Giuseppe Picciotto

Angiotensin II Local Hyperreactivity in the Progression of IgA Nephropathy

Immunologic and hemodynamic factors are likely to work in synergism in the progression of immunoglobulin A nephropathy (IgAN) toward sclerosis. The local activation of the renin-angiotensin system may be one the most relevant mechanisms. We investigated the hemodynamic effects of the acute administration of angiotensin-converting enzyme inhibitor (ACEI) (captopril 50 mg). The glomerular filtration rate (GFR) and the effective renal plasma flow (ERPF) were measured by 51Cr-EDTA and 125I hippurate clearances. The correspondent filtration fractions (FFs) in basal conditions and after administration of ACEI were calculated, then the changes in FF (delta FF and % delta FF) were determined. We studied 27 IgAN patients. Eighteen patients had normal renal function (GFR, 112 +/- 19 mL/min/1.73 m2) and nine had moderate renal impairment (GFR, 54 +/- 13 mL/min/1.73 m2). Sixteen patients had proteinuria > or = 0.5 g/d. In addition, 12 glomerulonephritis control cases and eight healthy subjects were investigated. After the administration of ACEI in healthy subjects we observed slight modifications in the GFR, a significant increase in the ERPF (P < 0.005), and a significant decrease in FF (P < 0.04). Similarly, in IgAN patients with normal renal function the GFR increased slightly, the ERPF increased significantly (P < 0.01), and there was a decrease in FF (P < 0.01). The delta FF and % delta FF values were not significantly different from those found in the controls. In patients with initial renal failure GFR remained unchanged, ERPF increased significantly (P < 0.005), and FF significantly decreased (P < 0.004). However, the changes in delta FF and % delta FF were significantly greater than those found in healthy controls (P < 0.01) and in IgAN patients with normal renal function (P < 0.001). IgAN patients with proteinuria levels > or = 0.5 g/d showed greater changes in delta FF and % delta FF after the administration of ACEI than patients with proteinuria levels lower than 0.5 g/d (P < 0.003 and P < 0.04, respectively) or proteinuric control cases (P < 0.05 and P < 0.01, respectively). This different response in proteinuric and nonproteinuric patients was evident even when the analysis was limited to the subgroup of IgAN patients with normal renal function. The decrease in FF consequent to an increase in the ERPF after the administration of ACEI suggests a local hyperactivity of the renin-angiotensin system in some cases of IgAN.(ABSTRACT TRUNCATED AT 400 WORDS)

Estimation of chromium-51 ethylene diamine tetra-acetic acid plasma clearance: a comparative assessment of simplified techniques

Chromium-51 ethylene diamine tetra-acetic acid (51Cr-EDTA) total plasma clearance was evaluated using a multi-sample method (i.e. 12 blood samples) as the reference compared with several simplified methods which necessitated only one or few blood samples. The following 5 methods were evaluated: terminal slope-intercept method with 3 blood samples, simplified method of Bröchner-Mortensen and 3 single-sample methods (Constable, Christensen and Groth, Tauxe). Linear regression analysis was performed. Standard error of estimate, bias and imprecision of different methods were evaluated. For 51Cr-EDTA total plasma clearance greater than 30 ml · min−1, the results which most approximated the reference source were obtained by the Christensen and Groth method at a sampling time of 300 min (inaccuracy of 4.9%). For clearances between 10 and 30 ml · min−1, single-sample methods failed to give reliable results. Terminal slope-intercept and Bröchner-Mortensen methods were better, with inaccuracies of 17.7% and 16.9%, respectively. Although sampling times at 180, 240 and 300 min are time-consuming for patients, 51Cr-EDTA total plasma clearance can be accurately calculated for values greater than 10 ml · min−1 using the Bröchner-Mortensen method. In patients with clearance greater than 30 ml · min−1, single-sample techniques provide a good alternative to the multi-sample method; the choice of the method to be used depends on the degree of accuracy required.

The Fate of Aggregated Immunoglobulin A Injected in IgA Nephropathy Patients and Healthy Controls

Organ uptake of IgA-containing immunologically active material was studied in humans by intravenous (IV) injection of 131I-labeled heat-aggregated human secretory IgA (HAS-IgA) in nine patients affected by primary IgA nephropathy and 10 normal volunteers. Aggregated secretory IgA was found to be removed almost exclusively by the liver. The peak activity in liver was reached at 21.1 minutes (range, 18 to 26 minutes) in patients and 19 minutes (range, 14 to 22 minutes) in controls. The rate of increase of liver radioactivity was found to be significantly slower in patients (with a mean slope of 5.0; range, 3.4 to 7.1 v 7.6, 5.6 to 11.4; P less than 0.02). The mean liver to precordium ratio at the peak time was significantly lower in patients (mean value, 2.3; range, 1.9 to 3.1) compared with controls (mean value, 3.3; range, 2.4 to 4.0) (P less than 0.02). These data confirm the pivotal role of the liver in the removal of aggregated IgA in humans and the defective clearance capacity of this test probe in IgA nephropathy patients.

Prospective Study on Captopril Renography in Hypertensive Patients

Six hundred and sixty-seven hypertensive patients were analyzed by captopril-enhanced scintigraphy. If time to reach maximal activity (Tmax) was > or = 5 min using 99mTc-diethylenetriaminepentaacetic acid (DTPA) or > or = 3 min with 123I-o-iodohippurate (OIH) and 99mTc-mercaptoacetyltriglycine (MAG3) and washout time > or = 15 min, a control study with nifedipine was performed. If the difference between Tmax under captopril and nifedipine premedication was > or = 5 min with 99mTc-DTPA or > or = 3 min with 123I-OIH and 99mTc-MAG3, the renogram was defined highly suggestive of renovascular hypertension. In the evaluation of bilateral abnormalities an additional parameter was considered, i.e. the presence of functional asymmetry of the emuntories susceptible of partial reversal in the control study under nifedipine. Based on these criteria, 58 out of 667 (8.7%) scintigrams were found to be abnormal. Thirty-five of these 58 patients and 32 of the remaining 609 scintigraphically negative cases underwent additional arteriographic examination. A renal vascular stenosis > or = 50% was found in 33 out of 35 (94.2%) patients with positive scintigraphy and in 3 out of 32 patients with negative scintigraphy. By examining results of the 67 patients undergoing arteriography, the sensitivity of captopril-enhanced scintigraphy was estimated to be 91.6%, with a specificity of 93.5%, an accuracy of 92.5%, and predictive values of a positive or negative result of 94.2 and 90.6%, respectively. By restricting analysis to bilateral stenosis, sensitivity was found to be 76.9%.(ABSTRACT TRUNCATED AT 250 WORDS)

Clearance of polymeric IgA aggregates in humans.

Clearance of aggregated human secretory immunoglobulin A (AHS-IgA) was studied in nine patients affected by primary IgA nephropathy (IgAGN) and six normal volunteers from the medical staff. Samples of whole blood, erythrocytes, and serum were taken from 3 to 120 minutes after injection of 0.5 mg of 131iodine-labeled AHS-IgA. No significant radioactivity was recorded on erythrocytes. The clearance curve of AHS-IgA from the circulation, calculated by measuring trichloroacetic acid precipitable radioactivity in serum, was found to be biexponential with an initial fast component significantly prolonged in patients (mean half-time, 19.4 minutes, range, 14 to 26 minutes) compared with controls (mean, 12.2 minutes, range, 7.6 to 16.8 minutes; P less than 0.01). These data indicate that clearance of aggregated polymeric IgA does not involve the erythrocyte transport system and seems to be defective in IgAGN patients.

Failure to Relate Mononuclear Phagocyte System Function to HLA-A, B, C, DR, DQ Antigens in Membranous Nephropathy

Nineteen patients with idiopathic membranous nephropathy were typed for HLA pattern and analyzed for the Fc receptor function of splenic macrophages by detecting in vivo the clearance of IgG-sensitized 51Cr-labelled autologous erythrocytes. Seven out of 19 patients were found to have a macrophage dysfunction. This defect was not related to any HLA-A, B, C, DR, DQ antigen tested nor to the levels of IgG-containing immune complexes, as detected by a Clq solid phase test, nor to the magnitude of proteinuria. Since HLA-B8 and HLA-DR3 antigens were significantly more frequent in patients than in the control group, the factors that may impair the macrophage system in individuals predisposed to this nephropathy are discussed.

Fc-receptor function of the mononuclear phagocyte system in glomerulonephritis secondary to some multisystem diseases.

The Fc-receptor function of the mononuclear phagocyte system was examined in 30 patients affected by multisystem diseases with glomerular involvement by measuring the immune clearance of IgG-sensitized autologous red blood cells in vivo and the immune phagocytosis of monocytes in vitro. Patients studied in the phase of clinically active renal disease showed a significantly reduced Fc-receptor function by both in vivo (p less than 0.001) and in vitro (p = 0.003) assays, as compared to those studied during an inactive phase. Though the nature of the defect remains uncertain, it appears to be related to the active phase of the renal disease as also confirmed by the analysis of individual cases studied longitudinally.

lndium-111-Labeled Granulocyte Head Accumulation in Patients with Wegener’s Granulomatosis

Among the symptoms of systemic vasculitis, purulent rhinorrhea with painful sinusitis is thought to be relatively specific to Wegener’s granulomatosis (WG). Sixteen patients with rapidly progressive g