Circulating immune complexes in IgA nephropathy consist of IgA1 with galactose-deficient hinge region and antiglycan antibodies.

Circulating immune complexes (CICs) isolated from sera of patients with IgA nephropathy (IgAN) consist of undergalactosylated, mostly polymeric, and J chain-containing IgA1 and IgG antibodies specific for N-acetylgalactosamine (GalNAc) residues in O-linked glycans of the hinge region of IgA1 heavy chains. Antibodies with such specificity occur in sera of IgAN patients, and in smaller quantities in patients with non-IgA proliferative glomerulonephritis and in healthy controls; they are present mainly in the IgG (predominantly IgG2 subclass), and less frequently in the IgA1 isotype. Their specificity for GalNAc was determined by reactivity with IgA1 myeloma proteins with enzymatically removed N-acetylneuraminic acid (NeuNAc) and galactose (Gal); removal of the O-linked glycans of IgA1 resulted in significantly decreased reactivity. Furthermore, IgA2 proteins that lack the hinge region with O-linked glycans but are otherwise structurally similar to IgA1 did not react with IgG or IgA1 antibodies. The re-formation of isolated and acid-dissociated CICs was inhibited more effectively by IgA1 lacking NeuNAc and Gal than by intact IgA1. Immobilized GalNAc and asialo-ovine submaxillary mucin (rich in O-linked glycans) were also effective inhibitors. Our results suggest that the deficiency of Gal in the hinge region of IgA1 molecules results in the generation of antigenic determinants containing GalNAc residues that are recognized by naturally occurring IgG and IgA1 antibodies.

[IgA nephropathy. Significance of immunoglobulin A glycosylation in pathogenesis and clinical presentation]. / IgA nefropatie. Význam glykozylace imunoglobulin A pro patogenezi a její klinický obraz.

Human immunoglobulin A is represented by two structurally and functionally distinct subclasses: IgA1 and IgA2. IgA1, which is almost exclusively present in the mesangial deposits in IgA nephropathy patients, contains in its hinge region three to five O-lined carbohydrate chains. A fraction of IgA1 molecules in the circulation of IgA nephropathy patients exhibits aberrant glycosylation. As a result of changes in glycosylation, the neoepitopes represented by glycans are exposed and recognized by naturally occurring antibodies with antiglycan specifciities, and immune complexes are generated. The deposits of these immune complexes in the glomerular mesangia elicit inflammatory response known as IgA nephropathy. Epidemiological studies have shown that dominant hematuria, either isolated or combined with mild proteinuria, is the most frequent urinary syndrome in glomerulonephritis. The morphologic finding of this syndrome is most frequently IgA nephropathy. Originally considered a benign disease, IgA nephropathy is now recognized as a frequent cause of chronic renal failure. The progression is signalized by increasing proteinuria and hypertension. Therefore, a control of blood pressure and lowering of proteinuria remain the corner-stones of the treatment. Angiotensin converting enzyme inhibitors and AT1 blockers may lower both blood pressure and proteinuria and are now increasingly promoted even for treatment of normotensive patients. Steroids are administered to patients with severe proteinuria. High-doses of fish oil seem to slow down the rate of renal failure.

[A controlled clinical trial of Consupren versus cyclophosphamide in chronic glomerulonephritis]. / Kontrolovaná klinická studie Consupren versus Cyklofosfamid u chronických glomerulonefritid.

BACKGROUND: Experience gained from recent studies shows, that Cyclosporine-A (Cy-A) may decrease proteinuria (PU) in some forms of chronic glomerulonephritis (GN) with the nephrotic syndrome. The aim of this study was to test the efficacy of Czech-made Cy-A, Consupren. METHODS AND RESULTS: 30 patients with chronic GN, confirmed by biopsy and PU higher than 3 g/d, corticodependent or corticoresistant, were randomized according to the month of birth to either therapy with Consupren at an initial dose of 5 mg/kg/d (CS group, after dropout of 3 patients who did not finish the treatment, n = 16) or Cyclophosphamide at a dose of 1.5 mg/kg/d (K group, n = 11), and prednisone maintained at the original dose in both groups. The treatment was stopped after six months or after achieving remission. The main criterion of efficacy was PU. The decrease in mean values, statistically evaluated by Holm's procedure was highly significant in the CS group and non-significant in the K group. A similar evaluation of PU corrected by glomerular filtration rate was significant in both groups. Partial or complete remission was reached in 50% of CS group patients and in 34% of K group patients (NS). In the CS group a significant increase in the mean values of albumin and gama-globulin, and a decrease in cholesterol levels were observed. In the K group, these changes were non-significant. CONCLUSIONS: In patients with chronic GN and the nephrotic syndrome, the efficacy of Consupren treatment gives comparable, or even better results versus treatment with Cyclophosphamide.

[Controlled clinical study of Consupren versus cyclophosphamide in chronic glomerulonephritis. II. Adverse effects]. / Kontrolovaná klinická studie Consupren versus cyklofosfamid u chronických glomerulonefritid. II. Nezádoucí úcinky.

BACKGROUND: The second part of the study was designed to assess Consupren side effects. METHODS AND RESULTS: The groups of patients studied were described in Part I. Side affects typical of Cy-A were evaluated only in the CS group. Gastrointestinal intolerance, only mild and temporary, was observed in 31%, neurotoxicity in 44%, hypertrichosis in 37%, nephrotoxicity in 25%, and gingival hypertrophy in 19%. Mean values of systolic and diastolic blood pressure did not change significantly in the course of treatment. When changes in blood pressure were individually investigated in particular patients, they were found in 31% in the CS group and in none in the K group. Mean values of uric acid non-significantly increased in the CS group and, on individual investigation, hyperuricaemia was observed in 31%. Mean values of serum potassium did not alter significantly. Signs of possible hepatotoxicity were found in 37% patients of the CS group. In this group, there was a significant decrease in haemoglobin mean values and a decrease in haemoglobin of more than 25 g/l was observed in 44% of CS group patients. In the K group significant decrease in mean leukocyte count was noted, but no patient developed real leukopenia. CONCLUSIONS: The occurrence of side effects was comparable to data known from the literature.

[Monitoring immunosuppression after kidney transplantation. I. Study of cellular reactions to antigenic stimulus in a skin abrasion]. / Monitorování imunosuprese po transplantaci ledviny. I. Sledování bunecné reakce na antigenní podnet v kozní abrazi.

In 20 patients the authors performed in the course of 6-8 weeks following renal transplantation a total of 74 examinations of the cellular reaction to an antigenic stimulus. In 68 instances (91.9%) agreement with the clinical picture was recorded, while in 6 patients (8.1%) the interpretation of the cytological impression did not correspond to the clinical course. In four instances activation of lymphocytes was found, i.e. possible risk of rejection which however was not confirmed. In two instances however incipient rejection was not detected.

[Monitoring immunosuppression after kidney transplantation. II. Evaluation of simultaneous monitoring of CD4+ lymphocytes and the cytological reaction to standard antigenic stimulation]. / Monitorování imunosuprese po transplantaci ledviny. II. Vyhodnocení soucasného sledování CD4+ lymfocytu a cytologické reakce na standardní antigenní podnet.

Monitoring of patients after renal transplantations by the concurrent follow up of absolute values of CD4+ lymphocytes and the cytological reaction to an antigenic stimulation in a skin abrasion reflects the actual immune state of patients and is an asset in the comprehensive diagnosis of rejection activity against the transplant in the early period (6-8 weeks) after transplantation. It can contribute also to the signalling of developing rejection activity against the graft, before the onset of the fully developed clinical picture of rejection, when it is possible by early anti-rejection therapy to prevent the functional impairment of the renal graft.

[Dual-photon bone densitometry in dialyzed patients]. / Dvoufotonová kostní denzitometrie u dialyzovaných nemocných.

In non-invasive diagnosis of renal osteodystrophy the levels of bone minerals and the extent of bone turnover are evaluated. The contents of bone minerals are assessed quantitatively by different modalities of bone densitometry, among which the most accurate one is double-energy bone densitometry. So far no standard examination method was defined nor the most suitable portion of the skeleton for densitometric examination. In order to find such an area and also to assess the prevalence of bone demineralization, its severity and regional differences the authors made a cross-sectional study of bone density in dialyzed patients. The group comprised 45 patients, 24 men and 21 women subjected to regular dialyzation treatment for 20-24 months. In a lambda whole body bone densitometry was performed with evaluation of regional densities of the trunk, upper and lower extremities. At the same time the state of bone turnover was assessed arbitrarily using values of serum concentrations of intact parathormone; parathormone concentrations below 50 pg/ml were considered low, above 200 pg/ml high and concentrations within the mentioned range as the normal bone turnover. In the group of patients 62% had a high, 22% a normal and 16% a low bone turnover. The study provided evidence of a significant reduction of bone density (Z score <-1) in 58% of patients. In 92% of patients demineralization affected most and first the extremities. In 69% it affected the lower extremities and in 23% the upper ones. 8% of the patients had the most severe affections in the area of the trunk. This order of affliction was not influenced by bone turnover, sex and in women by age. The diaphysis of long bones seems to be a representative examination area of the skeleton for densitometric measurements in patients with regular dialyzation treatment.

Rubber substrates and their influence on isomerization of conjugated dienes in pheromone dispensers.

Release rate and degree of isomerization of pheromones with conjugated double bonds were studied in dispensers prepared from several rubber substrates. The substrates compared were made of rubber, cured with elemental sulfur or accelerators based on organic sulfur compounds or organic peroxides. Isomerization of the double bonds occurs immediately after impregnation of the substrate, and the degree of isomerization increases during field use and/or storage. The propensity of the isomers to isomerize corresponds to their proportion in the equilibrium mixture. AnE,Z isomer is isomerized faster than theE,E isomer, and finally a near-equilibrium mixture of the four isomers is present. Minimal isomerization was found in non-sulfur-cured substrates which are the material of choice.

Characterizing formaldehyde emission rates in a gross anatomy laboratory.

The evaporation of formaldehyde from cadavers in gross anatomy laboratories can produce high exposures among students and instructors. To understand the system that produces exposures and to plan for implementing control options, the generation of formaldehyde vapors must be characterized. A gross anatomy laboratory with 47 dissecting tables was studied during 15 lab sessions over a period of 16 weeks. Area concentrations were measured using National Institute of Occupational Safety and Health (NIOSH) method 3500. Average daily area concentrations in the laboratory ranged from 0.635 to 1.82 mg/m3. The ventilation was characterized on three separate days. The laboratory had a general ventilation rate of 9.8 air changes per hour. There was no local exhaust ventilation. The concentration measurements were used in a mass balance model along with ventilation rates to determine formaldehyde emission rates. The daily average formaldehyde emission rate from all sources in the laboratory ranged from 95.2-274 mg/min, with an average of 148 mg/min over the course of the study. This total emission rate was used along with the number of dissecting tables to develop an emission factor of 3.15 mg/min per table. The emission factor is a generalizable tool that can be used in laboratories of various sizes to predict emission rates and develop control strategies. This emission factor is applicable where the cadavers are prepared with similar embalming fluid consisting of approximately 10 percent formaldehyde.

Kidney transplantation and malignant diseases.

Basing on three types of questionnaires, the authors summarized the incidence of all malignant diseases in kidney transplant patients in CSFR. The total number of registered tumours was 34. Previously to the transplantation, two patients with malignancies were found, another one was transplanted for a kidney tumour and 31 patients manifested malignant diseases in various time intervals following the transplantation. This number is five times greater than the incidence of tumours in the standard population. At classical immunosuppression, the mean time interval between transplantation and tumour formation is 48 months; at cyclosporine application, it decreases to 19 months. The most frequent sites of tumour formation are the skin and the kidney. The early diagnosis of tumours and the surgical treatment will increase the survival period up to 58 months. The systematic oncologic follow-up and preventive controls of transplant patients represent one of the possibilities of the prolongation of the patient's life with the functional graft.

Structure-activity correlations among analogs of the currant clearwing moth pheromone.

Eleven analogs of (E,Z)-2,13-octadecadien-1-yl acetate1, a main pheromone component of the currant clearwing moth,Synanthedon tipuliformis Clerk (Lepidoptera: Sesiidae) were synthesized and tested for their biological activities by electroantennography (EAG). To correct the EAG data for differences in volatility of the analogs, their vapor pressures were estimated by a gas chromatographic method. All structural changes in the parent molecule were found to reduce the biological activity to various degrees. The most active analog tested was the carbamate12, whose activity was almost comparable to that of the pheromone component1. Structure-activity correlations showed that hydrophobic, steric, and electronic effects of chain terminal groups might be responsible for variations in biological activity of the conformationally unchanged (E,Z)-2,13-analogs.

Single photon bone densitometry in hemodialysis patients.

Renal osteodystrophy is a common finding in patients with renal insufficiency. The maximum of its intensity is found in hemodialysis patients. Bone densitometry is so far the best method for non-invasive assessment of the extent of the illness. Some densitometric studies in hemodialysis patients have already been published but their results differ in prevalence and intensity of renal osteodystrophy. They also demonstrated a slight relationship between intensity of renal osteodystrophy and duration of the dialysis treatment. Opinions vary on the relationship between bone mineral density and markers of bone turnover. This cross-sectional study found high prevalence of renal osteodystrophy (Z-score below -1 in 57% of patients) as well as high a number of severely damaged patients (T-score below -2.5 in 40% of patients). It also showed some correlation between bone demineralisation and the duration of dialysis. None from evaluated markers of bone turnover correlated with bone mineral density.

Galactose-deficient IgA1 in sera of IgA nephropathy patients is present in complexes with IgG.

IgA1 proteins from sera of patients with IgA nephropathy (IgAN) are galactosylated to a lesser degree than those from healthy controls. The increased reactivity of intact or de-sialylated serum IgA1 with N-acetylgalactosamine (GalNAc)-specific lectins, Helix aspersa (HAA) and Caragana arborescens (CAA) and de-sialylated IgA1 with Helix pomatia (HPA) and Bauhinia purpurea (BPA) indicated that the Gal deficiency is in glycans located in the hinge region of IgA1 molecules. De-sialylated IgA from sera of 81 IgAN patients bound biotin-labeled lectin HAA more effectively than did de-sialylated IgA from 56 healthy controls (P < 0.0001). Similar results were observed for 67 IgAN patients and 52 controls with second lectin, CAA (P < 0.001). The binding patterns for 9 patients with mesangial proliferative glomerulonephritis of non-IgA origin were similar to those for controls. Incompletely galactosylated IgA1 capable of binding GalNAc-specific lectins was detected in complexes with IgG as demonstrated by ELISA, size-exclusion chromatography and sucrose gradient ultracentrifugation. The formation of IgA1-IgG complexes may affect the serum level of IgA1 by reducing the rate of its elimination and catabolic degradation by the liver.