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Introduction Chronic allograft injury is the most frequent cause of long-term kidney allograft loss. Cyclosporine (CsA) nephrotoxicity is an important factor contributing to graft loss. Increased fibrosis has been reported in renal transplants under CsA as compared with tacrolimus (Tac). Platelet-derived growth factor (PDGF) is a well-characterized fibrogenic growth factor in renal disease. Objective Here we investigated the effect of Tac on kidney grafts and PDGF expression both early after transplantation as well as during long-term follow-up of rat renal allografts, and compared it to CsA. Tac and CsA were also studied on PDGF secretion in macrophages in vitro. Materials and methods Kidney allografts were immunosuppressed with Tac or CsA. Grafts were analyzed by histology and immunohistochemistry. ELISA was used to measure PDGF-levels in Tac and CsA-treated macrophage cultures. Results Tac ameliorated markedly both acute and chronic changes, whereas moderate to intense histological changes were seen in CsA-treated allografts. Tac also significantly inhibited PDGF expression compared to CsA. At clinically adjusted concentration CsA induced PDGF in macrophages whereas Tac did not. Discussion Tac may be less fibrogenic than CsA by decreasing PDGF expression in kidney grafts as well as in macrophages. Data presented here suggests that decreased PDGF induction by Tac may be beneficial for later outcome of the kidney graft.

13-cis-Retinoic acid treatment causes insulin resistance and disturbances in lipid and glucose metabolism. We studied how 13-cis-retinoic acid affects inflammatory factors and adiponectin. A total of 23 healthy patients (age, 24.9 +/- 0.9 years; body mass index, 22.6 +/- 0.7 kg/m(2)) who received 13-cis-retinoic acid treatment of acne participated in the study. The patients were studied before the treatment, after 3 months of therapy, and 1 month after the treatment. Inflammatory parameters were measured, and a 4-hour oral glucose tolerance test was performed at each visit. Treatment with 13-cis-retinoic acid resulted in a significantly elevated serum adiponectin concentration (from 24.9 +/- 2.5 to 29.4 +/- 3.6 mg/L, P < .05), hemoglobin A(1c) (from 5.27% +/- 0.05% to 5.42% +/- 0.06%, P < .01), C-peptide area under the curve (from 314.2 +/- 16.6 to 350.0 +/- 21.0 (nmol . min)/L, P < .05), and triglycerides (from 0.97 +/- 0.06 to 1.29 +/- 0.10 mmol/L, P < .05), whereas high-density lipoprotein cholesterol decreased (from 1.50 +/- 0.07 to 1.38 +/- 0.08 mmol/L, P < .05). The increase in adiponectin during 13-cis-retinoic acid therapy correlated with baseline triglycerides (r = 0.51, P < .02). Many inflammatory markers, which were nonsignificantly elevated during therapy, decreased significantly after cessation of treatment. These were C-reactive protein (median from 1.78 to 1.23 mg/L, P < .05), soluble intercellular adhesion molecule 1 (from 210 +/- 10 to 204 +/- 10 microg/L, P < .02), ceruloplasmin (256 +/- 17 to 231 +/- 17 microg/L, P < .02), and erythrocyte sedimentation rate (from 6.4 +/- 1.3 to 4.7 +/- 0.9 mm/h, P < .02). Interleukin 6 concentration was unaffected by the therapy, but decreased significantly after the treatment (from 2.18 +/- 0.46 to 1.65 +/- 0.43 ng/L, P < .05). In conclusion, although treatment with 13-cis-retinoic acid results in disturbances in glucose and lipid metabolism, paradoxically serum adiponectin concentration increases. 13-cis-Retinoic acid has profound effects on the regulation of inflammatory markers.

Type 2 diabetes is characterized by increased acute phase serum proteins. We wanted to study how these proteins are related to complement activation in type 2 diabetes and how improvement of glycemic control affects them or complement activation. A total of 29 type 2 diabetic patients (age, 55.2 +/- 1.8 years, glycosylated hemoglobin [HbA(1c)] 8.9% +/- 0.2%, body mass index [BMI] 30.9 +/- 0.8 kg/m(2), duration 5.9 +/- 1.3 years) participated in the study. They were previously treated either with diet alone or in combination with 1 oral antihyperglycemic medication. After a period of at least 4 weeks run-in on diet only, the patients were randomized to pioglitazone, glibenclamide, or placebo. Blood samples were taken before the treatments and at the end of the 6-month therapy. Basal C-reactive protein (CRP) level was related to acylation-stimulating protein (ASP) concentration (r =.55, P

Background: Erythropoietic protoporphyria (EPP) is an inherited disease caused by deficient activity of ferrochelatase in the heme biosynthetic pathway. Accumulation of protoporphyrins and light exposure results in acute phototoxic skin reactions. The histopathologic findings of the light-exposed skin are thickening of the superficial dermal vessel walls and amorphous deposits around the vessels, but the origin and detailed composition of the perivascular material have been unclear. Objective: The vascular morphology and composition of the perivascular material were studied in the skin samples of patients with EPP. Methods: Skin biopsy specimens of 8 patients with EPP representing 7 Finnish EPP families with different genotypes were studied by means of light and electron microscopy and immunohistochemical methods. Results: The characteristic finding was thickened, periodic acid-Schiff-positive vessel walls caused by concentric reduplication of basal lamina and excess of fine granular material at the basal membrane zone in the superficial dermis. The perivascular deposits in the vicinity of vessel walls had a homogeneous or fine granular appearance without filaments. Direct immunofluorescence showed constant IgG deposits together with IgA, IgM, and C3 in the vessel walls. In immunohistochemistry, collagen IV and laminin could be demonstrated at the vascular basal membrane together with serum amyloid P protein, κ and λ light chains, and a 90-kd glycoprotein. Conclusion: The vascular involvement indicates that the blood vessel walls in the papillary dermis are the primary tissues affected during an acute photoreaction. The repeated acute damage and repair processes in the basement membrane zone result in thickening of the vessel walls. Perivascular deposits are a secondary and irreversible phenomenon resulting from the leakage and accumulation of different serum components. These changes were not found in the nonexposed skin, indicating that an increased level of erythrocyte protoporphyrin per se is not responsible for the cutaneous manifestations, but the interaction of solar radiation is mandatory. Amorphous deposits distinguish EPP from variegate porphyria and porphyria cutanea tarda; a histopathologic examination may be a helpful tool in differentiating porphyric and nonporphyric photosensitivity. (J Am Acad Dermatol 2000;43:489–97.)

Autosomal dominant periodic fever syndromes are characterized by unexplained episodes of fever and severe localized inflammation. In seven affected families, we found six different missense mutations of the 55 kDa tumor necrosis factor receptor (TNFR1), five of which disrupt conserved extracellular disulfide bonds. Soluble plasma TNFR1 levels in patients were approximately half normal. Leukocytes bearing a C52F mutation showed increased membrane TNFR1 and reduced receptor cleavage following stimulation. We propose that the autoinflammatory phenotype results from impaired downregulation of membrane TNFR1 and diminished shedding of potentially antagonistic soluble receptor. TNFR1-associated periodic syndromes (TRAPS) establish an important class of mutations in TNF receptors. Detailed analysis of one such mutation suggests impaired cytokine receptor clearance as a novel mechanism of disease.

Adhesion molecules and urinary tumor necrosis factor-α in idiopathic membranous glomerulonephritis. Adhesion molecules are required in several physiological processes, but their altered function/expression is associated with the pathogenesis of inflammatory diseases. In the present study on idiopathic membranous glomerulonephritis (MGN) the expression of adhesion molecules (ICAM-1, VCAM-1, PECAM-1, E-selectin, LFA-1, Mac-1) was analyzed in different cellular compartments of the kidney using an indirect immunoperoxidase technique and monoclonal antibodies. Relationships between the expression of these molecules and the clinical and morphological activity of the disease and the urinary excretion of tumor necrosis factor α (TNF-α) were studied in 20 patients. The results were compared with the findings in ten normal kidneys and urinary TNF-α in 17 healthy subjects. The expression of adhesion molecules in glomeruli and tubules was unchanged apart from a diminished expression of VCAM-1 (P = 0.014) in glomerular parietal epithelial cells and PECAM-1 in glomerular endothelial cells (P < 0.01). Interstitial peritubular capillaries expressed significantly (P = 0.009) more E-selectin compared with the controls. The interstitial compartment had a highly increased number of cells expressing ICAM-1 in MGN (32.4 ± 4.6 cells/high power field) compared with the controls (9.4 ± 1.2; P < 0.001). Also, cells expressing VCAM-1 (10.2 ± 1.6 vs. 2.8 ± 1.9; P = 0.005), PECAM-1 (25.9 ± 5.3 vs. 7.4 ± 2.1; P = 0.006), and LFA-1 (20.4 ± 3.6 vs. 8.3 ± 1.5; P = 0.041) were increased in the interstitium. Proteinuria correlated particularly with the expression of E-selectin in peritubular capillaries (r = 0.63, P = 0.004). The number of LFA-1 expressing inflammatory cells in the interstitium correlated with peritubular capillary E-selectin (r = 0.8, P < 0.001) and interstitial ICAM-1 (r = 0.61, P = 0.009) expression, but histological alterations did not correlate with the expression of adhesion molecules. Tumor necrosis factor-α excretion was significantly increased in MGN (41 ± 8 pg/mg creatinine) compared with the controls (13 ± 2; P = 0.001), and in particular, it correlated with the interstitial expression of LFA-1 (r = 0.71, P = 0.002). This study suggests that active MGN leads not only to proteinuria but also to increased urinary TNF-α excretion. These may serve as triggers for the up-regulation of adhesion molecules in the peritubular capillaries and interstitial cells thus enhancing the development of the interstitial injury.

In vitro infection of freshly isolated human peripheral blood mononuclear cells (HPBMC) with Chlamydia pneumoniae was found to induce a production of tumour necrosis factor alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6) and interferon alpha (IFN-alpha). The secretion was dependent on the amount of infecting chlamydiae and most of it occurred during the first 12 to 24 h. Lipopolysaccharide (LPS) of Salmonella minnesota Rechemotype, used as a positive control for HPBMC activation, induced a release of TNF-alpha, IL-1 beta and IL-6, but not of IFN-alpha, similar to the effect of C. pneumoniae. Viable chlamydiae could not be recovered from HPBMCs infected immediately after their isolation, whereas HPBMCs which were cultured in vitro for 3 to 9 days before infection were able to maintain the growth of C. pneumoniae. Growth inside HPBMCs as well as induction of cytokine response may have a role in the pathogenesis of C. pneumoniae infection.

Urinary excretion of protectin (CD59), complement SC5b-9 and cytokines in membranous glomerulonephritis. Protectin (CD59) is a low molecular weight glycophosphoinositol-anchored inhibitor of the membrane attack complex of complement (MAC) that is present, for example, on the membranes of endothelial cells and on epithelial cells of glomeruli and distal tubuli. To examine for the possibility that CD59 becomes detached from cell surfaces following cell injury, this study evaluated renal excretion of CD59 in patients with idiopathic membranous glomerulonephritis (MGN; N = 21), diabetic nephropathy (DNP; N = 15) and in healthy control subjects (N = 13). CD59 in human urine was quantitated by a competitive solid-phase radioimmunoassay having ≈13 kDa soluble urinary CD59 as a standard. Immunofluorescence microscopy demonstrated a decreased expression of CD59 in the glomeruli of MGN patients. Using a Triton X-114 phase separation method 91 to 97% of urinary CD59 was found to be in a soluble form without anchor-associated phospholipid. The mean (±sem) level of urinary CD59 was 5.6 ± 0.2 µg/ml in MGN patients, 3.7 ± 0.4 µg/ml in healthy controls (P < 0.001) and 2.6 ± 0.1 in DNP patients (P < 0.001). When related to urinary creatinine (UCr) the corresponding values were 11.9 ± 5.6, 4.8 ± 0.3 (P = 0.021) and 4.4 ± 0.2 (P < 0.002), respectively. The amount of CD59 in urine correlated with the urinary excretion of soluble terminal complement complexes, SC5b-9 (r = 0.594, P < 0.006) in MGN patients. The excretion of CD59 also correlated with the excretion of the inflammatory mediator IL-1β (r = 0.671, P = 0.001) but not with TNF-α (r = 0.314, P = 0.178). No correlation of CD59 excretion was observed with duration of the disease, level of proteinuria, serum albumin concentration or serum creatinine level. Based on these findings we speculate that the increased excretion of CD59 into urine in MGN patients is due to complement activation and inflammation induced shedding of CD59 from glomerular cells.

Urinary excretion of kappa light chains in patients with diabetes mellitus. The urinary excretion of kappa light chains,β 2 -microglobulin and albumin was examined in patients with newly diagnosed and long-standing insulin-dependent (IDDM) and non-insulin-dependent (NIDDM) diabetes mellitus, and compared to age-matched control subjects. Patients with IDDM diagnosed within two months, presented with normal albumin excretion, whereas the concentrations of β 2 -microglobulin and kappa light chain in urine were higher than in control subjects. The initiation of insulin therapy reduced, but did not completely normalize, the elevated rate of kappa light chain excretion. Patients with IDDM of long duration showed increased urine excretion of kappa light chains and albumin. In keeping with the findings in IDDM, patients with newly diagnosed NIDDM (within one year) showed increased urinary excretion of kappa light chains compared with control subjects. There was, however, no further increase in light chain excretion with longer duration of NIDDM. To study the effect of short-term hyperglycemia on urinary protein excretion, 12 normal subjects participated in a three-step hyperglycemic clamp study, during which their plasma glucose concentration was raised by +50, +125 and +300 mg/dl. The urine excretion of albumin and β; 2 -microglobulin rose progressively with each hyperglycemic clamp step, whereas that of kappa light chain excretion was unaffected by hyperglycemia. We conclude that increased urinary excretion of kappa light chain is a consistent finding in all types of diabetes mellitus, and can be observed even when the albumin excretion is normal. Since the serum concentration of kappa light chain is normal in diabetes, the increased urinary excretion of kappa light chains must be of renal origin. Although the underlying mechanism(s) responsible for the kappa light chainuria are unknown, it cannot be ascribed to the effect of acute hyperglycemia on glomerular and tubular function.

Human serum contains amyloid-A-degrading (AADP) activity. This activity is reduced in amyloidosis associated with rheumatoid arthritis. Since AADP co-migrates with albumin on agarose-gel electrophoresis, the relationship between these serum factors was studied in patients with amyloidosis and patients with amyloidosis and patients with altered albumin synthesis and/or distribution. AADP activity correlated positively with albumin levels in patients with rheumatoid arthritis complicated by amyloidosis. A weaker association was noted between serum activity and prealbumin levels. The AADP activity in patients with rheumatoid arthritis without signs of amyloidosis and patients with liver cirrhosis was also positively associated with serum albumin level. During the acute-phase reaction after surgery serum AADP activity fell in parallel with serum albumin level. Purified albumin preparations displayed AADP activity. The results show that serum albumin level reflects AADP activity. It is suggested that the development of hypoalbuminaemia in patients with amyloidosis may give rise to a vicious circle which leads to an accelerated reduction in AADP activity and accelerated amyloidogenesis.

Human epidermis, hair, nails, and kidney as well as bovine and horses' hooves were found to contain a lipid fraction, which on thin-layer chromatography migrated slightly ahead of the cerebroside sulfate esters and gave the color reaction specific for sialic acid. This fraction was isolated from horse hoof, in which it constituted nearly half of the total lipids. The purified fraction contained sulfur, but no phosphorus. The IR spectrum revealed the presence of a sulfate group, which was also determined by the benzidine method. Thin-layer and gas-liquid chromatography of the products of acid hydrolysis revealed the presence of sphingosine, galactose, galactosamine, and sialic acid. Fatty acid analysis showed that stearic acid was the major component, with minor amounts of palmitic and arachidic acids. The fraction isolated contained ceramide, sialic acid, galactose, galactosamine, and sulfate in equimolar amounts. We conclude that the new lipid is a ganglioside sulfate, which we have called "ungulic acid" because it was first separated and identified from a horse's hoof (Latin, ungula).