Serum levels of the soluble haemoglobin scavenger receptor CD163 in MPO-ANCA-associated renal vasculitis.

OBJECTIVES: The contribution of infections to the mortality of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is important, and early and careful infection control is necessary. We investigated the usefulness of the serum-soluble haemoglobin scavenger receptor CD163 for detecting the presence of infectious complications regardless of disease activity. METHOD: Soluble CD163 in serum obtained from 45 Japanese patients with myeloperoxidase (MPO)-AAV was measured by an enzyme-linked immunosorbent assay (ELISA). We evaluated 36 samples from active-vasculitis patients, 36 samples from inactive-vasculitis patients without infection, and 19 samples from inactive-vasculitis patients with infectious complications. Serum-soluble CD163 was also measured in 15 infectious patients without vasculitis and in 30 normal controls. RESULTS: The mean serum-soluble CD163 level was higher in the patients with infectious complications than in the active-vasculitis patients, inactive-vasculitis patients, and normal controls. There were significant positive correlations between serum-soluble CD163 levels and white blood cell (WBC) count, serum C-reactive protein (CRP) levels, and serum albumin levels, but only serum CRP levels were correlated with serum-soluble CD163 levels in a multiple regression analysis. On the receiver-operating characteristic (ROC) curve, serum-soluble CD163 levels had 80.6% sensitivity and 86.7% specificity for differentiating patients with infection from those without infection. Among the active-vasculitis patients, the mean serum-soluble CD163 level of the patients with alveolar haemorrhage was significantly lower than that of the patients with interstitial lung diseases and that of the patients without pulmonary lesions. CONCLUSIONS: The serum-soluble CD163 level may be a useful marker for the detection of infectious complications in MPO-AAV patients.

Increased endothelin: nitric oxide ratio is associated with erythropoietin-induced hypertension in hemodialysis patients.

Regular administration of recombinant human erythropoietin (rHuEPO) is frequently associated with a rise in arterial blood pressure in hemodialysis (HD) patients. The aim of this study was to examine the effects of rHuEPO on plasma endothelin (ET)-1 and nitric oxide products (NOx) concentration in HD patients. Fifteen patients on maintenance HD with hematocrit of less than 25% were included in the present study. All patients received 3,000 units of rHuEPO intravenously three times a week at the end of each HD session. Plasma levels of ET-1, NOx, thromboxane B2 (TXB2), prostacyclin (6-keto-PGF1alpha), and cyclic guanosine 3',5'-monophosphate (cGMP) were measured before, 2, and 4 weeks after rHuEPO treatment. Plasma concentrations of ET-1, TXB2, and 6-keto-PGF1alpha were measured by radioimmunoassay. Plasma NOx was measured by high-performance liquid chromatography. An rHuEPO-induced increase in mean arterial blood pressure of over 6 mmHg occurred in 7 patients (hypertensive group), whereas the elevation of mean arterial blood pressure was less than 5 mmHg in 8 patients (nonhypertensive group). Plasma ET-1 levels were elevated in all HD patients. Elevated plasma ET-1 levels remained unchanged after rHuEPO treatment in the hypertensive group, whereas the increase in plasma ET-1 levels was attenuated in the nonhypertensive group. Plasma NOx concentrations were also increased in all HD patients. This increase in plasma NOx levels was lessened in the hypertensive group after rHuEPO administration; however, plasma NOx levels remained increased in the nonhypertensive group. Changes in mean arterial blood pressure were significantly correlated with changes in plasma ET-1/NOx ratio. Plasma levels of TXB2, 6-keto-PGF1alpha, and cGMP were unchanged after rHuEPO administration in the hypertensive and nonhypertensive groups. These results suggest that an increase in ET-1/NOx ratio in blood, probably occurring in vascular endothelial cells, may be associated with rHuEPO-induced hypertension in HD patients.

Comparative effects of plasmapheresis and intravenous cyclophosphamide on urinary podocyte excretion in patients with proliferative Lupus nephritis.

Intravenous cyclophosphamide (IVC) in combination with steroids is standard therapy for Lupus nephritis. Reduction of autoantibodies and circulating immune complexes can be used in the treatment of autoimmune diseases. The aim of the present study was to compare the effects of IVC pulse therapy and double-filtration plasmapheresis (DFPP) on proteinuria and urinary excretion of podocytes in adult patients with diffuse proliferative Lupus nephritis (DPLN). Twenty patients were randomly assigned to two groups. Group A (n = 10) was treated with IVC (0.75 - 1.0 g/m2 body surface area) pulse therapy, given as boluses once a month for 6 consecutive months, combined with oral corticosteroid (up to 1 mg/kg/day) administration. Group B (n = 10) was treated with a combination of DFPP (performed 1-2 times weekly) and corticosteroid (up to I mg/kg/ day). The total average number of treatments was 8.4 and the therapeutic efficacies were evaluated after 6 months. Twenty healthy individuals participated as a control group. Urinary podocytes were examined by immunofluorescence with monoclonal antibodies against podocalyxin. Both Group A and Group B reduced proteinuria (p < 0.001) as well as the number of urinary podocytes (p < 0.001). Differences between the 2 treatment outcomes were not statistically significant. Cyclophosphamide pulse therapy and DFPP may be similarly effective in the treatment of podocyte injury in patients with DPLN.

Combination therapy of trandolapril and candesartan cilexetil reduces microalbuminuria and urinary endothelin-1 excretion in patients with type 2 diabetes.

Background. Angiotensin (AT)-converting enzyme inhibitors (ACEIs) and AT1-receptor blockers (ARBs) are widely used to reduce urinary albumin excretion (UAE) and slow the progression of diabetic nephropathy. The aim of the present study was to determine whether treatment with trandolapril (an ACEI) and candesartan cilexetil (an ARB) in combination has more effect on UAE and urinary endothelin (ET)-1 excretion than treatment with trandolapril or candesartan cilexetil alone in patients with type 2 diabetes. Methods. Sixty normotensive type 2 diabetes patients with microalbuminuria were randomly assigned to four treatment groups: (A) treatreatment with trandolapril at 2 mg/day (n = 15), (B) treatment with candesartan cilexetil at 8 mg/day (n = 15), (C) treatment with trandolapril at 2 mg/day and candesartan cilexetil at 8 mg/day (n = 15), and (D) treatment with placebo (n = 15). The study period was 18 months. UAE, urinary ET-1, and plasma ET-1 levels were measured in the patients before treatment and after 12 and 18 months of treatment. Results. Before treatment, UAE, urinary ET-1, and plasma ET-1 levels differed little between the four groups. Trandolapril and candesartan cilexetil administered alone reduced UAE and urinary ET-1 excretion to a similar extent (12 months; P < 0.05 and 18 months; P < 0.01). When trandolapril and candesartan cilexetil were coadministered, UAE and urinary ET-1 excretion decreased to a significantly greater extent at 12 and 18 months (P < 0.05) than with trandolapril or candesartan cilexetil alone. However, plasma ET-1 and systemic blood pressure levels were not affected. Conclusions. The data suggest that combination therapy with trandolapril and candesartan cilexetil has an additive effect on the reduction of microalbuminuria in microalbuminuric normotensive type 2 diabetes patients.

Changes in concentrations of type IV collagen and tissue inhibitor of metalloproteinase-1 in patients with paraquat poisoning.

Respiratory failure is one of the major causes of death in patients with paraquat poisoning. In paraquat-poisoned lungs, abnormal extracellular matrix regulation occurs. The aim of the present study is to determine whether serum concentrations of type IV collagen and tissue inhibitor of metalloproteinase-1 (TIMP-1) are altered during the course of paraquat poisoning and whether haemoperfusion therapy affects these concentrations. Twenty-one patients were admitted within 3 h after ingestion of paraquat and all patients received direct haemoperfusion therapy. Five out of 21 patients survived and 16 patients died within 28 days. Plasma paraquat concentrations in non-survivors (5740 +/- 380 microg l(-1)) were not significantly different from those in survivors ( 5920 +/- 280 microg l(-1)) before treatment. Haemoperfusion reduced these concentrations in both non-survivors (120 +/- 7 microg l(-1)) as well as survivors (136 +/- 9 microg l(-1)) on day 5. Serum concentrations of type IV collagen and TIMP-1 in survivors showed little change between day 1 (type IV collagen, 90.4 +/- 3.6 ng ml(-1); TIMP-1, 172.2 +/- 7.0 ng ml(-1)) and day 5 (type IV collagen, 92.6 +/- 4.2 ng ml(-1); TIMP-1, 174.2 +/- 7.2 ng ml(-1)). In contrast, these concentrations in non-survivors on day 5 (type IV collagen, 143.6 +/- 7.8 mg ml(-1); TIMP-1, 246.8 +/- 13.6 ng ml(-1)) were significantly higher than those on day 1 (type IV collagen, 88.4 +/- 4.2 ng ml(-1), P < 0.01; TIMP-1, 170.6 +/- 9.2 ng ml(-1), P < 0.05). These data suggest that serum concentrations of type IV collagen and TIMP-1 may be useful indicators for the development of respiratory failure in patients with paraquat poisoning.

Th2 predominance at the single-cell level in patients with IgA nephropathy.

BACKGROUND: Abnormalities of lymphocyte function have been reported to be involved in the pathogenesis of IgA nephropathy (IgA-N). The aim of this study was to investigate helper T (Th) predominance at the single-cell level, one of the abnormalities of lymphocyte function in IgA-N. METHODS: Using flowcytometry, we assessed the levels of circulating Th cells in IgA-N patients (n=30), and in normal individuals (n=30) based on the expression of intracellular Th1 cytokines for interleukin-2 (IL-2) and interferon-gamma (IFN-gamma), and of intracellular Th2 cytokines for IL-4, IL-10, and IL-13. Because the production of each cytokine had a specific time course, we examined cytokine synthesis at 3, 6, 9, and 12 h after stimulation. RESULTS: The percentages of IL-2-positive Th cells from IgA-N patients were significantly lower than in normal individuals at 6, 9, and 12 h, with the difference becoming greater with time. The number of IFN-gamma-positive Th cells in IgA-N patients was significantly lower than in normal individuals at 9 h, and the number of IFN-gamma-positive Th cells increased more at 12 h than at 3 h in both groups. IL-4 and IL-13 expression was increased in patients with IgA-N at 6 h compared with normal individuals. In IgA-N patients, the percentage of IL-10-positive Th cells was significantly higher than that in normal individuals at each time-point. CONCLUSION: A polarization toward Th2 response at the stimulated lymphocyte level may lead to immune abnormalities in IgA-N.

Effect of dilazep dihydrochloride on urinary albumin excretion in patients with autosomal dominant polycystic kidney disease.

Proteinuria and microalbuminuria occur with a highly variable severity and are associated with progression of autosomal dominant polycystic kidney disease (ADPKD). Dilazep dihydrochloride, an antiplatelet drug, is effective in patients with immunoglobulin A nephropathy or diabetic nephropathy. We studied whether dilazep dihydrochloride affects the urinary albumin excretion (UAE) in normotensive and hypertensive patients with ADPKD. Twelve normotensive ADPKD patients with microalbuminuria were randomly assigned to two groups: a dilazep (300 mg/day) treatment group (n = 6, group A) and a placebo group (n = 6, group B). In addition, 10 hypertensive ADPKD patients with microalbuminuria were randomly assigned to two groups: a dilazep (300 mg/day) treatment group (n = 5, group C) and a placebo group (n = 5, group D). Treatment with dilazep was continued for a period of 6 months, at the end of which the UAE was reduced form 130 +/- 52 to 46 +/- 26 microg/min (p < 0.01) in group A. There was no reduction in group C. There were no changes in UAE in placebo groups B and D. These results suggest that dilazep dihydrochloride may be effective in reducing UAE in normotensive ADPKD patients with microalbuminuria.

Comparative effects of pioglitazone, glibenclamide, and voglibose on urinary endothelin-1 and albumin excretion in diabetes patients.

Urinary endothelin (ET)-1 excretion is present in non-insulin dependent diabetes (NIDDM) patients with microalbuminuria, and an increase in circulating ET-1 precedes the microalbuminuric phase of renal injury related to diabetes. The aim of the present study was to determine whether various drugs alter urinary ET-1 levels and urinary albumin excretion (UAE) in NIDDM patients with microalbuminuria. Forty-five NIDDM patients with microalbuminuria were randomly assigned to three groups: those treated with pioglitazone at 30 mg/day (n=15), those treated with glibenclamide at 5 mg/day (n=15), and those treated with voglibose at 0.6 mg/day (n=15). Patients received these drugs for 3 months. UAE, urinary ET-1, and plasma ET-1 levels were measured in these patients before and after treatment. Before treatment, UAE, urinary ET-1, and plasma ET-1 levels differed little among the three groups. UAE in the 45 NIDDM patients (156.2+/-42.8 microg/min) was greater than that in 30 healthy controls (8.2+/-2.6 microg/min) (P<.001). Urinary ET-1 levels in the NIDDM patients (8.7+/-1.3 ng/g urinary creatinine (UC)) were significantly higher than that in the controls (2.4+/-0.2 ng/g UC) (P<.01). Plasma ET-1 levels, however, in the NIDDM patients (1.3+/-0.4 pg/ml) did not differ significantly from the levels in healthy controls (1.0+/-0.6 pg/ml). Pioglitazone but no glibenclamide or voglibose reduced UAE from 142.8+/-42.2 to 48. 4+/-18.2 microg/min (P<.01) and urinary ET-1 levels from 8.6+/-1.3 to 3.4+/-0.5 ng/g UC (P<.01). These data suggest pioglitazone to be effective in reducing UAE and urinary ET-1 concentrations in NIDDM patients with microalbuminuria.

Effects of angiotensin-converting enzyme inhibitor, angiotensin II receptor antagonist and calcium antagonist on urinary podocytes in patients with IgA nephropathy.

The urinary podocyte is postulated to be a marker for estimation of the severity of active glomerular injury and a predictor of disease progression in children with glomerulonephritis. Non-dihydropyridine calcium antagonist, including verapamil, reduce proteinuria to an extent similar to that of the angiotensin-converting enzyme inhibitor (ACEI), including trandolapril, but to a greater extent than other antihypertensives. Angiotensin (Ang) II receptor antagonists, including candesartan cilexetil, show potent and long-term preventive effects against the progression of renal injury. The aim of the present study is to assess whether verapamil, trandolapril and candesartan cilexetil affect proteinuria and urinary podocytes in patients with IgA nephropathy. Thirty-two normotensive patients aged 18-54 years with biopsy-proven IgA nephropathy, nonnephrotic proteinuria (1-3 g/day), and normal renal function (creatinine clearance >80 ml/min) were studied. Twenty patients with diffuse mesangial proliferative glomerulonephritis (non-IgA PGN) and 20 healthy controls were also included in this study. The number of urinary podocytes in patients with advanced IgA nephropathy (n = 16) was significantly higher than that in patients with the disease in the mild stage (n = 16) (p < 0.01) or in patients with non-IgA PGN (p < 0.01). Urinary podocytes were not detected in healthy controls. The 32 patients with IgA nephropathy were randomly divided into four treatment groups: those treated with verapamil (120 mg/day, n = 8); those treated with trandolapril (2 mg/day, n = 8); those treated with candesartan cilexetil (8 mg/day, n = 8), and those given a placebo (n = 8). Treatment continued for 3 months. Antiproteinuric response in the trandolapril group was similar to that in the candesartan cilexetil group (-38 vs. -40%). The action of trandolapril or candesartan cilexetil was greater than that of verapamil (p < 0.01). Reduction in the number of urinary podocytes from baseline was significantly greater in patients treated with trandolapril or candesartan cilexetil than in patients treated with verapamil (p < 0.01). However, there was no difference between patients treated with trandolapril and those treated with candesartan cilexetil. Proteinuria and urinary podocytes were unaffected in the placebo group. These data suggest that urinary podocytes may be a marker of disease activity in adult patients with IgA nephropathy and that trandolapril and candesartan cilexetil are more effective than verapamil in reducing the number of podocytes.

Urinary podocytes for the assessment of disease activity in lupus nephritis.

BACKGROUND: Detection of podocytes in the urine indicates that severe injury of podocytes occurred in the glomerulus in children. METHODS: The pathological significance of podocytes in the urine was determined in patients with lupus nephritis. Podocytes were detected by immunofluorescence using a monoclonal antibody against podocalyxin present on the surface of podocytes. Subjects who participated in the present study were of the following types: patients with systemic lupus erythematosus with stable renal function (group A, n = 8; WHO classes IlIa, b, IVb, and IVc at the time of biopsy); patients with clinically active lupus nephritis (group B, n = 8; WHO classes IVb and IVc); and healthy control subjects (group C, n = 10). RESULTS: Podocytes were absent in the urine of subjects in groups A and C. However, podocytes were present in the urine of group B subjects. Patients in group B were examined monthly for urinary podocytes and were treated with methylprednisolone followed by prednisolone. Urinary podocytes were absent in all patients in group B after treatment. CONCLUSIONS: These data indicate that urinary podocytes may be markers of the severity of lupus nephritis and that steroid therapy may be effective for podocyte injury in lupus nephritis.