Vascular amyloid of unknown origin and senile transthyretin amyloid in the lung and gastrointestinal tract of old age: histological and immunohistochemical studies.

The histological and immunohistochemical characteristics and the incidence of amyloid deposits in the tissues of the lung and gastrointestinal tract were investigated in 64 autopsied individuals who were 80 years and older (age range: 80-92 years; mean: 83.3 years). Immunohistochemical examination was performed with antibodies against amyloid A, transthyretin, immunoglobulin lambda and kappa light chain amyloid fibril proteins, beta2-microglobulin, beta protein, apolipoprotein AI, apolipoprotein AII, atrial natriuretic peptide, apolipoprotein E, and amyloid P component. Transthyretin amyloid fibril protein (ATTR) deposits were observed in five cases (7.8%). Gastrointestinal amyloid deposits of unknown origin were observed in the veins of the gastrointestinal tract in 26 cases (40.6%). This amyloid was regarded as portal amyloid with respect to distribution pattern. Pulmonary vascular amyloid deposits of unknown origin were observed in 12 cases (18.8%). These amyloid deposits were found mainly in medium-sized veins in the lungs and did not react with any antibodies against amyloid fibril proteins except apolipoprotein E and amyloid P component. Eleven of the 26 cases (42.3%) showing portal amyloid also showed pulmonary vascular amyloid of unknown origin. The pulmonary vascular amyloid deposits were similar to the portal amyloid deposits with respect to their morphological features and their relation to elastic fibers in the vessels. Further morphological investigation and biochemical analysis of the pulmonary vascular amyloid and portal amyloid will resolve questions of their origins and relation.

Long-term effects of immunosuppressants in steroid-dependent nephrotic syndrome.

In order to elucidate long-term effects of immunosuppressants, we studied 60 children with steroid-dependent nephrotic syndrome who were treated with three immunosuppressants: cyclophosphamide (n=34), chlorambucil (n=11), and cyclosporin A (n=15). Each relapse before and after the administration of immunosuppressants was evaluated longitudinally in terms of the relapse-free period and the maintenance dose of prednisolone required. The median follow-up period after immunosuppressants was 5.2 years (range 0.5-20.3 years). The relapse-free period was significantly longer in all groups after the initiation of immunosuppressants. However, the relapse-free period after subsequent relapses as compared with the previous relapse was longer in the cyclophosphamide group, similar in the chlorambucil group, and shorter in the cyclosporin A group. The prednisolone dosage at relapse was reduced in subsequent relapses after cyclophosphamide and chlorambucil treatment, but tended to be higher in later relapses after the initiation of cyclosporin A. These findings suggest that the effects of cyclophosphamide are long lasting, while those of chlorambucil and cyclosporin A are of short duration. Children who relapse after cyclosporin A treatment may experience a worse relapsing course.

Enhanced regeneration response of laryngeal and hypopharyngeal mucosa with accelerated hyperfractionated radiation therapy for glottic cancers.

The course and severity of acute mucosal reactions in 22 patients with previously untreated T1-2N0 glottic cancers were compared between two treatment schedules with different dose intensities: accelerated hyperfractionated radiation therapy (AHF) and standard conventional fractionation radiation therapy (CF). AHF consisted of a twice-daily fractionation of 1.5 Gy 10 times weekly to a total dose of 66 Gy given in 30-40 (median, 33) days. For CF, the fractionation was 2 Gy five times weekly for a total dose of 66 Gy in 45-51 (median, 49) days. Both treatment schedules were well tolerated and no treatment interruptions were necessary. The mucosal reaction reached a peak score clearly earlier with AHF than CF and already demonstrated improvement in the final treatment week. In contrast, the reaction persisted with CF. It is suggested that damaged mucosal tissues with AHF can be effectively compensated by enhanced regeneration response due to an adequately high dose intensity, suggesting a possible tolerability advantage for AHF.

Risk factors for relapse in childhood nephrotic syndrome.

We investigated the risk factors for relapse in 48 children with steroid-sensitive nephrotic syndrome using univariate and multivariate proportional hazard analysis. All patients were treated with the same corticosteroid regimen. A low serum level of total protein and young age at onset increased the relapse rate. Recurrence risk was not associated with the patient's sex, the percentage body weight gain, blood urea nitrogen level, serum level of creatinine, the hematocrit, or the administration of human albumin. We conclude that young age and a low serum level of total protein at onset were independent risk factors for relapse of childhood nephrotic syndrome.

Long-term corticosteroid and dipyridamole treatment of membranoproliferative glomerulonephritis type I in children.

Eighteen patients with biopsy-proven membranoproliferative glomerulonephritis (MPGN) type I (16 diffuse, 2 focal) and a minimum of three years of follow-up (median 6.0 years, range 3 to 15.5 years) were treated with corticosteroids combined with dipyridamole. Initial therapy consisted of intravenous methylprednisolone pulses and/or daily oral prednisolone at the dose of 1 mg/kg combined with dipyridamole at the dose of 5 mg/kg, depending on the disease severity. Corticosteroid dosage was then reduced according to clinical improvement. At the start of therapy, 12 patients had microscopic hematuria or mild proteinuria, three patients had heavy proteinuria and three patients had insufficient renal function. At a median of 53 months of treatment, 89% of the children had normal or mildly abnormal urinary findings with normal renal function. Follow-up biopsy revealed improved active glomerular injury in all children. Although one case progressed to end-stage renal failure, the renal survival of our patients was 94% at 4 to 10 years after clinical onset. No patient suffered a relapse during corticosteroid dosage adjustment, nor did any unacceptable complications arise during the regimen. Eleven patients stopped the regimen because their renal function and urinalysis had normalized, and they remained in remission for a median of 32 months. These results suggest that long-term, tapering and limited use of corticosteroids combined with dipyridamole is useful and safe for children with MPGN type I.

Measurement of beta 2 microglobulin in dried urine spotted on filter paper by means of a forward sandwich enzyme-linked immunosorbent assay.

We devised a highly sensitive forward sandwich enzyme-linked immunosorbent assay (ELISA) for estimation of the beta 2-microglobulin concentration in dried urine spotted on filter paper. This method is suitable for mass screening because of the good reproducibility, satisfactory stability, low operation cost and easy sample collection. However, preliminary studies using our new method for detecting renal diseases in the Tokyo infant population did not produce good results. The high cut-off value may have been the main reason. To make this ELISA more suitable for mass screening, we plan to reduce the cut-off value, test older children and improve the extraction step.

Partial deficiency of cytochrome c oxidase with isolated proximal renal tubular acidosis and hypercalciuria.

We report the case of a 5-year-old boy with mitochondrial cytopathy due to a partial deficiency of cytochrome c oxidase who had isolated proximal renal tubular acidosis and hypercalciuria. The patient developed hypotonia and blepharoptosis and exhibited growth retardation. Biochemical examination of muscle tissue revealed a partial deficiency of cytochrome c oxidase. He was treated with an alkali, hydrochlorothiazide, and indomethacin. After treatment, metabolic acidosis and hypercalciuria improved, and the patient had a catch-up growth phase. This case emphasizes the importance of performing renal tubular functional investigations and treatment in patients with mitochondrial cytopathy, even in the absence of multiple proximal tubular dysfunction.

[Rapid deterioration of renal function in minimal change nephrotic syndrome].

This report concerns two boys with minimal change nephrotic syndrome progressed to renal failure. The first case aged 17 being a steroid sensitive infrequent relapse developed acute renal failure at his third relapse and recovered soon after the treatment with diuretics and corticosteroids. The second case aged 15 being a steroid dependent frequent relapse became steroid resistant at his 11th relapse and progressed to renal failure seven months later. As the causes of renal failure, acute tubular necrosis and tubular obstruction by casts were suspected in the former. Renal vein thrombosis, morphological transition of renal histology, hemodynamic change and change in glomerular permeability might be occurred in the latter. Renal failure is a rare complication of minimal change nephrotic syndrome and the cause is variable. Precise diagnosis and prompt treatment should be needed to improve the prognosis.

Severe glomerulonephritis and tubulo-interstitial nephritis accompanied with urticaria and vasculitis.

We report a 9-year-old girl who developed recurrent urticaria, arthritis and serious renal involvement. She was treated by prednisolone with considerable improvement. Biopsy examinations revealed cutaneous vasculitis and moderate mesangial proliferation with crescents and tubulo-interstitial nephritis on light microscopy. Immunofluorescence study showed IgG, IgM and complement deposits in the mesangium and along the capillary wall. On electron microscopy, electron-dense deposits were identified in the mesangium and paramesangium. Her disease resembled the hypocomplementemic vasculitis syndrome, but her serum complement values were normal throughout the course of the illness. The pathogenesis of her disease is unknown, but it seems to be a sort of systemic immune-complex disease.

[Studies on absorption, distribution and excretion of 14C labeled pivaloyloxymethyl (+)-(6R,7R)- 7-[(Z)-2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]- 3-[(5-methyl-2H-tetrazol-2-yl)methyl]-8-oxo-5-thia- 1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (14C-T-2588) in rats and mice].

Absorption, distribution and excretion of T-2588 were studied in rats and mice using (aminothiazole-2-14C) T-2588 and (pivaloyloxymethyl-14C) T-2588. Results are summarized below. The binding rate of 14C-T-2525, an activated form of 14C-T-2588 in vivo, to serum protein was 90 approximately 100% in rats and mice after an oral administration of (aminothiazole-2-14C) T-2588. Blood levels of radioactivity reached to the highest concentration at 1 hour after an oral administration of (aminothiazole-2-14C) T-2588 to rats, and then gradually diminished. After an oral administration of (aminothiazole-2-14C) T-2588 to rats and mice, the highest radioactivity distribution was found in kidney among all the organs except stomach, intestine and bladder. Radioactivity was widely distributed into other organs such as adrenal, lung, liver, heart and pancreas. But little radioactivity was found in the brain. In new born rats, tissue levels of radioactivity were lower and diminished slower than those of adult rats. After an oral administration of (aminothiazole-2-14C) T-2588 to rats and mice, urinary excretion of radioactivity was about 26% and 35% of the dosed radioactivity in rats and mice, respectively, and fecal excretion was about 76% and 63% of the dosed radioactivity in rats and mice, respectively. Urinary and fecal excretion patterns of radioactivity after multiple oral administration of (aminothiazole-2-14C) T-2588 for 7 days to mice were similar to those after a single administration. This result suggests that T-2588 did not accumulate in the body. After an oral administration of (pivaloyloxymethyl-14C) T-2588 to rats and mice, urinary excretion was both about 8% of the dosed radioactivity, and fecal excretion was both about 6%. Then excretion of 14CO2 into respiratory air was about 55% and 66% of the dosed radioactivity in rats and mice, respectively. Biliary excretion was about 6.5% of the dosed radioactivity after an oral administration of (aminothiazole-2-14C) T-2588 to rats. Small amount of radioactivity was secreted to the milk after intravenous administration of (aminothiazole-2-14C) T-2525 to nursing rats. After an administration of (aminothiazole-2-14C) T-2588 to pregnant mice, radioactivity hardly transferred into the fetus.

[The autoradiographic studies on the distribution of 14C-labeled pivaloyloxymethyl (+)-(6R,7R)- 7-[(Z)-2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]- 3-[(5-methyl-2H-tetrazol-2-yl)methyl]-8-o xo-5-thia- 1-azabicyclo [4.2.0]oct-2-ene-2-carboxylate (14C-T-2588) in mice].

The distribution of T-2588 was studied with whole body autoradiography in normal male mice and pregnant mice using two radioactive T-2588 labeled at the aminothiazole or pivaloyloxymethyl moieties. When (aminothiazole-2-14C) T-2588 was orally administered, the radioactivity was distributed widely to whole tissues except central nervous systems such as brain and spinal cord. In pregnant mice, no detectable radioactivity was present in the fetus. These results suggested that T-2588 was well absorbed and hardly crossed the blood-brain barrier and placenta. At 4 hours after administration, radioactivity was only observed in gastrointestinal tract implying rapid excretion of T-2588. When (pivaloyloxymethyl-14C) T-2588 was orally administered, radioactivity was accumulated to all tissues and fetus. From these results we speculated that formaldehyde formed by hydrolysis at the pivaloyloxymethyl ester and entered the C1-metabolic pathway.