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Notes: IgA nephropathy (IgAN) is a common disease characterized by predominant IgA deposits in the renal mesangium. It is well-known that IgA1 among two subclasses, IgA1 and IgA2, is the dominant deposit in the glomeruli during IgAN. The most prominent structural difference between the IgA1 and IgA2 subclasses was the duplicated proline-rich hinge portion and the characteristic O-linked oligosaccharide chains on the IgA1 hinge portion. There are many reports on the presence of an incompletely glycosylated O-linked oligosaccharide (s) on the IgA1 hinge region in some of the IgAN patients. It was also reported that the artificially deglycosylated IgA1 acquired binding ability for fibronectin, type IV collagen and laminin.In this experiment, preparation and analysis of binding protein (IgA1-BP) to the hypoglycosylated IgA1/Sepharose column were carried out. In order to examine the presence of the specific binding protein to the hypoglycosylated IgA1 in human serum, IgA1, asialo-IgA1 and asialo-agalacto-IgA1/Sepharose column chromatography of normal human serum was carried out. A portion of the serum protein was bound to those columns and eluted with the buffer containing 1.0 M NaCl. About four times the amount of protein was eluted from the hypoglycosylated IgA1/Sepharose column than that from IgA1/Sepharose. Most of the eluted protein was IgG, and the IgG1 and IgG3 subclasses but neither IgG2 nor IgG4 was dominant (〈link href="#f1"〉Fig. 1). The Protein A passed-fraction (PAP fraction) of the IgA1-BP seemed to contain proteins other than IgG, a detailed analysis of the PAP fraction was carried out. The PAP fraction was composed of a relatively large amount of IgA, IgM and complement C3 besides IgG. The relative content of IgG : IgA : IgM : C3 : C4 was 25 : 10 : 41 : 22 : 2 in the PAP fraction. Meanwhile, the Protein A bound-fraction of IgA1-BP was essentially composed of IgG (78%) and IgM (19%) (〈link href="#f2"〉Fig. 2). Since the deposited IgA1 in IgA nephropathy patient was reported as hypoglycosylated IgA1, the obtained results might explain well the high frequency of copresence of IgM and C3 with the deposited IgA1 in IgAN patients. With respect to the IgA content in the IgA1-BP from IgAN patients, it was significantly higher than that from other nephropathy patients (〈link href="#f3"〉Fig. 3). Both of the samples contained a few microgram of abberant IgA per millilitre of serum.〈figure xml:id="f1"〉1〈mediaResource alt="image" href="urn:x-wiley:13205358:NEP5:NEP_5_f1"/〉IgG subclass ratio in normal serum and IgA-BP.〈figure xml:id="f2"〉2〈mediaResource alt="image" href="urn:x-wiley:13205358:NEP5:NEP_5_f2"/〉Relative content of IgG, IgA, IgM, C3 and C4 in the PAP and PAB fractions of IgA1-BP.〈figure xml:id="f3"〉3〈mediaResource alt="image" href="urn:x-wiley:13205358:NEP5:NEP_5_f3"/〉Total amount of IgA1-BP and content of IgA in IgA1-BP prepared from nephropathy patients.Thus, the obtained results indicated hypoglycosylated IgA-BP were IgG1, IgG3, IgA, IgM, C3.

Notes: This study was undertaken to clarify prognostic indices of a long-term clinical course in IgA nephropathy in large series.〈section xml:id="abs1-1"〉〈title type="main"〉PATIENTSFrom 1972 to 1990, a total of 603 patients were diagnosed to have primary IgA nephropathy in our renal unit. Of these patients 366 patients were continuously followed up for 10 years or more. These patients were the subjects of this study.〈section xml:id="abs1-2"〉〈title type="main"〉METHODSAs predictive factors, several parameters were evaluated as follows: initial proteinuria; initial creatinine clearance (Ccr) values; initial hypertension; histological severity (eight parameters and total score); % duration of massive proteinuria (%DP); % duration of hypertension (%DH). %DP was defined as [(duration of proteinuria of 1.0g/day or more ÷ total duration of follow-up observation) × 100]. %DH was defined as [duration of hypertension ÷ total duration of follow-up observation] × 100].As histological severity, eight parameters were evaluated according to the semiquantitative method of Pirani et al. Each of these lesions was graded from 0 to 3. A total score was defined as a total of all eight scores, graded from 0 to 24.During the 10-year follow-up observation, corticosteroid treatment was conducted in 112 patients. Most of the patients received antiplatelet drugs. Hypertensive patients were treated with antihypertensive therapy.Final outcome at 10 years since the initial renal biopsy was divided into three clinical courses as follows: a stable course was defined as no decrease of renal function for 10 years; a progressive course was defined as a decrease of 15% or more of initial Ccr values without going into HD; and haemodialysis (HD).Univariate analysis for these predictive factors was performed by using one-factor ANOVA corrected by Bonferroni/Dunn or Kruskal-Wallis test to determine the final outcome. A multivariate analysis was done by using a logistic model.〈section xml:id="abs1-3"〉〈title type="main"〉RESULTSThe age of the 366 patients was 33 ± 10 (range: 13–61); gender (M/F) 181/185; initial proteinuria 1.0 ± 1.0g/day (range: 0–6.6); initial Ccr values 85 ± 21 mL/min (range: 25–139); initial hypertension 63 cases (17%); total score as histological severity 7.7 ± 4.6.The final proteinuria was 0.9 ± 1.0 g/day (range: 0–5.7); final Ccr values 58 ± 38 mL/min (0–128); final hypertension 94 cases (25%); %DP 33 ± 39; %DH 18 ± 30. Numbers of patients having a stable course, a progressive course and haemodialysis were 192 (52%), 89 (25%) and 85 (23%), respectively.Clinical prognostic indices showed significant differences in age, initial proteinuria, initial Ccr, initial hypertension, %DO and %DH, respectively (P 〈 0.0001). Treatment with corticosteroids was significantly frequent in progressive and haemodialysis groups than a stable group (P 〈 0.0003).Histological prognostic indices showed significant differences in hypercellularity, active crescent, tuft adhesion, mesangial sclerosis, global sclerosis, tubular atrophy, interstitial fibrosis, vascular sclerosis and total score (P 〈 0.005).Multivariate analysis of clinical prognostic indices showed the highest relevance in %DP (relative risk 32.9, P 〈 0.0001), followed by %DH (relative risk 14.2, P 〈 0.0001).Multivariate analysis of histological prognostic indices showed the highest relevance in tubular atrophy (relative risk 9.2, P 〈 0.002), followed by interstitial fibrosis (relative risk 3.0, P 〈 0.05).Multivariate analysis of clinicohistological indices showed the highest relevance in %DP (relative risk 38.0, P 〈 0.0001), followed by %DH (relative risk 18.7, P 〈 0.0001).Patients with 30% or less in %DP underwent a favourable clinical course, while patients with 40% or more had a poor prognosis.%DH was one of the most reliable prognostic indices. However, there was no evidence of a turning point determining a long-term prognosis.〈section xml:id="abs1-4"〉〈title type="main"〉COMMENTThirty-three years have passed since IgA nephropathy was first reported in 1968. Many investigations have documented a long-term prognosis of the disease and predictive factors for a long-term clinical course. It is generally accepted that the renal survival rate of the disease is recognized to be 70–80% 10 to 20 years after clinical onset. Clinically, initial proteinuria and initial renal function are well related with a long-term prognosis. Histologically, interstitial fibrosis is a most reliable predictive factor for a poor prognosis as well. However, there are few reports evaluated by a large series with a long-term follow-up observation.In this study, all 366 patients have been continuously followed up for 10 years since the first renal biopsy. About 50% of the patients underwent a progressive course, with 25% of the total patients entering into chronic haemodialysis. Multivariate analyses of clinical and histological predictors at the time of the first renal biopsy indicated that not only initial proteinuria and initial renal function but also tubular atrophy and interstitial fibrosis are very important factors, as reported previously.However, in practical clinical observation, it is difficult to predict a long-term prognosis merely at the time of renal biopsy. Therefore, careful follow-up observation is needed to evaluate the disease activity.In the present study, the continuous examination of daily urinary protein excretion and blood pressure was performed during a follow-up period of 10 years. As the result, %DP of 1.0 g/day or more is clarified to be the most reliable independent predictor for a long-term prognosis, followed by %DH. Moreover, 40% or more of %DP is found to be well related with a poor prognosis.In conclusion, the most reliable, independent factor determining a long-term prognosis in IgA nephropathy is persistent massive proteinuria of 1.0 g/day or more.

Notes: Summary The male-to-female sex ratio at birth of the first-born babies delivered in Japan to mothers aged 25 years or less was investigated in two groups: a hospital group and a questionnaire group. The sex ratio fluctuated according to their mother's month of birth. Between 1924 and 1928, the sex ratio of the offspring of the mothers born in March-May in both groups was significantly higher than that of the other mothers. We speculate about the relationship between the sex ratio at birth and the mother's month of birth.