Mitsuhiro Sato

Cohort Study of Advanced IgA Nephropathy: Efficacy and Limitations of Corticosteroids with Tonsillectomy

Background: Elevated serum creatinine is associated with poor outcome in IgA nephropathy (IgAN). The efficacy and limitations of corticosteroids in advanced IgAN (Cr ≧1.5 mg/dl), however, remains controversial. Methods: We retrospectively investigated 70 patients with advanced IgAN (Cr ≧1.5 mg/dl) classified into three groups according to their treatment regimens, that is, steroid pulse with tonsillectomy, conventional steroid, and supportive therapy. We evaluated the three groups to elucidate predictors for the endpoints ESRF and doubled serum creatinine from baseline. Results: Steroid pulse with tonsillectomy, conventional steroid and supportive therapy were performed in 30, 25 and 15 patients, respectively. During the mean follow-up period of 70.3 (12–137) months, 41.4% of patients reached ESRF (13.3 vs. 56.0 vs. 73.3%, p < 0.001) and 45.7% doubled serum creatinine from baseline (16.7 vs. 64.0 vs. 73.3%, p < 0.001). The incidence of ESRF in the patients treated by steroid pulse with tonsillectomy was significantly lower than the incidences in the patients treated by conventional steroid and supportive therapy at a baseline creatinine level of 1.5–2 mg/dl, but no statistical difference was observed at a level of >2 mg/dl. The Kaplan-Meier estimated probability of renal survival without ESRF was 89.2, 74.1 and 72.2% at 5 years and 82.8, 51.0 and 45.1% at 8 years, respectively (p = 0.017). The predictors for ESRF, identified in a Cox proportional hazards model, were baseline serum creatinine (p < 0.001) and interstitial infiltrate (p = 0.003). Steroid pulse with tonsillectomy also had a protective effect on the risk of reaching ESRF (p = 0.013). By target cross-stratification, the patients with baseline creatinine of 1.5–2 mg/dl who underwent steroid pulse with tonsillectomy showed a better renal survival rate than the others (p < 0.001). Conclusion: Steroid pulse therapy combined with tonsillectomy may be more effective than conventional steroid therapy in patients with a baseline creatinine level of ≤2 mg/dl.

Glomerulo-tubular junction stenosis as a factor contributing to glomerular obsolescence in IgA nephropathy

Periglomerular fibrosis (PF) is an interstitial injury observed in various renal diseases. It is speculated that this lesion, by occluding the glomerulo‐tubular junction (GTJ) and causing atubular glomeruli, may result functionally in a reduction of the glomerular filtration rate (GFR) and may be a factor contributing to the progression of renal disease. In the present study, 340 renal biopsy specimens were analysed to determine whether or not there was nephron injury derived from such a mechanism, as well as direct glomerular injury, in IgA nephropathy (IgAN). The patients were divided into five groups according to the degree of glomerular sclerosis. The average age was lower in groups with milder sclerosis and serum creatinine (Cr) was elevated in groups with more severe sclerosis. Because the GTJ was assumed to disappear when an atubular glomerulus was formed, the ratio of the number of glomeruli with discernible GTJ to the total number of glomeruli was evaluated. As glomerular sclerosis progressed, discernible GTJ reduced significantly (p<0.001) and the degree of PF increased significantly (p<0.05). By serial section study in cases with pronounced PF, transitions between the stages of stenosis of the GTJ and atubular glomeruli were observed. It is speculated that the occlusion of the GTJ eventually hyalinizes the glomerulus; in such cases, glomerular obsolescence of the collapse type might be formed. On the other hand, obsolescence of the mesangial proliferative type might be formed in the hyalinization derived from direct glomerular injury. In this context, glomerular obsolescence of the collapse type was observed more frequently and was accompanied by more increased PF than obsolescence of the mesangial proliferative type (p<0.001). These results suggest that in addition to direct glomerular injury, nephron injury derived from interstitial damage of this type plays an important contributory role in the progression of IgAN. Copyright

Fabry's disease discovered with chance urinary mulberry cells: a case report

Fabry’s disease (FD) is a rare X-linked lysosomal storage disorder. Novel enzyme replacement therapy (ERT) at an early stage can slow the progression of cardiovascular and renal dysfunction. Urinary mulberry cells are occasionally found in renal FD. We report a case of variant FD in which detection of urinary mulberry cells led to an early diagnosis. A 36-year-old Japanese man was referred to our hospital because mulberry cells had been detected during urinalysis. Proteinuria and renal dysfunction were not observed. His plasma alpha-galactosidase activity was very low. Renal biopsy revealed typical foamy changes in the glomerular podocytes and tubular epithelial cells that are found in renal FD. Based on the detection of urinary mulberry cells, we successfully started ERT before the patient’s renal function deteriorated. Clinical nephrologists and laboratory technicians should recognize the importance of screening for mulberry cells during urinalysis as this is a simple, inexpensive, and non-invasive method for diagnosing FD.

Proliferative glomerulonephritis with monoclonal IgM-κ deposits in chronic lymphocytic leukemia/small lymphocytic leukemia: case report and review of the literature

A 48-year-old man with chronic lymphocytic leukemia presented with nephrotic syndrome, hematuria, and mild deterioration of renal function. Further analysis using serum immunofixation electrophoresis detected monoclonal immunoglobulin (Ig) M-κ and IgG-κ M-protein. Testing for cryoglobulin in serum was negative. Light microscopy of a renal biopsy specimen showed membranoproliferative glomerulonephritis features with marked mononuclear cell infiltration in the interstitium. On immunofluorescence study, the deposition of IgM heavy chain was predominantly observed with the same distribution of κ light chain, whereas no λ light chain was found. Electron microscopy revealed fine granular deposits in the mesangial, subendothelial, and subepithelial areas, mimicking those observed in the immune complex-mediated glomerulonephritis. These pathological findings were consistent with recently described cases of proliferative glomerulonephritis with monoclonal IgG deposits. Thus, monoclonal IgM deposition can also cause proliferative glomerulonephritis.

Steroid pulse therapy transiently destroys the discriminative histological structure of tonsils in IgA nephropathy: Tonsillectomy should be performed before or just after steroid pulse therapy

OBJECTIVE Tonsillectomy combined with steroid-pulse therapy is a widely accepted method for the treatment of IgA nephropathy (IgAN) in Japan. However, the indication of tonsillectomy for IgAN is still controversial, and the timing of tonsillectomy is not clearly defined for the protocol of this therapy. Based on the results of a randomized control trial in Japan, the Evidence-Based Clinical Practice Guidelines for IgA nephropathy 2014 (edited in Japan) recommended tonsillectomy combined with steroid-pulse therapy for Grade C1. However, this is not widely accepted worldwide. To clarify the validity and timing of tonsillectomy, we evaluated how the three-consecutive steroid-pulse therapy method affects the tonsil tissues of IgAN patients. METHODS We examined tonsil specimens from 35 IgAN patients and 8 chronic tonsillitis patients. We compared the proportion of follicular area to total tonsillar area and the number of germinal centers between each group on hematoxylin and eosin stained pathological specimens to clarify the histopathological characteristics of tonsils from IgAN patients. Based on these findings, we examined the tonsils of patients after three-consecutive steroid-pulse therapy treatments (n=34) to determine the influence of this therapy on the tonsil tissues of IgAN patients. Moreover, we observed chronological changes in tonsil tissues after steroid-pulse therapy. RESULTS The extrafollicular area was enlarged in IgAN patients before steroid-pulse therapy compared with chronic tonsillitis patients. Just after steroid-pulse therapy, the follicles became very small with blurry outlines, and the number of germinal centers was remarkably decreased. With a gradual decrease in oral prednisolone, the tonsil tissue structure was gradually restored. CONCLUSION Tonsillectomy combined with steroid-pulse therapy is considered a reasonable treatment for IgAN. Steroid-pulse therapy-induced histological changes in tonsils were transient, indicating tonsillectomy should be performed before or just after steroid-pulse therapy.

Suboptimal initiation predicts short-term prognosis and vulnerability among very elderly patients who start hemodialysis: Prognosis of elderly hemodialysis patients

A recent, growing concern regarding haemodialysis in Japan is a sustained increase in the elderly population. Among very elderly people who start haemodialysis, the prognosis is considered to be poor; however, this has not been fully elucidated. This study aimed to discover the short‐term prognosis and related factors in very elderly patients who commence haemodialysis.

The size of palatine tonsils cannot be used to decide the indication of tonsillectomy for IgA nephropathy

Abstract Background. Tonsillectomy is one of the treatment strategies for immunoglobulin A nephropathy (IgAN). The relationship between the indication of tonsillectomy and the size of palatine tonsils (PTs) in patients with IgAN remains controversial. Methods. This retrospective cohort study investigated 57 patients with IgAN who underwent tonsillectomy combined with steroid pulse therapy (SPT). They were classified into two groups, the hypertrophy group and the nonhypertrophy group, according to the weight of their excised PTs. The effects of tonsillectomy combined with SPT on clinical remission (CR) and the histopathological findings of PTs were compared between the two groups. Results. During the mean follow-up period of 45.5 (range 6–133) months, 78.9% of the patients achieved CR (79.3 versus 78.6%, P = 0.945) and the baseline serum creatinine doubled only in one patient in the nonhypertrophy group (0 versus 3.6%, P = 0.491). No significant difference was observed in the incidence of CR between the two groups by the Kaplan–Meier method (P = 0.839). The predictor for CR, identified in Cox proportional hazards models, was baseline proteinuria [hazard ratio 0.14 (95% CI 0.032–0.621) P = 0.010]. Although macroscopic pus plugs were observed on the surface of PTs in almost 60% of patients in each group, microscopic pus plugs in the crypt and the enlarged interfollicular area were observed in all patients. Conclusions. The treatment effect of tonsillectomy combined with SPT and the pathological features of PTs in IgAN were equal, regardless of the size of the PTs. Therefore, the size of PTs should not be included as a factor when deciding the indication of tonsillectomy for IgAN.

Efficacy of statin on vascular access patency in diabetic hemodialysis patients

Introduction An effective approach to prevent hemodialysis vascular access dysfunction is still unclear despite previous studies, which have shown conflicting results of several drugs on vascular access outcomes. In this study, we focused on diabetic hemodialysis patients with native arteriovenous fistula and evaluated the impact of statin treatment on vascular access patency. Methods A retrospective cohort study of 268 consecutive patients who newly started hemodialysis due to diabetic nephropathy between January 2011 and December 2013 at Japan Community Health Care Organization Sendai Hospital was performed and the patients were followed for two years. The primary outcome was vascular access dysfunction. Effect of statin treatment was examined using Kaplan Meier analysis and Cox proportional hazard, after adjusting for covariates. Results The mean follow-up period was 426.7 days, and 117 (52.2%) patients developed vascular access dysfunction. The two-year patency rate was 55.0% among statin users and 36.1% in non-users. Vascular access survival period was significantly longer among statin users (log-rank test, p = 0.004). In multivariable analysis, statin treatment is significantly associated with better vascular access outcomes, in which the hazard ratio was 0.71 (95% CI, 0.52 to 0.97; p = 0.028) in the unadjusted model and 0.63 (95% CI, 0.45 to 0.88; p = 0.007) after adjustment for covariates. Conclusions Statin treatment could be associated with improved vascular access dysfunction among diabetic hemodialysis patients.

Evaluation of coagulation and fibrinolysis in haemodialysis patients at different haematocrit levels: Comparison between patients with and without diabetes

SUMMARY: There is an insufficient number of reports concerning the optimal haematocrit level for haemodialysis patients with diabetes. Although many reports have indicated that recombinant human erythropoietin (rHuEPO) therapy does not influence the incidence of intravascular thrombosis, no study has focused its attention on the difference of the coagulation‐fibrinolysis system between haemodialysis patients with and without diabetes. We studied eight patients with diabetes and seven patients without diabetes who had been undergoing regular haemodialysis. In all 15 patients, rHuEPO administration was started at a haematocrit level of 20% and toe haematocrit tevels were gradually increased from 20 to 30%. Coagulation and fibrinolysis functions, measured at haematocrit levels of 20,25 and 30%, respectively, were compared between the two groups. In the diabetic group, platelet count, fibrinogen, thrombin‐antithrombin III complex, frtmn/fibrinogen degradation products = D dimer, platelet factor 4 and platelet adhesion were statistically higher (P < 0.05), and plasminogen and α2‐plasmin inhibitor was statistically lower (P < 0.05) than those in the non‐diabetic group, even at the 20% level. These abnormalities at the baseline were extremely enhanced in connection with haematocrit increased by rHuEPO. the diabetic group, in particular, showed greater increases of platelet factor 4, platelet adhesion and thrombomodulin and a decrease of α2‐plasmin inhibitor from the 20% to the 30% level (P < 0.05) than the non‐diabetic group. These findings suggest that haemodialysis patients with diabetes generally have enhanced thrombotic parameters compared with haemodialysis patients without diabetes, and the increase of haematocrit makes the difference greater. Accordingly, the target level of haematocrit for patients with diabetes should be set separately from that of patients without diabetes.