Steroid pulse therapy combined with tonsillectomy in IgA nephropathy associated with diabetes mellitus.

Ten patients with biopsy-confirmed IgA nephropathy associated with diabetes mellitus underwent dietary weight control and three courses of intravenous pulses of methylprenisolone followed by prednisolone for 6-12 months and tonsillectomy. The average length of the follow-up period was 47.8 (range 30-96) months. As compared with pretreatment values, hematuria, proteinuria, body mass index, and hemoglobin A(1c) were significantly improved after treatment. There were no significant differences with regard to blood pressure and glycemic blood glucose control. There was no worsening of diabetic retinopathy and nephropathy. During steroid pulse therapy, the patients who were treated with insulin needed a higher dosage of insulin; after steroid pulse therapy, the dosage returned to baseline. Even patients with IgA nephropathy and diabetes mellitus could be treated with combined therapy and showed beneficial responses, it they succeeded in reducing body mass index.

Tonsillectomy and steroid pulse therapy significantly impact on clinical remission in patients with IgA nephropathy.

We conducted a retrospective investigation of renal outcome in 329 patients with immunoglobulin A (IgA) nephropathy with an observation period longer than 36 months (82.3 +/- 38.2 months) in our renal unit between 1977 and 1995. Clinical remission, renal progression, and the impact of covariates were estimated by Kaplan-Meier analysis and a Cox regression model. In 157 of 329 patients (48%), disappearance of urinary abnormalities (clinical remission) was obtained. None of these 157 patients showed progressive deterioration, defined as a 50% increase in serum creatinine (Scr) level from baseline, during the observation period. Conversely, in patients without clinical remission, the Kaplan-Meier estimate of probability of progressive deterioration was 21% +/- 5% at 10 years. In the multivariate Cox regression model with 13 independent covariates, initial Scr level, histological score, tonsillectomy, and high-dose methylprednisolone therapy had a significant impact on clinical remission, whereas proteinuria, age, sex, levels of hematuria, blood pressure, conventional steroid therapy, angiotensin-converting enzyme inhibitor therapy, and cyclophosphamide therapy had no significant effect. These findings indicate that interventions aimed at achieving clinical remission have provided encouraging results applicable to managing patients with IgA nephropathy.

Autonomic insufficiency as a factor contributing to dialysis-induced hypotension.

BACKGROUND: Autonomic insufficiency is considered a factor that contributes to dialysis-induced hypotension (DIH). However, the relationship between the two conditions has not been fully elucidated. METHODS: We investigated 44 haemodialysis patients using [(123)I]-meta-iodobenzylguanidine (MIBG) scintigraphy and power-spectral analysis (PSA) of heart rate variability. The patients were divided into four groups: a diabetic group with DIH, a diabetic group without DIH, a non-diabetic group with DIH, and a non-diabetic group without DIH. In these groups the heart to mediastinum average count rate (H/M), MIBG washout rate, and low- and high-frequency components of PSA were compared. RESULTS: From the [(123)I]-MIBG scintigraphy, for both early and delayed images, H/M of the groups with DIH were lower than in groups without DIH, in both diabetics and non-diabetics (P<0.05). For the early images, H/M of the diabetic groups were lower than in the non-diabetic groups, in the groups both with and without DIH (P<0.01). For the delayed images, H/M of the diabetic group was lower than in the non-diabetic group, in the groups with DIH (P<0.05). The MIBG washout rate was the highest in the diabetic group with DIH (P<0.05 vs diabetic and non-diabetic groups without DIH). The PSA of heart rate variability showed a good discrimination of the low-frequency component between the non-diabetic patients with and without DIH (P<0.05). Mean ultrafiltration volume and its rate were not different among the four groups. CONCLUSION: Autonomic insufficiency is more severe in patients with DIH than in those without, and its degree may be enhanced in diabetic patients. For the management of DIH, special care should be addressed not only to dry weight but also to autonomic insufficiency.

Peritoneal dialysis--associated peritonitis caused by gram-negative bacteria: characteristics similar to spontaneous bacterial peritonitis?

The aim of the study was to investigate the characteristics of PD-related peritonitis caused by gram-negative bacteria (GNP). We retrospectively studied the medical records of 164 patients (114 males, 50 females; mean age 46 +/- 15 years) who continued PD beyond 5 months between 1984 and 1998. The average observation time was 40 +/- 28 months (total of 6609 patient-months). A total of 166 episodes of peritonitis occurred during that time (mean incidence: 1 episode/40 patient-months). Of these, 35 were GNPs, and GNP incidence stayed almost constant over time. Most GNP patients (63%) recovered without complication with an average of 14 days' antibiotic treatment. In only 4 cases was PD abandoned. Clinical features of GNP were similar to those of spontaneous bacterial peritonitis (SBP). The unchanged incidence of GNP over time with advanced connection devices suggests that there are important mechanisms promoting micro-organisms of endogenous origin into the peritoneal cavity in PD patients.

Dihydropyridine type calcium channel blocker-induced turbid dialysate in patients undergoing peritoneal dialysis.

We previously reported that manidipine, a new dihydropyridine type calcium channel blocker, produced chylous peritoneal dialysate being visually indistinguishable from infective peritonitis in 5 patients undergoing continuous ambulatory peritoneal dialysis (CAPD) [Yoshimoto et al. 1993]. To study whether such an adverse drug reaction would also be elicited by other commonly prescribed calcium channel blockers in CAPD patients, we have conducted postal inquiry to 15 collaborating hospitals and an institutional survey in International Medical Center of Japan as to the possible occurrence of calcium channel blocker-associated non-infective, turbid peritoneal dialysate in CAPD patients. Our diagnostic criteria for drug-induced turbidity of dialysate as a) it developed within 48 h after the administration of a newly introduced calcium channel blocker to the therapeutic regimen, b) absence of clinical symptoms of peritoneal inflammation (i.e., pyrexia, abdominal pain, nausea or vomiting), c) the fluid containing normal leukocyte counts and being negative for bacterial and fungal culture of the fluid, and d) it disappeared shortly after the withdrawal of the assumed causative agent. Results showed that 19 out of 251 CAPD patients given one of the calcium channel blockers developed non-infective turbid peritoneal dialysis that fulfilled all the above criteria. Four calcium channel blockers were suspected to be associated with the events: benidipine [2 out of 2 (100%) patients given the drug], manidipine [15 out of 36 (42%) patients], nisoldipine [1 out of 11 (9%) patients] and nifedipine [1 out of 159 (0.6%)] in descending order of frequency. None of the patients who received nicardipine, nilvadipine, nitrendipine, barnidipine and diltiazem (25, 7, 2, 1 and 8 patients, respectively) exhibited turbid dialysate. In conclusion, we consider that certain dihydropyridine type calcium channel blockers would cause turbid peritoneal dialysate being similar to that observed in patients developing infective peritonitis. To avoid unnecessary antibiotic therapy the possibility of this adverse reaction should be ruled out whenever a CAPD patient receiving a dihydropyridine type calcium channel blocker develops turbid dialysate.

Clinicopathological significance of intratubular giant macrophages in progressive glomerulonephritis.

Very large macrophages, which we have termed "giant macrophages" (G-M phi), have been found in renal tubules, some containing cytoplasmic vacuoles. To elucidate their pathophysiological roles, we examined renal biopsy tissues from various primary glomerulonephritis (GN) and tubulointerstitial nephritis (TIN) using immunohistochemistry with monoclonal antibodies against M phi and other cell surface markers. Giant macrophages were absent or rare in TIN, minimal change nephrotic syndrome, and minor glomerular abnormalities, but G-M phi was plentiful in progressive glomerulonephrides such as IgA nephropathy with crescents, membranoproliferative GN, focal segmental glomerulosclerosis, and especially in crescentic GN. These G-M phi were usually seen in the lumen of renal tubules, but occasionally were found in the Bowman's spaces and glomerular tufts, and similar cells were also found in urine. Moreover, they frequently made contact with tubular epithelial cells expressing intercellular adhesion molecule-1, and the tubular epithelial cells in such lesions often had degenerative changes. Giant M phi may damage tubular epithelial cells from the luminal side. Phenotypically, G-M phi showed activated (CD71+) and mature (25F9+) characteristics along with features of M phi (CD68+), and the cytoplasm contained a great deal of lipids. The numbers of G-M phi in renal tissues closely correlated with the degree of hematuria (rho = 0.5, P < 0.001), serum creatinine value (r = 0.63, P < 0.001) in GN patients (N = 96) and with proteinuria in IgA nephropathy patients (r = 0.89, P < 0.001, N = 27). These data suggest that G-M phi are M phi that were activated and matured in certain active inflammatory sites, which flowed into tubules and then into urine. Thus, the existence of G-M phi in biopsy tissue or urine reflect the activity of GN and may have a predictive value for the progression of GN.

Involvement of neutrophil elastase in crescentic glomerulonephritis.

To elucidate the role of neutrophils in the tissue damage of crescentic glomerulonephritis (GN), we examined neutrophils infiltrated in renal tissues and the localization of neutrophil elastase (NE), as a neutrophil-derived tissue destructive mediator, using an immunohistochemical technique with antibodies specific for neutrophils and neutrophil elastase; the enzyme histochemical technique (chloroesterase staining) also was used to detect neutrophils. In normal controls, neutrophil infiltration was scarce, and NE was localized in neutrophil cytoplasm. Neutrophils were abundant in crescentic GN and infiltrated in the glomerulus and interstitium; the infiltrating neutrophils were often aggregated. NE was localized in the cytoplasm of neutrophils and also appeared extracellularly (in granular or diffuse patterns) in glomerular necrotizing lesions, crescents, ruptured portions of Bowman's capsules, and in periglomerular and perivascular sites of the interstitium. Moreover, urinary concentration of NE measured by enzyme-linked immunosorbent assay (ELISA) in crescentic GN patients was significantly higher than in normals (93.6 +/- 13.3 v 1.4 +/- 0.5 microg/g x Cr, respectively; P < .001). These data suggest that NE plays a significant role in renal tissue damage, especially in the formation of glomerular necrotizing and crescentic lesions and in periglomerular interstitial lesions of crescentic GN.

Possible relationship between hyperinsulinemia and glomerular hypertrophy in nephrosclerosis.

Hyperinsulinemia is potentially associated with the development of vascular sclerosis. On the other hand, the relationship between hyperinsulinemia and nephrosclerosis has not been elucidated. In this investigation clinicopathological studies were performed in 40 patients with nephrosclerosis, with special attention to the relationship between hyperinsulinemia and glomerular hypertrophy. Forty patients with biopsy-proven nephrosclerosis were divided into two groups by the 75-g oral glucose tolerance test (OGTT): group A, 2-hr plasma glucose concentration > 140 mg/dL (n = 25); group B, 140 < or = 2-hr plasma glucose < 200 mg/dL (n = 15). Patients with diabetes mellitus or diabetic nephropathy were not included. Morphometric analysis of the glomeruli revealed a significantly larger mean glomerular volume in subjects with nephrosclerosis in both subgroups. In addition, the mean glomerular volume was significantly correlated with the fasting insulin level, while no significant correlation was observed between the mean glomerular volume and creatinine clearance or degree of global sclerosis. These results indicate that hyperinsulinemia may be intimately related to glomerular hypertrophy in patients with nephrosclerosis.

[Clinicopathological study of interstitial foam cells in idiopathic membranous nephropathy. Consideration of the appearance of interstitial foam cells in renal tissue].

We conducted an immunohistological investigation on the pathogenesis of interstitial foam cell formation in patients with idiopathic membranous nephropathy (MN). The patients were divided into two groups: Group I consisted of 23 MN patients with interstitial foam cells; Group II consisted of the other 159 patients without foam cells. Age at renal biopsy, duration of proteinuria, blood pressure and other clinical parameters were not significantly different between the two groups. The proportion of nephrotic patients in Group I was 52.2% (12/23), and was not significantly different from that in Group II (48.4%, 77/159). Renal biopsy specimens were examined by immunoperoxidase studies using monoclonal antibodies. The interstitial foam cells were positive for EBM11 (CD68) and 25F9, which are markers of macrophage (M phi) and mature M phi, respectively, but did not express markers of T cells. In interstitial infiltrating cells, both M phi and T cells were observed, but mature M phi were seldom seen. Furthermore, LFA-1 and ICAM-1, but not ICAM-3 (the third ligand for LFA-1) were observed in the interstitial foam cells. LFA-1 and ICAM-3 were observed mainly in interstitial infiltrating cells, but ICAM-1 was observed to a much lesser extent in these cells. These results suggest that interstitial foam cells in MN may be independent of severe hyperlipidemia and proteinuria, and that there may be different mechanisms underlying the accumulation of interstitial foam cells and infiltrating m phi s. Further investigations are required to clarify the pathogenesis of interstitial foam cells in renal tissue.

Long-term effects of intensive therapy combined with tonsillectomy in patients with IgA nephropathy.

IgA nephropathy (IgAN) is the most common form of glomerular disease in the world. However, there is currently no established therapy for IgAN. To assess treatment regimens for IgAN, we investigated a retrospective long-term follow-up study comparing an intensive therapy with a conventional therapy. Clinical outcomes 5 years after the initiation of treatment in two centers were compared. In one center, patients were treated with tonsillectomy combined with steroid pulse, cyclophosphamide, anti-platelet drugs and warfarin (intensive therapy group, Group A, n = 50). In the other center patients were treated with anti-platelet drugs, warfarin or no treatment (conventional therapy group, Group B, n = 50). At the beginning of treatment, the two groups were well matched in terms of age, sex, blood pressure, urinalysis, and creatinine clearance. Five years after the initiation of treatment, proteinuria was remarkably reduced from 1.6 g/day to 0.5 g/day in Group A, whereas no significant change in proteinuria was observed in Group B. Creatinine clearance significantly improved from 77.6 ml/mm to 89.4 ml/min in Group A, whereas creatinine clearance deteriorated from 70.9 ml/min to 62.5 ml/min during 5 years in Group B. Our results indicate that early intensive therapy for IgAN is potentially of great value, and warrants close investigation.

[Successful treatment of interstitial pneumonitis with cyclosporin A in a patient with rheumatoid arthritis accompanied by acute interstitial nephritis].

A 49-year-old male was admitted to our hospital because of acute renal failure. He had been treated by a local doctor for rheumatoid arthritis (RA) during the past eight years. We treated him with steroid pulse therapy, because of suspected acute interstitial nephritis. We confirmed this diagnosis by renal biopsy and steroid pulse therapy markedly improved his renal dysfunction. Immunohistochemical studies revealed that interstitial infiltrating leukocytes consisted mainly of polymorphonuclear leukocytes (PMNs), macrophages and B lymphocytes, while T lymphocytes were less predominant. ELAM-1 and GMP-140 were expressed in the peritubular capillaries. These findings suggest that endothelial activation of the peritubular capillaries may cause interstitial infiltration of PMNs and macrophages, resulting in the development of acute interstitial nephritis. Four months later, he developed severe interstitial pneumonitis, and his symptoms were not improved by high-dose steroid pulse and cyclophosphamide pulse treatment. Eight weeks after the second admission, cyclosporin A (Cy A) was started. Three weeks after starting Cy A, he was free from symptoms and his chest radiograph was normalized. Renal function was also improved by Cy A. These observations suggest that endothelial activation by adhesion molecules may play an important role in RA-related autoimmune diseases and that Cy A might be efficacious in such cases.

Clinicopathological study of IgA nephropathy in patients with congenitally reduced nephron mass.

In experimental animal models, a reduction in the number of functioning nephrons is considered to play a role in the progression of glomerular injury. In human renal diseases, however, whether a superimposed reduction in the number of nephrons causes the exacerbation of preexistent glomerulopathy has not been elucidated. We herein report the results of a clinicopathological study of five patients with IgA nephropathy (IgAN) which occurred in a reduced nephron mass status (four cases of congenital solitary kidney and one case of bilateral hypoplastic kidneys). Four of the five patients had chronic renal failure (CRF) and exhibited a relatively rapid course to CRF as primary IgAN. Renal biopsy revealed that all four of the patients with CRF had glomerular hypertrophy and focal segmental glomerular sclerosis. In addition, two of them had a focal active lesion. In one patient with bilateral hypoplastic kidneys renal biopsies were performed twice in eight years. During this period her creatinine clearance deteriorated from 60.0 ml/min to 20.7 ml/min. Her first renal biopsy showed mild mesangial proliferation without sclerotic lesions, glomerular hypertrophy and mesangial IgA deposition, while all of them were prominent in the second renal biopsy. These observations suggest that IgAN superimposed on a nephron loss status may be frequently associated with a progressive course of disease, and careful follow-up and early treatment should be considered in such a condition.

[A case of IgA nephropathy with numerous interstitial foam cells--analysis of infiltrating mononuclear leucocytes in renal tissue].

A 27-year-old female was admitted to our hospital in order to examine proteinuria and microscopic hematuria. Light microscopic findings of her kidney showed proliferation of mesangial cells and numerous interstitial foam cells. Immunofluorescent and electron microscopic findings revealed IgA nephropathy. Immunoperoxidase studies using monoclonal antibodies disclosed that interstitial foam cells were positive for antibodies of the monocyte/macrophage lineage and also expressed adhesion molecules (CD11a, b, c, LFA-1) and MHC-class II antigens. Hereditary nephritis as Alport syndrome was negated by her familial history and electron microscopic study. We considered that it was a rare and interesting case with numerous interstitial foam cells, because the patient did not have hyperlipidemia as in nephrotic syndrome.

Usefulness of dialysate fibrin degradation products and lactic dehydrogenase isoenzyme patterns in assessing the clinical course of peritonitis.

OBJECTIVE: To establish the usefulness of fibrin degradation products (FDP) and lactic dehydrogenase isoenzyme patterns (LDH isoenzyme) in assessing the clinical course of peritonitis. DESIGN: A retrospective study of patients with peritonitis who were divided into three groups according to their clinical course. SETTING: Single dialysis unit of a general hospital. INTERVENTIONS: Patients were treated by intraperitoneal and oral antibiotics. PATIENTS: Twenty-six patients with 34 episodes of peritonitis were studied. Group 1 consisted of 21 patients with 26 recoveries from peritonitis; Group 2 consisted of 5 patients with 5 relapsing episodes of peritonitis, and Group 3 consisted of 3 patients with 3 persistent episodes of peritonitis. MAIN OUTCOME MEASURES: Concentrations of WBCs, FDP, LDH isoenzyme and microbiological culture of the dialysate were determined. RESULTS: In most of Group 1, WBCs, FDP, and LDH isoenzyme returned to normal within 2 weeks. In 4 patients of Group 1, who had complications (diverticulitis, cholecystitis, cystitis, and tunnel infection), WBCs, FDP, and LDH isoenzyme returned to normal gradually within 3 weeks. In Group 2, WBCs returned to normal, but FDP remained relatively high and LDH isoenzyme did not normalize. In Group 3, WBCs, FDP and LDH isoenzyme did not normalize. CONCLUSIONS: Failure of normalization of FDP and LDH isoenzyme suggests an incomplete recovery from peritonitis. FDP and LDH isoenzyme are useful in assessing the course of peritonitis.

Predictive value of small crescents in IgA nephropathy: analysis of four patients showing a deteriorated renal function during a long follow-up period.

Four patients with IgA nephropathy developed a chronic renal failure during a long follow-up period ranging from three to 8.5 years (mean 6.4 years). All patients showed a normal renal function, normal blood pressure and mild proteinuria at the time of the first renal biopsy. The first biopsies showed focal mesangial proliferation with small cellular crescents in a small percentage of the observed glomeruli. No case showed sclerotic changes in the interstitium and vessels. In contrast, at the second biopsies, all of them exhibited a deteriorated renal function, hypertension and massive proteinuria. The second biopsies revealed marked sclerotic changes in the glomeruli, interstitium, and vessels with significant focal segmental glomerular sclerosis and adhesions. Since no established factors predisposing the patients to chronic renal insufficiency had been observed at the time of the first biopsy, it was suggested that small crescents, even if focal, should be regarded as indicating an unfavorable prognosis.

Early intensive therapy for clinical remission of active IgA nephropathy: a three-year follow-up study.

To achieve clinical remission, intensive therapy in active IgA nephropathy was conducted on a trial basis. Forty-five patients with active IgAN in which cellular crescents were present were divided into two groups. The patients in one group (Group A, N = 19) were treated with a combined regimen of steroid pulse, cyclophosphamide (4 months), dipyridamole (36 months) and warfarin. The patients in the other group (Group B, N = 26) were treated with tonsillectomy in addition to the same regimen as Group A. Three years after the initiation of treatment, proteinuria and hematuria had significantly decreased in both groups, and the renal function in Group B was significantly improved. Remission of proteinuria and hematuria was achieved in five patients (26.3%) and eight patients (42.1%), respectively, in Group A, and 14 patients (53.8%) and 20 patients (76.9%), respectively, in Group B. These results indicate that early intensive therapy combined with tonsillectomy in active IgAN is potentially of great benefit from both the medical and socioeconomic points of view.

Quantitation of C4 nephritic factor by an enzyme-linked immunosorbent assay.

We have developed an enzyme-linked immunosorbent assay (ELISA) for the quantitation of C4 nephritic factor (C4NeF). Incubation of the C4NeF-positive serum from patient M.I. with normal human serum (NHS) in the presence of human aggregated IgG (AHG) resulted in the formation of stable C4-C2 complex. No complex was formed in EDTA or under the condition free of AHG. The reaction mixture was filtered through an ACA 22 column, from which the C4-C2 complex was eluted at the first protein peak. When IgG purified from M.I. serum was incubated with NHS and AHG, C4-C2 complex also increased in proportion to dose of the purified M.I. IgG. These results show that C4NeF in M.I. serum stabilizes C4b2a convertase of the classical complement pathway, and is quantified by the ELISA. C4NeF activity was measured, using the ELISA method, in patients with various glomerular diseases, and found elevated in three of 24 patients with membranoproliferative glomerulonephritis (MPGN) type I and slightly but distinctly positive in seven of 24. No C4NeF was detected in two C3 nephritic factor-positive patients with MPGN type II and six with active systemic lupus erythematosus. The new method was more simple and quantitative than C4b2a stabilization assay for C4NeF.