Effects of cyclosporin A on glomerular barrier function in the nephrotic syndrome.

1. To elucidate the mechanisms by which cyclosporin A diminishes proteinuria, we studied 20 patients with severe nephrotic syndrome. Biopsy-established pathologies included minimal change disease (n = 5), membranous glomerulopathy (n = 6), membranoproliferative glomerulonephritis (n = 5) and focal segmental glomerulosclerosis (n = 4). Before, at the end of a 90 day course of cyclosporin A, and finally 1 month after stopping cyclosporin A we determined 24 h protein excretion. Measurements of glomerular filtration rate, effective renal plasma flow, fractional clearance rates of albumin and immunoglobulins with different charges and the transglomerular sieving of uncharged dextrans of broad size distribution were used to study the effects of cyclosporin A on renal perfusion and the glomerular filtration barrier. The findings were analysed with a theoretical model of solute transport. 2. Among the different forms of glomerulopathy the response to low-dose cyclosporin A (trough levels 32.0-36.9 ng/ml) varied markedly. In minimal change disease, proteinuria decreased from 9.5 +/- 3.1 to 1.3 +/- 0.2 g/24 h (mean +/- SEM, P less than 0.01). This response was due to restoration of the charge selectivity of the glomerular barrier. The depressed value of the glomerular permeability coefficient also returned to normal. Glomerular filtration rate, effective renal plasma flow and renal vascular resistance did not change. Proteinuria returned after stopping cyclosporin A, although it did not reach pretreatment levels. In membranous glomerulopathy, proteinuria fell from 9.9 +/- 1.5 to 1.8 +/- 0.3 g/24 h (P less than 0.01). Changes in protein excretion and dextran sieving were compatible with an increase in glomerular permselectivity and a decrease in filtrate flow through the 'shunt' pathway. Glomerular filtration rate was maintained, although effective renal plasma flow fell significantly. Proteinuria relapsed after stopping cyclosporin A. In membranoproliferative glomerulonephritis and focal segmental glomerulosclerosis proteinuria did not respond to cyclosporin A, although cyclosporin A exerted important haemodynamic effects. 3. In minimal change disease and membranous glomerulopathy cyclosporin A exerts its beneficial effects on proteinuria through changes in the properties of the glomerular barrier, resulting in increased charge and size selectivity, respectively.

A new model for diurnal blood pressure profiling. Square wave fit compared with conventional methods.

For the characterization of diurnal blood pressure variation, we developed a simple mathematical model that nevertheless does justice to the specific form characteristics of individual blood pressure registrations. Analysis was based on 24-hour continuous intra-arterial measurement of blood pressure obtained in 23 hospitalized patients with mild-to-moderate untreated essential hypertension (mean +/- SD, 112 +/- 13 mm Hg). The day-night difference for mean arterial pressure varied markedly (mean, 18.6 mm Hg; range, 6.8-36.0). Inspection of profiles suggested a model of blood pressure as two contiguous, complementary periods of constant pressure, a so-called square wave. Determination of the times of transience between both periods (segmentation) was performed individually using a least-square error criterion. Results were compared with those obtained by conventional methods, including analysis by Fourier modeling. The square wave fit accounted for a larger fraction (66%) of circadian variance of mean arterial pressure than modeling based on segmentation by visual inspection (59%, considerable observer bias) or by clock time (50%). Application of the Minnesota Cosinor Method resulted in the poorest description (47%). Segmentation based on harmonic modeling (61%) appeared to be cumbersome (10 harmonics needed), and the significance of additional information offered over the square wave fit is dubious. Observer bias makes segmentation by visual inspection unsuitable for assessment of the circadian variance of blood pressure. Even when daily activities are strictly regulated (hospital environment), circadian variance is not well modeled by clock time. As compared with harmonic analysis, square wave fitting is simple, and it appears to best model the circadian variance. The method can also be applied to data obtained from noninvasive ambulatory blood pressure monitoring.

First passage radionuclide cardiography for determination of cardiac output: a critical analysis.

First-pass radiocardiography, by single probe or gamma camera, has the theoretic potential to be an attractive non-invasive indicator dilution method of measuring cardiac output. Registrations, once programmed, require little time to perform and entail hardly any risk for the subject. At the same time, they are to varying degrees inaccurate. As long as technology is not standardized, each institution that wishes to employ these measurements has to do its own critical validation before results can be accepted. As with any other indicator dilution technique, precision of radiocardiography is served by repetitive measurements. However, radiation dose and disturbing background radioactivity preclude taking multiple measurements within a short period. This holds particularly for the gamma camera. The speed and simplicity of the probe system make this device very suitable for serial evaluation of cardiac function at the bedside. Depending on collimation of the probe and extracardiac background activity, a correction factor has to be derived empirically to avoid overestimation of cardiac output. The major advantage of the gamma camera linked to a data system is that an infinite number of first-pass curves can be obtained from different parts of the heart. Provided that appropriate regions of interest are selected, first-pass studies can yield reasonably accurate and reproducible determinations of cardiac output. In addition, functional image analysis during the equilibrium phase enables calculation of other cardiac variables such as ejection fraction and chamber size. Nevertheless, standardization of 'hardware' and 'software' is imperative.

Acute effects and mechanism of action of ketanserin in patients with primary Raynaud's phenomenon.

This study evaluates the vasoactive effects and mode of action of ketanserin, a selective 5HT2 receptor antagonist, on digital circulation in 11 patients with primary Raynaud's phenomenon. Reflex digital vasoconstriction was induced by moderate body cooling. We found that ketanserin given intravenously in a dose of 10 mg, normalized digital skin temperature and digital blood flow as estimated by venous occlusion plethysmography and laser-Doppler flowmetry. However, effects of ketanserin on transcutaneously measured oxygen pressure were modest. This could imply a preferential effect of ketanserin on arteriovenous shunt flow. Pretreatment with high doses of the selective and nonselective alpha-adrenoreceptor antagonists prazosin and phentolamine did not abolish the effects of ketanserin on digital blood flow. However, under alpha-adrenoceptor blockade the small effects of ketanserin on normal blood pressure disappeared. Thus, in contrast to the effects in the systemic circulation, the principal mechanism underlying digital vasodilation after ketanserin is unlikely to involve alpha-adrenoceptor antagonism. We conclude that 5HT2 receptors are present in the digital vasculature. In patients with primary Raynaud's phenomenon, their activation plays an important role in cold-induced digital vasoconstriction.

Prevention of cytomegalovirus-related death by passive immunization. A double-blind placebo-controlled study in kidney transplant recipients treated for rejection.

In a double-blind placebo-controlled study, the value of prophylactic anti-CMV immunoglobulin administration was evaluated in 39 kidney transplant recipients treated for rejection with rabbit antithymocyte globulin. Passive immunization completely prevented CMV-related death, although it did not reduce the incidence of CMV isolation, viremia, or disease. The effect of passive immunization was exclusively observed in CMV-seronegative recipients of a CMV-seropositive kidney donor. It could be demonstrated even when instituted when antirejection therapy was started. Seropositive recipients did not benefit from immunoglobulin treatment. Moreover, CMV-seronegative recipients of a kidney from a seronegative donor were not at risk for CMV infection at all. Therefore passive immunization should be restricted to seronegative recipients of seropositive allograft donors treated for rejection.

Contrasting response to cyclosporin in refractory nephrotic syndrome.

We studied the effects of cyclosporin A (CsA), given for three months, in 14 patients with nephrotic syndrome refractory to treatment with prednisone and/or other immunosuppressants. CsA was given in a starting dose of 6 mg/kg and plasma through levels (RIA) were kept between 50 and 150 ng/ml. Diagnosis included: idiopathic membranous glomerulonephritis (n = 6), focal segmental glomerulosclerosis (n = 3), minimal change disease (n = 3) and membranoproliferative glomerulonephritis (n = 2). Three patients with non-immunologically mediated nephrotic syndrome due to Alport's syndrome were studied as well. Considering all patients and diagnostic groups together, proteinuria decreased from 9.0 +/- 4.3 to 4.7 +/- 3.8 g/24 h during CsA treatment (mean +/- SD; p less than 0.01). However, serum creatinine increased from 121.8 +/- 60.5 to 150.4 +/- 64.6 mol/l (p less than 0.01) and glomerular filtration rate as estimated by 24-hour creatinine clearance fell from 85.5 +/- 33.7 to 72.1 +/- 37.2 ml/min (p less than 0.05). When compared to other diagnostic groups, fractional excretion of protein, i.e. protein excretion corrected for changes in glomerular filtration rate, fell only in IMGN (ANOVA, p less than 0.05). We conclude that CsA reduced proteinuria in patients with refractory nephrotic syndrome. In the majority of these patients this reduction could be due to a renal hemodynamic, rather than an immunomodulatory effect of the drug. Only in IMGN the latter action of the drug may be of importance.

Atrial wall stress rather than pressure per se might be responsible for the increased secretion of atrial natriuretic factor after heart transplantation.

Plasma atrial natriuretic factor (ANF) concentrations were measured, and relationships to intracardiac pressures and atrial dimensions were assessed in a series of 17 heart transplant recipients undergoing cardiac catheterization during their annual evaluation. Despite excellent cardiac function (normal filling pressures, adequate cardiac output, ejection fraction above 60%), plasma levels of ANF were elevated. Step-up levels across the heart were consistent with increased cardiac secretion, whereas both the metabolic clearance rate and plasma half-life were normal. Correlations between plasma concentrations of ANF at different cardiac sites and atrial filling pressures were low. However, right and left atrial dimensions in our patients were greatly enlarged. These findings suggest that increased atrial size (by virtue of the atrial anastomoses) and augmented wall stress (law of Laplace) rather than pressure per se are responsible for the increased ANF production after heart transplantation.

Mononuclear cells infiltrating kidney allografts in the absence of rejection. Effect of conversion from cyclosporin to azathioprine therapy.

Focal small mononuclear cell infiltrates were found in renal allograft biopsies of 13/14 transplant recipients with a stable function after long-term cyclosporin A (CsA) therapy. Phenotypical analysis of the infiltrating cells using monoclonal antibodies showed a slight preponderance of T cells (56% +/- 8%), with only small percentages of B cells (5% +/- 2%), NK cells (2% +/- 1%), and monocytes (2% +/- 1%). Within the T-cell population the median calculated CD4/CD8 ratio was 1:3. Thirty-five percent of the infiltrating mononuclear cells remained unidentified with the monoclonal antibody panel used (silent cells). Three months after immunosuppressive therapy had been changed from CsA to azathioprine (AZA), the size of the infiltrates was significantly increased and there was a marked invasion of mononuclear cells between tubular epithelium despite a significant improvement in creatinine clearance (P less than 0.01). the phenotypical composition of these infiltrates was dominated by T cells (84% +/- 3%), with a median CD4/CD8 ratio of 2:7 due to an increase in CD4+ cells and a decrease in CD8+ after conversion (P less than 0.05). The percentages of B cells, NK cells, and monocytes showed no significant changes after conversion. During AZA therapy nearly all infiltrating mononuclear cells were stained with the monoclonals used, leaving no silent cells postconversion.

Treatment with cyclosporin and risks of graft rejection in male kidney and heart transplant recipients with non-O blood.

In a consecutive series of 146 kidney transplant recipients treated with cyclosporin A a strong correlation between matching for the HLA-A, HLA-B, and HLA-DR loci specificities and outcome of the grafts was observed in male recipients with non-O blood groups. Such a beneficial effect of matching was not found in female patients or male patients with blood group O. In these patients survival of the grafts at one year was good irrespective of the number of HLA-A, B, and DR mismatches. Also in 47 male heart transplant recipients immune responsiveness against mismatched HLA antigens was related to blood group. A significantly higher incidence of rejection episodes was observed in male patients with non-O blood groups (n = 32) than in those with blood group O (n = 15). Matching for HLA-DR reduced the number of acute rejection episodes in male patients with non-O blood. These findings may help explain the controversial reports about the importance of HLA matching in organ transplantation. Furthermore, as most candidates for heart transplantation are male and not of blood group O, the higher incidence of graft rejection in these patients underscores the need for an exchange strategy of donor hearts.

Histological lesions associated with cyclosporin: incidence and reversibility in one year old kidney transplants.

To determine the type and reversibility of the long term effects of cyclosporin A, biopsy specimens were taken from 20 recipients of kidney allografts, twelve months after transplantation, and three months later, during which time azathioprine was substituted for cyclosporin A. Arteriolar IgM and complement deposits and tubular isometric vacuolisation associated with cyclosporin A treatment significantly regressed after stopping this drug one year after transplantation. Conversion to azathioprine was accompanied by an increase in mononuclear cell infiltrates and tubulitis despite an evident improvement in renal function. Nephrotoxicity as a result of cyclosporin A is common but can be reversed--at least partially.