Nature of the glomerular capillary injury in human membranous glomerulopathy.

A differential solute clearance technique was used to evaluate glomerular capillary wall function in 20 patients with membranous glomerulopathy and massive proteinuria. The clearance of inulin, the filtration fraction, and the fractional clearance of uncharged dextrans of a radius of 28-48 A were depressed significantly below control values in 20 healthy volunteers (P less than 0.01). In contrast, the fractional clearance of dextrans of radius greater than 50 A was elevated markedly. A theoretical model of solute transport that depicts the major portion of the glomerular capillary wall as an isoporous membrane and the minor portion as a nondiscriminatory shunt pathway revealed the calculated glomerular ultrafiltration coefficient to be five times lower and mean pore radius of the major membrane component to be 4 A smaller than control values. However, the fraction of filtrate volume permeating the shunt pathway was three- to fourfold above control values and correlated strongly in individual patients with the fractional clearance of albumin (r = 0.76) and of IgG (r = 0.80). Lowering renal plasma flow by 24% during indomethacin therapy in seven patients resulted in a 74% reduction in proteinuria accompanied by a corresponding diminution of filtrate formed through the shunt pathway. Morphometric analysis of glomerular ultrastructure revealed the magnitude of depression of the glomerular filtration rate and of urinary protein leakage to be related strongly to changes in the epithelial layer of the glomerular capillary wall, but not to the density of subepithelial immune deposits. We conclude that glomerular capillaries in membranous glomerulopathy are characterized by a loss of ultrafiltration capacity and of barrier size-selectivity, and that subepithelial immune deposits do not provide a structural basis for these functional alterations.

Recurrent Neisseria meningitidis bacteremia. Association with deficiency of the eighth component of complement (C8) in a Sephardic Jewish family.

A 24-year-old man had repeated episodes of meningococcal meningitis. Selective deficiency of the eighth component of complement (C8) was demonstrated in the patient, his twin brother, and in one of five siblings. As the parents were first cousins of normal phenotype, this pattern is suggestive of an autosomal recessive heredity. The present report brings the total number of patients given the diagnosis of C8 deficiency to 14, and calls attention to the existence of this condition in Jews of Sephardic (Mediterranean) origin.

The effect of chromium on established atherosclerotic plaques in rabbits.

Twenty-three rabbits were fed for 8 weeks with standard diet to which was added a 1.5% cholesterol supplement. After this the cholesterol supplement was discontinued, but 11 rabbits received a daily intraperitoneal injection of 20 micrograms of potassium chromate while the remaining 12 received distilled water. The aortas were examined after a further 30 weeks; their mean weight per unit length was 1.27 g (SE +/- 0.17) in the control group and 0.81 g (SE +/- 0.08) in the chromium treated group (t = 2.36; P < 0.05). The percentage area of intimal surface covered by plaques was 94.8% (SE +/- 1.7) and 62.6% (SE +/- 10.4), respectively (t = 3.53; P < 0.005), and the total cholesterol content per unit length of aorta was 729 mg/100 ml (SE +/- 44.0) and 457.8 mg/100 ml (SE +/- 117.1), respectively (t = 23; P < 0.05). The results show a significant effect of chromium on the regression of cholesterol-induced atherosclerotic plaques in rabbits.

Effects of hydrochlorothiazide, diltiazem and enalapril on mononuclear cell sodium and magnesium levels in systemic hypertension.

Sixteen patients (mean age 68 years) with mild to moderate hypertension were treated with either diltiazem or hydrochlorothiazide for 6 weeks, followed by enalapril for a further 6 weeks. A second group of 40 patients (mean age 71 years) was treated with either hydrochlorothiazide or enalapril for 12 weeks; nonresponders received both drugs for 8 weeks. Treatment with hydrochlorothiazide or enalapril resulted in a lowering of systolic and diastolic blood pressures, but diastolic pressure was lower in patients treated with enalapril (89 +/- 2 and 82 +/- 2 mm Hg, respectively; p less than 0.05). Treatment with diltiazem resulted in a decrease in diastolic pressure only. Treatment with hydrochlorothiazide resulted in a 17% decrease in serum potassium (p less than 0.05), which returned to normal when enalapril was substituted. Hydrochlorothiazide also produced a 23% decrease in mononuclear cell sodium content at 4 weeks (p less than 0.01), with a further 15% decrease at 12 weeks (p less than 0.05). Mononuclear cell potassium and magnesium also decreased at 12 weeks by 18 and 16%, respectively (p less than 0.05). All these effects were reversed when enalapril was substituted. A similar pattern of events was seen with diltiazem, which was again reversed with enalapril. Finally, there was no relation between changes in mononuclear cell sodium or other cation content and changes in blood pressure.

The relationship between beta-endorphin levels and uterine muscle contractions during labor.

Plasma beta-endorphin (BE) levels (8.6 +/- 0.8 pmol/l) (mean +/- SE) were lower in the third trimester than in non-pregnant controls (14.8 +/- 1.1 pmol/l) (P less than 0.001), increased during labor, to 29.3 +/- 4.4 pmol/l (P less than 0.005) and decreased, 72 h after delivery, to 3.5 +/- 0.4 pmol/l (P less than 0.001). BE levels were found to correlate significantly with uterine muscle contraction (r = 0.966, P less than 0.05) and with cervical effacement (r = 0.974, P less than 0.05) during labor.

Serum and mononuclear cell potassium, magnesium, sodium and calcium in pregnancy and labour and their relation to uterine muscle contraction.

Thirty women in their third trimester of pregnancy (37-42 weeks), 40 women during and 72 h after labour and 18 non-pregnant controls were studied for changes in serum and mononuclear cell cation content, and their relationship to cervical effacement and intensity of pain as measured by plasma beta endorphin concentrations during labour. Serum magnesium fell from 0.95 +/- 0.01 (mean +/- SEM) to 0.84 +/- 0.02 mmol/litre at late pregnancy and further to 0.76 +/- 0.01 during labour (P < 0.001); serum potassium fell from 4.25 +/- 0.05 to 3.79 +/- 0.06 mmol/litre (P < 0.0001) during labour; and serum calcium fell from 2.40 +/- 0.02 to 2.28 +/- 0.01 mmol/litre at late pregnancy (P < 0.001) and further to 2.25 +/- 0.02 mmol/litre during labour (P < 0.001). Mononuclear cell magnesium content rose from 4.5 +/- 0.3 to 5.6 +/- 0.04 fmol/cell (P < 0.02); potassium content rose from 37.7 +/- 2.0 to 50.9 +/- 3.0 fmol/cell (P < 0.001); and calcium content rose from 4.4 +/- 0.4 to 7.6 +/- 1.1 fmol/cell (P < 0.105). On the other hand, mononuclear cell sodium content fell from 7.2 +/- 0.5 to 3.8 +/- 0.3 fmol/cell (P < 0.001). Plasma beta endorphin concentrations increased with increasing degrees of effacement, as did intracellular Na, whereas intracellular Mg and K showed an inverse trend. A significant correlation was found between intracellular cation and beta endorphin levels (r = -0.98, Mg; -0.99, K; 0.83, Na). These changes are probably due either to intercompartmental cation shifts or possibly to endometrial ischaemia and damage during labour.

Serum and intracellular electrolytes in patients with and without pain.

The effect of acute stress, with and without pain, on serum and mononuclear cell cation content was studied in 205 healthy women in their last trimester of pregnancy or during normal labour, in patients with acute medical conditions in which pain was or was not present, in acute surgical conditions, and immediately prior to elective surgery. In all subjects there was a fall in serum sodium, potassium, magnesium and calcium concentrations during stress, with an apparent shift into the intracellular space. An inverse correlation was present between the severity of pain and the fall in serum cations.

Mechanism of the antiproteinuric effect of indomethacin in nephrotic humans.

To elucidate the mechanisms by which indomethacin lowers proteinuria, we studied 20 patients with the nephrotic syndrome. We performed differential macromolecule clearances before and after 3 days of therapy (150 mg/24 h). The fractional clearances of albumin and immunoglobulin G (IgG) decreased by 42 +/- 7 and 44 +/- 10%, respectively (P less than 0.05). Separation of IgG into fractions by preparative electrofocusing in eight selected individuals revealed a proportionate reduction of fractional clearances among anionic (pI = 5.0), neutral (pI = 7.5), and cationic species (pI = 8.5) of IgG. Indomethacin elevated the fractional clearance of uncharged dextrans of radius 28-44 A, while depressing those of dextrans of radius 50-60 A. A heteroporous model that depicts the major portion of the glomerular capillary wall as an isoporous membrane (pore radius = 56 A) and the minor portion as a nondiscriminatory shunt, revealed the former to be unchanged and the latter to be less prominent following indomethacin. A lower fraction of total filtrate volume permeating the shunt, together with a concomitant lowering of overall glomerular filtration rate by 24%, reduced the absolute rate of flux of macromolecule-rich fluid through the shunt pathway from 0.40 to 0.25 ml.min-1.73(-2) (P less than 0.01). We conclude that indomethacin lowered the filtered protein load by restoring barrier size-selectivity while reducing the rate of glomerular ultrafiltration.

Brucellosis with nephrotic syndrome, nephritis and IgA nephropathy.

A patient with systemic brucellosis due to Brucella melitensis had severe renal involvement. Clinical features included hypertension, macroscopic haematuria, massive proteinuria of 10 g per 24 hours and azotaemia. Following treatment with antibiotics, the azotaemia resolved and proteinuria decreased to less than 0.5 g per 24 hours, but microscopic haematuria and hypertension persisted. Renal biopsy during recovery revealed IgA nephropathy with minimal mesangial changes, suggesting a causal relation between brucellosis and IgA nephropathy with a reversible nephrotic syndrome.

Effect of angiotensin II infusion on the human glomerular filtration barrier.

Angiotensin II (ANG II) infusion has been reported to impair barrier size selectivity and exacerbate proteinuria in the rat. To examine whether this is also true of humans, we infused a pressor dose of ANG II into seven healthy controls and seven nephrotic patients. A prompt depression of glomerular filtration rate (GFR) and renal plasma flow was observed in each group (P less than 0.01). Surprisingly, the excretion rates of albumin (5.3 +/- 1.6 to 2.8 +/- 0.3 in controls and 4,791 +/- 1,244 to 3,833 +/- 800 micrograms/min in nephrotics) and immunoglobulin G (1.5 +/- 0.4 to 0.8 +/- 0.2 and 305 +/- 87 to 255 +/- 94 micrograms/min, respectively) fell significantly during ANG II infusion. Fractional clearances of dextrans of broad size distribution (radii 34-54 A) were uniformly elevated by ANG II infusion in controls but tended to decline in nephrotics. A heteroporous model of the glomerular capillary wall revealed ANG II to have a negligible effect on membrane-pore structure. However, the depressed GFR lowered the rate at which macromolecule-rich filtrate was formed through a subset of nondiscriminatory pores from 272 to 176 microliters/min in controls and from 394 to 334 microliters/min in nephrotics. We conclude that, in striking contrast to the rat, pressor ANG II infusion has little or no influence on barrier size selectivity in humans but exerts an antiproteinuric effect by lowering the filtered protein load.

An unusual case of Q fever endocarditis.

We describe a patient with unusual features of Q fever endocarditis. The unusual features of this case were the presence of an abscess surrounding the involved aortic valve and the appearance of circulating anticoagulants in the patient's serum.

Effect of colloid volume expansion on glomerular barrier size-selectivity in humans.

Colloid volume expansion magnifies proteinuria in subjects with the nephrotic syndrome. To elucidate this phenomenon, we performed differential solute clearances prior to and following infusion of hyperoncotic albumin in 21 nephrotic subjects and seven healthy controls. Urinary excretion rate and fractional clearance of albumin (radius = 36 A) and immunoglobulin G (radius = 55 A) increased significantly in nephrotic subjects. However, urinary albumin excretion rate was unchanged in controls. The fractional clearances of dextrans of broad size distribution (radii = 28 to 58 A) were markedly altered in both groups following albumin infusion. A heteroporous model which depicts the major portion of the glomerular capillary wall as an isoporous membrane (pore radius approximately 55 A) and the minor portion as a non-discriminatory shunt, revealed the latter to be much more prominent in nephrotic subjects than in controls, and to be enlarged further following albumin infusion. By contrast no increase in pore size of the non-shunt pathway occurred in either group. We infer that enhancement of a pre-existing defect of glomerular size-selectivity in nephrotic subjects accounts, in large part, for exaggerated proteinuria in the colloid volume-expanded state. Increases in glomerular perfusion rate and pressure associated with plasma hypervolemia may mediate this alteration in glomerular membrane-pore structure.

The rise of serum creatinine levels during labor.

Serum creatinine, blood urea nitrogen and creatine phosphokinase were measured in 32 women during the last 3 weeks of pregnancy and, in a further 39 women, during and after labor. The serum creatinine increased from 61.9 +/- 0.9 to 69.8 +/- 1.8 mumol/l (mean +/- SEM) (P less than 0.05) in the third stage of labor and returned to normal by 72 h after delivery. The muscle creatine phosphokinase increased from 54 +/- 7 to 77 +/- 9.9 units (P less than 0.05) during the third stage and remained high (87 +/- 13.3 units) 72 h later. We conclude that these changes are due to muscle contraction and injury during delivery.

Polyarteritis nodosa and drug abuse: is there a connection?

Drug abuse has been controversially linked to polyarteritis nodosa. A 28-year-old man with a history of drug abuse with inhaled heroin presented with an enigmatic illness consisting of refractory fever, bilateral pleural effusions, migratory polyarthritis, and a leukaemoid reaction. An abdominal angiography confirmed the diagnosis of polyarteritis nodosa, and treatment with both prednisone and cyclophosphamide resulted in significant clinical and laboratory improvement.

Limitations of creatinine as a filtration marker in glomerulopathic patients.

To determine the reliability of creatinine as a measure of the glomerular filtration rate (GFR), we compared the simultaneous clearance of creatinine to that of three true filtration markers of graded size in 171 patients with various glomerular diseases. Using inulin (radius [rs] = 15 A) as a reference marker, we found that the fractional clearance of 99mTc-DTPA (rs = 4 A) was 1.02 +/- 0.14, while that of a 19 A rs dextran was 0.98 +/- 0.13, with neither value differing from unity. In contrast, the fractional clearance (relative to inulin) of creatinine (rs = 3 A) exceeded unity, averaging 1.64 +/- 0.05 (P less than 0.001), but could be lowered towards unity by acute blockade of tubular creatinine secretion by IV cimetidine. Cross-sectional analysis of all 171 patients revealed fractional creatinine secretion to vary inversely with GFR. This inverse relationship was confirmed also among individual patients with either deteriorating (N = 28) or remitting (N = 26) glomerular disease, who were studied longitudinally. As a result, changes in creatinine relative to inulin clearance were blunted considerably or even imperceptible. We conclude that true filtration markers with rs less than 20 A, including inulin, are unrestricted in glomerular disease, and that creatinine is hypersecreted progressively by remnant renal tubules as the disease worsens. Accordingly, attempts to use creatinine as a marker with which to evaluate or monitor glomerulopathic patients will result in gross and unpredictable overestimates of the GFR.

Transient methimazole-induced bone marrow aplasia: in vitro evidence for a humoral mechanism of bone marrow suppression.

A patient with methimazole-induced aplastic anemia is described. Despite severe pancytopenia and the complete disappearance of hemopoietic elements from the bone marrow, recovery of hemopoiesis has been observed within 14 days of discontinuing methimazole therapy. In vitro studies of CFU-C inhibition of peripheral mononuclear cells harvested in remission, were performed by incubation with autologous sera collected at earlier phases of the disease. These studies provide evidence in favor of a humoral, and most probably autoimmune mechanism as the cause of transient bone marrow aplasia.

Serum chromium in patients with recent and old myocardial infarction.

The serum chromium in 45 subjects with no clinical evidence of ischemic heart disease was found to be 1.71 parts per billion (ppb) (S.E. +/- 0.14). In 34 patients with a previously documented myocardial infarction, it was 1.84 ppb (S.E. +/- 0.18). The difference was not significant nor was there any difference with age or sex. In 37 patients with acute myocardial infarction the serum chromium level rose to a mean of 6.36 ppb (S.E. +/- 0.51; p less than 0.001) during the first five days following the infarct, returning to normal over the next five days. There was no correlation between the serum chromium and blood glucose levels in these patients or in a further 14 patients who were receiving glucose infusions (chest pain without electrocardiographic or enzyme changes) or who were diabetics.