Glycosaminoglycans prevent the functional and morphological peritoneal derangement in an experimental model of peritoneal fibrosis.

Chronic peritoneal dialysis results in fibrosis of the peritoneal membrane, which leads to progressive reduction in dialytic efficacy. It was recently shown that the intraperitoneal administration of glycosaminoglycans (GAGs) improves the efficiency of peritoneal dialysis in CAPD patients. To verify whether the favorable effects of GAGs are purely functional or involve a morphological amelioration of the peritoneal membrane structure, a study was carried out in an animal model of plasticizer-induced peritoneal fibrosis. Rats, in which chronic renal failure had been induced by subtotal nephrectomy, received either placebo, plasticizers (i.p.), or GAGs (s.c.), or plasticizers (i.p.) and GAGs (s.c.). Urea dialysate-to-plasma equilibrium, urea and albumin peritoneal clearance, and glucose reabsorption were determined. The peritoneal membrane was evaluated morphometrically and histologically. In plasticizer-treated animals, peritoneal function tests and morphology were dramatically deranged. On the contrary, the subcutaneous administration of GAGs in plasticizer-treated rats maintained the peritoneal physiology and normal structure. The subcutaneous administration of GAGs protects peritoneal functions by affecting the remodeling of the peritoneum, rather than by a purely functional or simple mechanical effect.

Activated T cells with immunoregulatory functions at different sites of involvement in sarcoidosis. Phenotypic and functional evaluations.

Cells from recovered BAL fluid and from infiltrates in different involved tissues (lungs, lymph nodes, conjunctiva, liver, spleen, and skin) were studied in 22 patients with active sarcoidosis in order to define the surface phenotype, functional in vitro properties, and topographic distribution of the cells in granulomatous lesions. Our data demonstrated a compartmentalization of activated T cells with immunoregulatory functions from the blood to all sites of disease activity. In fact, these cells were found to express the T4+ Leu 8- 5/9+ T17- phenotype, which belongs to cells with helper activity, and that provide heightened responses in functional assays of helper activity, IL-2 release, and the ability to respond in AMLR's. Both a cellular redistribution and a local in vitro replication account for this tissue compartmentalization in sarcoidosis. The microanatomic location of activated T cells, as defined by immunohistological evaluation, showed that the state of activation in these T cells may be a consequence of an intimate contact between helper cells and macrophages within the sarcoidosis granulomas.

Renal structure and function in non-insulin dependent diabetic patients with microalbuminuria.

We have recently described heterogeneity in renal structure in non-insulin-dependent diabetic patients (NIDDM) with microalbuminuria (MA; defined as albumin excretion rate from 20 to 200 micrograms/min). Thus, at variance with IDDM patients, "typical" diabetic glomerulopathy by light microscopy is observed only in a third of NIDDM with MA (Category II, CII). Further, despite persistent MA, 30% of NIDDM have normal or near normal renal structure (Category I, CI). Another one-third shows "atypical" patterns of renal injury with absent or mild diabetic glomerular changes, associated with disproportionately severe tubulointerstitial lesions and/or arteriolar hyalinosis and global glomerular sclerosis (Category III, CIII). The aims of this study were to evaluate whether similar patterns of renal lesions could be confirmed in a larger group of NIDDM with MA and to investigate tubular function in order to understand the mechanisms underlying MA in NIDDM patients. Renal biopsies were performed in 53 NIDDM with MA. Categories I, II and III were found in 41%, 26% and 33% of NIDDM with MA, respectively. All 8 patients with proliferative diabetic retinopathy were in CII. We also studied the urinary daily excretion rate of alpha 1-microglobulin (alpha 1 m), a low molecular weight protein, which is a useful indicator of tubular function. alpha 1 m was markedly increased only in CII patients (CI vs. CII vs. CIII: 6.2 +/- 1.2 vs. 13.7 +/- 2.1 vs. 7.3 +/- 0.9 mg/day, ANOVA, P < 0.01). In conclusion, we confirm that there is heterogeneity in renal structure in NIDDM patients with MA. This heterogeneity is not due to renal diseases other than diabetes. Increased alpha 1 m and proliferative retinopathy are useful indicators of the subgroup of MA NIDDM patients with typical diabetic glomerulopathy. It is suggested that diabetic microangiopathy explains the simultaneous occurrence of typical diabetic glomerulopathy, proliferative retinopathy and tubular dysfunction in a subgroup of NIDDM patients with MA.

Predictive value of ANCA in atypical primary brain localization of Wegener's granulomatosis.

Wegener's Granulomatosis is a necrotizing vasculitis generally involving upper and lower respiratory tract and kidneys. The central nervous system is involved in less than 10% of the patients during the course of the disease and primary involvement is even rarer. We present and discuss the case of a patient with primitive cerebral localization of Wegener's Granulomatosis in which the diagnosis and the beginning of correct therapy were delayed, in spite of a rising c-ANCA titer, due to a misinterpretation of a bioptic specimen. This delay caused renal damage and pulmonary cavitations which needed a long time to recover. This case report suggests that the central nervous system can be the site of a primary localization of Wegener's Granulomatosis even without any other organ involvement. The diagnosis must be made as soon as possible in order to prevent spread to other sites since the disease is usually very aggressive and severe.

Therapy of acute pancreatitis in systemic lupus erythematosus with plasmapheresis and corticosteroids.

A 24-year-old woman with systemic lupus erythematosus had, after reduction of corticosteroid therapy, a severe relapse of the disease with hepatitis, nephritis and pleurisy. After admission to the hospital, she was given 60-80 mg/day of prednisone and acute pancreatitis developed on the third day. Plasmapheresis, followed by injection of 1 g of methylprednisolone, was started. This combined therapy induced a prompt and complete recovery in a few days.

HLA expression in type II mixed cryoglobulinemia and chronic hepatitis C virus.

OBJECTIVE: Hepatitis C virus infection is closely associated not only with hepatic damage, but also with mixed cryoglobulinemia (MC) and other autoimmune and lymphoproliferative disorders. Because HCV is both hepatotropic and lymphotropic, the aim of this study was to investigate whether the genetic background may influence the clinical pattern seen in different patients. METHOD: Two groups of patients with HCV infection were studied: 16 with type II MC and 18 with chronic active hepatitis (CAH). 120 bone marrow donors were considered as the control group. In all patients HLA-A-B-C antigens were evaluated using the microlymphocytoxicity technique, and HLA-DR by the PCR-SSP method. RESULTS: The frequency of the HLA antigens expressed was not precisely defined in the two groups. However, the HLA-B51 and B35 antigens, which are often correlated with autoimmune disorders, were highly expressed in the MC patients (31.2%) compared to the controls (6.9%) and to the CAH group (11%). Moreover, HLA-A9 with its split A24 were present in 50% of the MC patients. More interesting was the expression of the HLA-DR7 antigen, which was found only in the CAH group, suggesting that it may influence the specific liver involvement in HCV infections. CONCLUSION: These findings indicate that the HLA system may play an important role in the clinical manifestations of HCV infection.

Alterations in renal tubular sodium and water transport in polycystic kidney disease.

Thirty patients with chronic renal diease -10 with polycystic kidney disease (PKD) and normal GFR; 10 with PKD and GFR is less than 30 ml+min; 10 with chronic glomerulonephritis (CGN) and GFR is less than 30 ml+min -and 10 normal subjects were investigated. The ability to concentrate urine maximally (T-CH2O) after water deprivation and the renal handling of water and electrolytes following hypertonic volume expansion were studied. A defect in T-CH2O was common in PKD patients even with normal GFR. In PKD patients with normal GFR, volume expansion was not followed by a natriuretic effect of the same magnitude as in controls. This ""inadequate natriuresis after volume expansion"" may be explained partly by chronic hyponatremia and partly by a functional defect, i.e. the incomplete arterial vasodilation in the kidney. At comparable degrees of renal insufficiency, T-CH2O was lower in PKD than in CGN patients. It seems likely that in PKD patients the increased endogenous osmotic load has exaggerated the tubular defect in urine concentration already present at normal GFR. Furthermore, volume expansion was followed by a significant increase in fractional sodium excretion only in PKD patients with renal insufficiency.

Renal tubular defects in recurring bilateral nephrolithiasis.

A metabolic study was performed in 28 patients with bilateral recurrent calcium-containing renal staghorn calculi and chronic pyelonephritis ("obstructive nephropathy"). Fourteen had normal GFR and 14 mild renal insufficiency. Ten normal subjects were used as controls. Under basal conditions, polyuria and negative sodium balance were commonly observed in patients with obstructive nephropathy and normal renal function. After an acute acid load (NH4Cl) an acidifying defect, i.e. high values for urine pH and reduced excretion of titratable acid and ammonium, was observed in 64% of patients with normal GFR and in 71.4% of those with renal insufficiency. During intravenous infusion with neutral sodium phosphate, the urine pH changed little but the rate of excretion of titratable acid increased in direct proportion to that of urinary phosphate in both groups of patients. These results, associated with the finding of normal blood pH in almost all patients, lead to the conclusion that an incomplete Type 1 or "distal" renal tubular acidosis is a frequent complication of obstructive nephropathy secondary to bilateral nephrolithiasis. The anatomical abnormalities of renal tubules and collecting ducts and the superimposed interstitial nephritis might be the pathogenetic factors responsible for the acidifying defect and for the impairment in sodium and water conservation.

Hepatitis B virus-related markers in secondary and in essential mixed cryoglobulinemias: a multicentric study of 596 cases. The Italian Group for the Study of Cryoglobulinemias (GISC).

The aim of this study was to assess the prevalence of HBV-related markers in cryoglobulinemias and the possible association between hepatitis B virus (HBV) and essential mixed cryoglobulinemia (EMC). A retrospective survey of the prevalence of HBV infection in cryoglobulinemic patients was carried out in 596 cases of cryoglobulinemia. On the basis of clinical and laboratory criteria the cases were grouped as secondary to connective tissue disease, to lymphoproliferative disorders, to chronic liver diseases or to chronic infectious diseases. The cases in which an associated disease was not evidenced were considered as essential mixed cryogobulinemias. Subjects in which liver dysfunction was first diagnosed simultaneously with cryoglobulinemia, were considered as a separate group. A greater prevalence of HBsAg and anti-HBc antibodies was found in cryoglobulinemias secondary to chronic liver disease (p < 0.0001) and in those associated with liver involvement at diagnosis (p < 0.05) than that found in EMCs. The prevalence of anti-HBs antibodies did not differ significantly among the groups. Proven contact with the virus, documented by at least one positive marker, was evidenced more frequently in cryoglobulinemias secondary to liver disease than in the other groups (p < 0.01). The prevalence of HBV related markers in EMCs and in hospitalized patients not suffering from diseases associated with cryoglobulin production were similar, and seems to reflect the epidemiological situation of HBV infection in Italy. In conclusion, our findings do not support an association of HBV with EMC.

Interactions between metals in rat liver and kidney: localization of metallothionein.

The interactions between two essential metals, Cu and Zn, and the localization and concentration of metallothionein have been studied in rat liver and kidney. Rats receiving daily intraperitoneal injections of Cu for 3 days, or Zn for 2 days, or Cu for 3 days followed by Zn for 2 days, were sacrificed 24, 72, 120 h after the final injection. Our data indicate that Cu and Zn are both good inductors of metallothionein synthesis in rat tissues. Synergism between Cu and Zn in metallothionein synthesis was also observed as indicated by immunocytochemical experiments and chemical analysis. Moreover, in rats injected with Cu followed by Zn, the localization of metallothionein and the concentrations of both metallothionein and metal differed over time according to the organs considered. In rat kidney, a delay in the excretory process was also observed and metallothionein was present 120 h after the last injection.

Calcium and phosphorus metabolism in chronic uremia.

In chronic uremia, the clinical disorders o calcium and phosphorus metabolism are influenced by the following factors: (1) intestinal absorption of calcium and phosphate, resulting in a negative calcium and phosphate balance at normal dietary intakes; (2) renal handling of calcium and phosphate: the fractional transport of calcium (the isoosmotic reabsorption taking place in the proximal tubule) is not affected by GFR modifications, whereas the Tm-limited reabsorption is severely impaired; the external phosphate balance is kept, even in the presence of a reduced nephron population, by means of a proportional reduction in TmPO4 values; (3) physiochemical state and turnover of body calcium and phosphate: in uremic patients, the distribution spaces, turnover rate of calcium, and accretion rate of bones are increased in comparison with the controls; the calcium infusion test in patients with renal osteomalacia is followed by a regular increase in plasma [PO4], whereas a significant decrease is observed in patients with renal osteitis fibrosa, due to the extreme 'avidity' of bones for calcium phosphate; the role of hyperphosphatemia is critical in keeping the plasma [Ca] lower than the expected values for a given metabolic set; moreover, an increased cell uptake of phosphate could counteract to some extent the reduced renal clearance of phosphate; (4) structural and biochemical modifications of bone tissue: uremic osteodystrophy consists mainly of two components: (a) osteomalacia, with osteoid excess, disappearance of the calcification front, and diffuse pathologic mineralization, and (b) osteitis fibrosa, with severe resorption of normally mineralized bone, slight osteoid excess, and almost normal calcification front; (5) hormonal factors: chronic stimulation of parathyroid glands may result in suppressible or even autonomous hyperparathyroidism. As to vitamin D, it has been suggested that the uremic kidney is not able to synthesize the 1,25-di-OH-cholecalciferol, the active metabolite of vitamin D: this results in an impaired intestinal absorption of calcium. On the contrary, the role of calcitonin in chronic uremia is still uncertain, since low values of plasma [Ca] are usually observed.

Von Willebrand factor abnormalities in IgA nephropathy.

BACKGROUND: Plasma concentration of von Willebrand factor (vWF) has been used as an index of endothelial dysfunction. Increased release of vWF from endothelial cells has been reported in several conditions, and there is also evidence that dysfunctioning endothelial cells synthesize defective molecules. In fact, unusually large vWF multimers have been described and related to the pathogenesis of some microangiopathic diseases. Abnormal levels of vWF have been reported in primary glomerulitis, but this was no referred to histological diagnosis. Furthermore, no qualitative vWF analysis was performed in these glomerulopathies. Therefore the aim of our study was to analyse quantitatively and qualitatively vWF in patients with IgA (IgAN) and non-IgA mesangial proliferative glomerulonephritis (PGN). METHODS: Fourteen IgAN patients, eight PGN patients, seven subjects with different glomerulonephritides, and 10 healthy controls formed the basis of this study. On peripheral venous blood collected in the presence of protease inhibitors, vWF parameters were investigated. vWF antigenic activity (vWF:Ag) was measured by electroimmunodiffusion. vWF subunits mobility was studied by crossed immunoelectrophoresis (CIE) and in some patients vWF multimeric analysis was performed by SDS-agarose gel electrophoresis. RESULTS: Mean vWF:Ag was significantly higher in PGN patients as compared to controls, while there was no significant difference between PGN and IgAN patients and between IgAN and controls. CIE revealed a pre-peak in 12 of 14 IgAN patients and a migration index which did not differ between controls, IgAN, and PGN subjects. No pre-peak was observed in PGN and in other glomerulonephritides. Analysis of plasma vWF multimeric pattern by SDS-agarose gel electrophoresis disclosed in four IgAN patients abnormally large vWF multimers that were not documented in PGN subjects. CONCLUSIONS: This study, by showing the presence of a pre-peak and of large vWF multimers in IgAN patients, suggests an altered postsecretory handling of the vWF in IgAN and possibly a different role of the vWF in IgAN in respect to PGN.

Deposition of immune complexes in the ovarian follicle of rabbits with experimental chronic serum sickness. I. Immunopathology.

In the present study, deposition of antigen-antibody complexes in the ovarian follicles of the rabbit is described. Forty-one rabbits were immunized with multiple daily injections of bovine serum albumin. Twenty-two rabbits developed systemic chronic serum sickness. The ovaries of rabbits with systemic chronic serum sickness, those of the immunized rabbits that did not develop systemic chronic serum sickness, and those of the nonimmunized rabbits were studied by light, electron, and immunofluorescence microscopy. It was found that granular deposits of bovine serum albumin, rabbit IgG, and C3, presumably as antigen-antibody complexes, were frequently present in the zona pellucida of secondary and tertiary follicles, and in the corpora atretica of rabbits with systemic chronic serum sickness. The oocytes showed an increased number of vacuoles and phagosomes containing electron-opaque material. These observations may contribute to the study of immunologic mechanisms in the pathophysiology of the female reproductive system.

Asymptomatic ocular sarcoidosis.

Sarcoidosis, as multisystem disease, may affect the entire visual apparatus and its adnexa: the eye hence is an optimal observation point to confirm diagnosis and assess disease activity. However, the eyes are affected only in one-fourth of cases, and the majority of the lesions are asymptomatic, requiring appropriate examination techniques to be detected. In this paper we reviewed the ophthalmic changes found in a group of 163 Italian patients affected with sarcoidosis, comparing the data collected with those published in the literature. Conjunctival granulomata, chorio-retinal lesions and lacrimal gland involvement were the more common ocular manifestations of the sarcoidosis detected; these were asymptomatic in two patients out of three. Ocular changes in sarcoidosis are more common than generally appreciated even in white patients, but their detection requires meticulous eye examination, the use of 67 Gallium scans of the head, fluorangiography, and the yield of biopsies from available eye tissues.

Transplacental transmission of antibodies to tubular basement membrane in guinea-pigs with autoimmune tubulointerstitial nephritis.

The offspring of female guinea-pigs with tubulo-interstitial nephritis were studied for possible passive transfer of disease. Whereas no immune deposits were seen on or before day 30 of gestation, IgG was detected in the tubular basement membrane (TBM) of fetuses at and after day 44. Serum of offspring contained antibodies to TBM, albeit in much lower titres than found in circulation of the mother guinea-pigs. No histopathological changes were seen in fetal kidneys. Thus, autoantibodies induced by heteroimmunization of pregnant guinea-pigs may be transmitted to offspring in the last third of the gestation period and can bind to fetal TBM. However, this transfer of antibodies does not cause disease.