Th2-type cytokines) markedly increased compared with measurements in control mice. At 40 weeks of age, mice given SEB showed marked glomerular hypercellularity and enhanced glomerular C3 deposition by renal histology, compared with control mice.ConclusionThese results suggest that bacterial superantigen SEB may modify glomerular lesions through activating Th2 cells, while inducing deletion of Th1 cells in this experimental model.

Clinical and Pathological Characteristics of Elderly Japanese Patients with IgA Vasculitis with Nephritis: A Case Series

Objective This case series aimed to identify the clinical and pathological characteristics of elderly patients (≥60 years) with biopsy-proven IgA vasculitis with nephritis (IgAVN). Methods The clinical and pathological presentation and treatment outcomes were compared between two groups. Patients Patients with IgAVN who were ≥19 years old at the time of their renal biopsy were divided into elderly (≥60 years) and adult (19-59 years) groups. Results Of the 23 patients in our study, 13 were elderly. In the elderly group, the median age at the diagnosis was 68 years (range, 60-85 years), with a median follow-up period of 15 months (range, 3-80 months). Twelve elderly patients had comorbidities, including hypertension, diabetes mellitus, chronic kidney disease, cardiovascular disease, and malignancies. A decrease in the estimated glomerular filtration rate, as well as massive proteinuria and rapidly progressive nephritic syndrome, were more frequent in the elderly group than in the adult group. Furthermore, renal pathological changes, including cellular or fibrocellular crescents, interstitial fibrosis, tubular atrophy, and arteriosclerosis, were more severe among elderly patients than adult patients. All elderly patients were treated with glucocorticoids and had no incidence of end-stage renal disease at the final follow-up; in addition, nine elderly patients had reduced proteinuria with a preserved renal function. Adverse events, including infection, diabetes mellitus, and vascular disorders, were identified in nine patients. Three elderly patients died from severe infections. Conclusion IgAVN in elderly patients is characterized by severe renal involvement. Elderly patients are at higher risk than adults for treatment-related adverse events.

Warning from constricted and wrinkled internal jugular vein

A 76-year-old man was admitted to our hospital for induction of hemodialysis due to advanced diabetic nephropathy. Since he had no permanent blood access, insertion of a temporary hemodialysis catheter was attempted at the right internal jugular vein. As the targeted vessel was easily confirmed by ultrasound, the initial puncture was not difficult. However, when the guiding wire was introduced, it did not advance beyond 10 cm from the puncture site. Venography was immediately performed, which showed narrowing and meandering of the central part of the internal jugular vein, which was hardly confirmed by ultrasound (Fig. 1). Finally, another temporary hemodialysis catheter was inserted at the right femoral vein. Today, ultrasound-guided method is the mainstay for internal jugular vein cannulation at bedside [1]. However, the present case demonstrated an important disadvantage of ultrasound-guided cannulation. Physicians should be reminded of clinical implications of classical venography in cases where smooth passage of guiding wire is impossible under ultrasound guidance.