Proteinuria in multiple myeloma and related diseases.

Proteinuria is frequently found in multiple myeloma and related disorders. Immunofixation electrophoresis is very helpful for the identification and characterization of the monoclonal component. In multiple myeloma, the presence of Bence-Jones (BJ) proteinuria is significantly associated with renal failure. The coexistence of BJ proteinuria and the nephrotic syndrome in myeloma patients should suggest AL amyloidosis or light chain deposition disease. In the latter, BJ proteinuria is absent in 30% of the cases and diagnosis is based on the demonstration of the monoclonal light chain deposits in tissues, predominantly in kidneys.

Massive systemic amyloidosis associated with light-chain deposition disease.

A 72-year-old woman presented with rapidly progressive renal failure and multiple myeloma. The patient died 6 months later of severe hepatic insufficiency. The light-microscopic, immunological and ultrastructural findings showed widespread kappa-light-chain deposits including the kidneys, liver, spleen, heart, lungs, tongue, ovary, pancreas and bone marrow associated with massive AL amyloid deposits in the same organs and in the thyroid gland. The concurrent presence of two different deposits is very unusual and the possible mechanisms for such an association are discussed.

[Ankylosing spondylitis with type AA amyloidosis. 6 cases]. / Spondylarthrite ankylosante avec amylose de type AA. Six observations.

The authors have studied 6 cases of systemic AA amyloidosis associated with ankylosing spondylitis. Renal failure occurred in all patients a mean of 19 years after the clinical onset of the rheumatic disease. Three patients progressed rapidly (between 3 months and 3 years) to end-stage renal failure. Such an outcome did not depend upon early onset of the renal impairment, degree of inflammation or treatment with colchicine. All patients were alive 2 to 10 years later, and this confirms a better prognosis than with AL amyloidosis. The utility of combining Wright's permaganate reaction with immunological methods to characterize the amyloid deposits was also confirmed. It is concluded that amyloidosis is a rare complication of ankylosing spondylitis and probably depends on a genetic predisposition. The possibility of amyloidosis should be kept in mind when proteinuria or renal failure appear in the course of ankylosing spondylitis.

Immunoglobulin synthesis in primary and myeloma amyloidosis.

Bone marrow cells from 14 patients with primary amyloidosis and two patients with myeloma amyloidosis were studied by immunofluorescence and biosynthesis experiments after incorporation of radioactive amino acids. Cells from four patients affected with non-myeloma secondary amyloidosis were also studied as controls. In primary amyloidosis, monoclonal plasma cell populations were demonstrated by immunofluorescence in virtually every case, even in patients without serum and urine monoclonal immunoglobulin and with a normal percentage of bone marrow plasma cells. Biosynthesis experiments showed the secretion of large amounts of free light chains, most often of the lambda type, in every primary or myeloma amyloidosis case and the presence of light chain fragments in almost all cases. Special features in certain patients were the synthesis of short gamma chains (two cases), assembly block at the HL half molecule level of a monoclonal IgA (one case) and secretion of decameric abnormally large kappa chains (one case). This is in contrast with non-myelomatous secondary amyloidosis where the distribution of bone marrow plasma cells was normal by immunofluorescence and where normal sized immunoglobulins were synthesized, without free light chain secretion and fragments. These data confirm that primary amyloidosis belongs to plasma cell dyscrasias and emphasize the role of free light chains and light chain fragments in the pathogenesis of amyloid deposition.

Immunohistochemical characterization of renal amyloidosis.

Forty-five renal biopsies with amyloidosis were studied by light microscopy with Congo red staining and action of potassium permanganate and by immunofluorescence with antihuman tissue A component antiserum antilight and heavy chains of immunoglobulins antisera. The patients were classified on the basis of concordance between immunohistochemical characterization by immunofluorescence and the results of Congo red staining after potassium permanganate treatment. Thus, 37 of 45 cases (82%) were classified by immunohistochemical characterization (15 with AL amyloidosis and 22 with AA amyloidosis) when the amyloid type could be hypothetized in only 31 of these cases (66%) on the basis of clinical criteria. This study suggests that the association of these two technics is more reliable than clinical data alone in distinguishing between AA and AL amyloidosis.

Steady-state levels of pefloxacin and its metabolites in patients with severe renal impairment.

Twenty patients (aged 26-70 years) with severely impaired renal function received pefloxacin twice daily for 5 days as 12 mg.kg-1 administered as a 1 h i.v. infusion, or 800 mg administered as tablets. On Day 5 the minimal and maximal plasma concentrations were 5.9 and 11.5 mg.l-1 respectively, after oral administration. The steady-state level of the N-desmethyl metabolite ranged from 0.9 (infusion) to 1.2 mg.l-1 (oral route), and that of the N-oxide metabolite ranged from 6.2 (infusion) to 9.0 mg.l-1 (oral route). The minimal concentration of unchanged drug was related to the age of the patients (infusion), but the N-oxide concentration was influenced by the degree of renal impairment (both routes). The pefloxacin levels were similar to those achieved in healthy subjects, but reduced renal function leads accumulation of its biotransformation products, especially of the N-oxide metabolite which lacks antibacterial activity.

Influence of renal insufficiency on the pharmacokinetics and pharmacodynamics of terazosin.

Renal insufficiency was not shown to affect the pharmacokinetics of terazosin in fifteen patients receiving oral terazosin (1 mg once daily) for two weeks. Five patients had normal renal function (creatinine clearance 80 ml per minute or more), five had moderate renal insufficiency (creatinine clearance 30 to 79 ml per minute), and five had severe renal insufficiency (creatinine clearance 10 to 29 ml per minute). Urine and blood samples were collected, and blood pressure and pulse rate were determined on days one and 15 of the study. Renal insufficiency had no significant effect on the absorption lag time, rate of absorption, rate of elimination in the urine, volume of distribution, or plasma clearance of terazosin. The plasma half-life of terazosin in patients with normal renal function was 10.0 hours, compared with 8.4 hours in patients with moderate renal insufficiency and 9.8 hours in the group with severe renal insufficiency. There was also no apparent relationship between renal insufficiency and the maximum change in blood pressure or pulse rate. Renal excretion was found to play a minor role in the elimination of terazosin, and this explains the lack of a relationship between renal insufficiency and the pharmacodynamics of terazosin. After the administration of terazosin on day 1 of the study, 1.6 +/- 0.3 percent and 5.1 +/- 1.4 percent of the total dose was excreted in the urine of patients with severe renal insufficiency and normal renal function, respectively. Adverse experiences were reported by four patients and caused one patient to withdraw from the study. Symptoms reported included gastralgia, headache, dizziness, malaise, weakness, and palpitations. The results of this study indicate that terazosin may be safely administered to patients with renal insufficiency without altering the usual dosing regimen.

Pharmacokinetics of warfarin in the nephrotic syndrome and effect on vitamin K-dependent clotting factors.

The behavior of warfarin, a drug tightly bound to albumin, was studied in patients with nephrotic syndrome (NS) to assess the influence of hypoalbuminemia on its pharmacokinetics and its effect on vitamin K-dependent coagulation factors. A single dose of warfarin (8 mg) was given orally to 11 nephrotic patients with normal or nearly normal renal function and to 11 controls. In every subject the following measurements were performed: albuminemia before (t0) warfarin administration; plasma warfarin and vitamin K-dependent coagulation factors (FII, FVII, FIX, FX) levels, before and at time intervals from 0 to 48 h after drug administration; warfarin urinary excretion from 0 to 24 h. Urinary warfarin excretion was null in 19 out of the 22 subjects and very low in two nephrotic patients and in one control. Low serum albumin in NS patients induced a twofold increase of unbound warfarin vs controls (3.5% vs 1.8%, p less than 0.001) which led to a threefold increase in plasma clearance of warfarin (9.70 vs 3.26 ml X min-1, p less than 0.001); as warfarin distribution volume showed only a slight (non significant) increase in NS patients, the elimination half-life was thus markedly shortened in NS patients vs controls (18 vs 36 h, p less than 0.01). Maximum warfarin effect on vitamin K-dependent factor levels occurred at 18 h in controls and 24 h in nephrotics, and these lowest values were similar, in spite of a higher level at 0 in NS patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemoglobin J Iran alpha 2 beta 2 77 (EF1) his----Asp in a Russian-Armenian family.

A third case of Hb J Iran is reported. The propositus is of Russian-Armenian origin and was investigated for hematuria. The electrophoretic behavior and the characterization of primary structure are described. Hb J Iran is stable and has normal functional properties. High resolution Nuclear Magnetic Resonance spectra suggest the presence of structural perturbations in the heme pocket of the variant. Solubility studies of Hb S/Hb J Iran mixture indicated that His beta 77 belongs to a contact region of deoxy Hb S polymers.

[Articular chondrocalcinosis and hypomagnesemia of renal origin. Apropos of 2 cases]. / Chondrocalcinose articulaire et hypomagnésémie d'origine rénale. A propos de 2 cas.

The authors report two cases of the articular chondrocalcinosis associated with a laboratory profile compatible with Bartter's syndrome and masked diuretic intoxication in 2 women aged 31 and 59 years. An extensive study of the literature revealed 7 similar cases. The pathogenic relationship between the two conditions could be the hypomagnesemia. 5 other reports concerning young patients presenting the association of chondrocalcinosis and hypomagnesemia, not part of Bartter's syndrome, add further support to this hypothesis. This study suggests that the serum electrolytes and the serum magnesium should be assayed routinely in cases of chondrocalcinosis, especially in young patients.

Effects of antiglucocorticoids on glucocorticoid hypertension in the rat.

The early phase of hypertension induced in rats by a glucocorticoid agonist RU 26988 was studied. Systolic blood pressure increased by 35 mm Hg. Water and sodium urinary excretion increased transiently, and plasma volume decreased. Total and ouabain-sensitive sodium efflux, as well as rubidium efflux, were enhanced by glucocorticoid administration. Low salt intake did not prevent hypertension. Pretreatment with RU 38486, a steroid with antiglucocorticoid properties, largely prevented the rise in blood pressure (+10 mm Hg) and suppressed transient natriuresis and the decrease in plasma volume. Changes in total and ouabain-sensitive sodium efflux were completely prevented, whereas changes in rubidium efflux were only partly reversed. Similarly, administration of progesterone, a steroid with antiglucocorticoid effects, prevented glucocorticoid hypertension (+11 mm Hg) and vascular ionic changes. In contrast administration of RU 28318, an antimineralocorticoid agent, was without effect on glucocorticoid hypertension (+38 mm Hg). Progesterone or RU 38486 administered after glucocorticoid also decreased blood pressure. Present data indicate that glucocorticoid hypertension may be prevented or reversed in its early phase by steroid drugs with antiglucocorticoid properties. These drugs also appeared to prevent the sodium and rubidium flux abnormalities induced by glucocorticoid. We suggest that activation of the vascular glucocorticoid receptors may be involved in the pathophysiology of glucocorticoid hypertension.

[Necrotizing glomerulonephritis with linear fixation along the glomerular basement membranes (GBM) without circulating anti-GBM antibodies]. / Glomérulonéphrite nécrotique avec fixation linéaire le long des membranes basales glomérulaires (MBG) sans anticorps circulants anti-MBG.

We report a case of necrotizing glomerulonephritis with linear fixation along the glomerular basement membrane (GBM) atypical by: 1) the absence of significant renal failure or evidence of pulmonary involvement; 2) no detectable circulating anti GBM antibody by indirect immunofluorescence or radioimmunoassay.

[Effect of an antiglucocorticoid steroid on the arterial hypertension induced by glucocorticoids in the rat]. / Effet d'un stéroïde antiglucocorticoïde sur l'hypertension artérielle induite par les glucocorticoïdes chez le rat.

Hypertension was induced in male rats by administration of a glucocorticoid agonist, RU 26988. Systolic blood pressure (SBP) increased by 35 mmHg. Administration of an antimineralocorticoid derivative, RU 28318, did not modify hypertension. In contrast administration of a steroid derivative with antiglucocorticoid properties, RU 38486, prevented glucocorticoid-induced hypertension in a large part. SBP augmented only by 10 mmHg. The glucocorticoid increased total and active, ouabain-sensitive, 22Na efflux, as measured from caudal arteries, whereas concomitant administration of the antiglucocorticoid derivative prevented these changes. It is suggested that glucocorticoid-induced hypertension may be related to vascular Na pump activation and to the subsequent ionic changes. These changes, as well as hypertension, are antagonized by steroid derivatives with antiglucocorticoid properties.

Liver involvement in nonamyloid light chain deposits disease.

Liver examination performed in seven patients who had renal failure related to light chain deposits demonstrated in all cases the presence of liver light chain deposits. In all of our patients clinical renal involvement antedated the liver disease. The portal areas and the Disse spaces contained a granular material which strongly reacted with antilight chain antiserum (kappa or gamma). In one patient in whom lesions were severe, the sinusoid edge was ruptured and a pelliosis -like lesion was observed. In the five patients who were hemodialyzed for more than several months at the time of discovery of liver deposits, increased amounts of collagen were present in the Disse spaces, and one patient had extensive liver fibrosis by light microscopy. Clinical liver involvement was defined by moderate hepatomegaly in five patients, with ascites in two. A slight increase in phosphatase alkaline activity was frequently observed and bromsulphalein retention was present in two. In one patient liver tests remained entirely normal despite the presence of diffuse kappa light chain deposits.

Renal granular monoclonal light chain deposits: morphological aspects in 11 cases.

Eleven cases of renal light chain deposition without amyloïdosis are reported (7 multiple myeloma, one Waldenström's disease, 3 without multiple myeloma without spike in serum or urine). Ten had kappa light chain deposits and 1 lambda light chain deposits along tubular basement membranes and in glomeruli. Ultrastructural study showed granular electron dense material on the external side of tubules with a very dark appearance in 4 cases and lighter appearance in the others. Five cases had nodular glomerulosclerosis with a finely granular, light appearance, corresponding to membrane-like material with kappa fixation in 4. Granular light chain deposition is analogous to type AL amyloïdosis in that their distribution is identical and both originate from light chains. The major difference between AL type amyloïdosis and light chain deposits lies in their ultrastructural appearance. Amyloïd substance is characterized by a fibrillar appearance and light chain substance by a granular appearance.

[Light chain or monoclonal immunoglobulin deposition disease: physiopathogenic concepts]. / La maladie des dépôts de chaînes légères ou d'immunoglobulines monoclonales: concepts physiopathogéniques.

Although recently identified, this disease is by no means exceptional. It is characterized by the deposition in various organs of an amorphous substance which differs from the amyloid substance and contains monoclonal immunoglobulin determinants: either a light kappa or lambda chain, or a light and a heavy chain. The severity of the disease is due to various organs being involved, notably the kidneys. There is in every case a monoclonal plasmocytic or lymphoplasmocytic proliferation which may appear as benign. In almost one-third of the cases no monoclonal immunoglobulin can be detected in the serum. In a study of immunoglobulin biosynthesis, 6 out of 8 patients showed striking structural abnormalities. The relationship between these very unusual lg's and tissue deposition is discussed in detail.