Persistence of Ca2+-sensing receptor expression in functionally active, long-term human parathyroid cell cultures.

An original human parathyroid cell culture model from uremic patients with IIo hyperparathyroidism has been developed, with its main feature being long-term functionally active viability up to 5 months, as assessed by persistent responsiveness to changes of extracellular Ca2+ concentrations ([Ca2+]e). In addition to the inhibitory effect of increasing [Ca2+]e, increasing extracellular phosphate exerted a biphasic effect on parathyroid hormone (PTH) secretion. The presence of the Ca2+-sensing receptor (CaR), on which depends the response to [Ca2+]e and its persistence, has been demonstrated in our culture system both by direct detection and by inhibition of its activity. CaR protein was detected by Western blot analysis with a specific anti-CaR antibody. CaR gene transcripts have been identified by reverse transcription-polymerase chain reaction analysis. mRNA (by in situ hybridization) and protein (by immunocytochemistry) expression were detected for both CaR and PTH. Adding a specific anti-CaR antibody to the medium induced a marked reduction of low [Ca2+]e-stimulated PTH release, which decreased to levels equivalent to those obtained in high [Ca2+]e medium. The described long-term functionality could be due to several factors, including the clustered cell type of culture yielded by our preparation procedure, the growth characteristics of hyperplastic uremic tissue, and the use of a phosphate-rich medium. The present model, because of its long-term functionality, is a unique tool for the exploration of PTH synthesis and secretion and for studies of parathyroid cell growth in vitro.

Guillain-Barré syndrome following danazol and corticosteroid therapy for hereditary angioedema.

A case of hereditary angioedema secondary to C1 esterase inhibitor deficiency associated with lupus-like nephritis is reported. The patient was initially treated with both corticosteroids and danazol and subsequently had Guillain-Barré syndrome together with appearance of circulating immune complexes and an increase in total complement and C1q, C3, C4, B, and C1 esterase inhibitor levels. Guillain-Barré syndrome might be secondary to danazol therapy since this drug could increase both circulating immune complex production and complement synthesis, thereby providing additional substrate for the underlying immune complex disease. Normalization of complement might therefore be hazardous in lupus with underlying complement deficiency states.

Lack of evidence that cyclosporine treatment impairs calcium-phosphorus homeostasis and bone remodeling in normocalcemic long-term renal transplant recipients.

Since the effects of cyclosporine on mineral and bone metabolism are controversial, we studied calcium regulating hormones, calcium-phosphorus (Ca-P) metabolism, and bone remodeling, assessed by serum osteocalcin, in long-term renal transplant recipients (RT). Forty-seven normocalcemic patients with good renal function receiving cyclosporine (CT, n = 27) or not (NC, n = 20) were studied at baseline and after an oral Ca load. CT and NC had similar age, daily dose of steroids, GFR level, and duration of transplantation. Baseline evaluation included 24-hr urinary Ca, P, TRP, TmP/GFR, fasting serum intact PTH, 1,25-(OH)2D, 25OHD, osteocalcin, Ca, and P. Subjects of the two groups had excessive secretion of PTH, tubular P wasting, and high serum osteocalcin level, as is usual in RT. However, there was no difference between CT and NC regarding any baseline variable. Ten CT and ten NC, matched for duration of transplantation and serum PTH level, ingested 1g Ca to achieve an acute dynamic study of PTH secretion and Ca-P metabolism. In both CT and NC, this Ca load caused the same decreases in serum PTH (P < 0.001), NcAMP (P < 0.05), and urinary P (P < 0.001) and the same increases in serum and urinary Ca (P < 0.001), and in both TmP/GFR and TRP (P < 0.001). These results strongly suggest that cyclosporine treatment had no significant effect on calcium-regulating hormone secretion, P-Ca metabolism, and bone remodeling level. We therefore consider that cyclosporine is unlikely to have any prominent role in the abnormalities of bone endocrine and mineral metabolism that are common in long-term kidney recipients.

Pharmacokinetic of a very low molecular weight heparin in chronic renal failure.

The pharmacokinetic characteristics of a low molecular weight heparin (LMWH) (Cy 222; mean mw: 2500 daltons) are studied in 24 patients with 3 degrees of chronic renal failure (CRF) stage I (creatinine clearance between 50 and 30 ml/mn), stage 2 (creatine clearance between 30 and 10 ml/mn), stage 3 (creatinine clearance below 10 ml/mn). Patients with CRF have significantly higher values of anti Xa activity at 3 hours (p less than 0.05), 5 hours (p less than 0.05), and at 8 hours (p less than 0.03) after injection than controls, CMAX values, VDSS and AUC do not differ, whereas patients with the highest stage of CRF are characterised by the most important t1/2 a (p less than 0.001) and the smallest total body clearance (p less than 0.01). Consequences of these disturbances of pharmacokinetic characteristics have to be evaluated before adequate posology of heparin fragments could be determined in patients with CRF.

Glomerulonephritis and hereditary angioedema: report of 2 cases.

Hereditary deficiency of C1 esterase inhibitor (C1 INH) responsible for hereditary angioedema (HAE) is the most common hereditary complement deficiency. HAE has occasionally been reported in association with lupus erythematosus and with glomerulonephritis (GN). We report 2 cases of GN-associated C1 INH deficiency. Renal manifestations have been discovered respectively 6 to 17 years before onset of attacks. Kidney biopsy of the 1st patient showed diffuse proliferative GN with a rare and scattered wire loop pattern whereas the 2nd patient displayed a type I membranoproliferative GN. Chronic renal failure appeared in both cases and the 2nd patient recently received a kidney transplant. The onset of GN in patients with HAE outline the relationship between a genetic deficiency of complement components, the susceptibility to immune complex (IC) disease and the role of complement and its receptors in the elimination of IC.

Glomerular lesions in juvenile cystinosis: report of 2 cases.

We report glomerular lesions in 2 siblings presenting a juvenile cystinosis. Kidney biopsy in one of them showed focal, segmental, mesangial proliferative and hyalinosis lesions, and the second showed segmental juxtahilar hyalinosis in one third of glomeruli. Neither of the 2 patients displayed a Toni-Debre-Fanconi syndrome. In one of the patients, cystine crystals were found by means of electronic microscopy. The first patient developed chronic renal failure and a kidney transplantation was performed. No recurrence of the cystine deposits was observed in the graft. Pedigree of the described family seems to be in accordance with an autosomal dominant pattern of inheritance.

Adult Still's disease and mesangial glomerulonephritis. Report of two cases.

Two patients with adult Still's disease and abnormal urinalysis underwent kidney biopsy 2 to 21 years after onset of the disease. Unexpectedly, mesangial glomerulonephritis was discovered. Even if a fortuitous association could not be excluded, the real prevalence of glomerular involvement in ASD should be determined by further studies in view of a potential immune complex pathogenesis of this condition.

[Hereditary deficiency of C1 esterase inhibitor. Lupus and glomerulonephritis]. / Déficit héréditaire en inhibiteur de la C1 estérase. Lupus et glomérulonéphrite.

Congenital deficit of the inhibitor of C1 esterase (C1 INH) usually presents by oedema of the lower limbs, abdomen and glottis (sometimes lethal), which explains its clinical denomination of angioneurotic oedema. The association of this condition with disseminated lupus erythematosis has been reported in 4 cases and with discoid lupus in 4 cases. Antinuclear factors were found in all these cases but there were only two documented cases of nephropathy (one diffuse proliferative glomerulonephritis and one local glomerulonephritis). The association of a deficit of C1 INH and membrano-proliferative glomerulonephritis has only been reported in 2 cases (one lobular glomerulonephritis and one glomerulonephritis with dense basal membrane deposits). Our case had C1 INH deficiency and proliferative lupic glomerulonephritis in the absence of other clinical and immunological signs of DLE. Nephropathy was not looked for in 9 cases of association of C1 INH deficiency and C3-shearing autoantibody (C3 NEF). A common genetic mechanism for these associations seems very improbable. The aptitude of patients with C1 INH deficiency to synthesise autoantibodies under the influence of infections factors, for example, could explain the higher incidence of lupus and glomerulopathies in these patients.

[Acquired C1 esterase inhibitor deficiency and lymphoproliferative syndromes]. / Déficit acquis en inhibiteur de la C1 estérase et syndrome lymphoprolifératif.

About 20 cases of acquired C1 esterase inhibitor deficiency have been reported in association with malignant lymphomas. We describe 3 such patients. The 3 patients studied were asymptomatic and had low C1q level. Danazol administration resulted in an increase of C1 esterase inhibitor in 2 patients. The complement activation in acquired C1 esterase inhibitor deficiency could be explained by interaction with pathological cells of the spleen, the blood or the bone-marrow. The mechanism of decrease of C1 INH is discussed.

[The key to the calcium regulation and calcium metabolism: G protein coupled membrane calcium receptor]. / La clé de la régulation de la calcémie et du métabolisme calcique: le récepteur membranaire du calcium couplé aux protéines G.

CALCIUM RECEPTOR: The calcium receptor can ìperceiveî small vanations in extracellular calcium concentrations and adapt cell response. The ìcalciostatî was hypothesized for several years before its discovery on parathyroid and other cells, particularly renal cells. It can couple with protein G and has 7 transmembrane domains. FUNCTION: The calcium receptor is stimulated by increased extracellular calcium level which, via a GDP/GTP exchange by the heterotrimeric protein G and a transduction network, triggers release of intracellular calcium ion stores and influx of extracellular calcium ions through the cationic channels. A FUNDAMENTAL ROLE: The calcium receptor controls not only parathormone and thyrocalcitonin secretion, but also plays an important role in calcium transfer from the mother to fetus, in reabsorption of calcium by the large ascending cortial portion of the Henlé loop, and in reabsorption of water by the collecting tubes. DISEASE STATES: Mutations affecting the calcium receptor sequence cause hereditary or familial parathyroid diseases. In addition, decreased expression of the calcium receptor protein and signal has been demonstrated in primary hyperparathyroidism as well as in secondary hyperparathyroidism. The calcium receptor is also expressed in a large variety of tissues and could be implication in other disease states. THERAPEUTICS: Medical treatment of primary hyperparathyroidism using specific calcium receptor agonists derived from phenylalkylamines is now possible. The efficacy of these drugs should be demonstrated in the treatment of secondary hyperparathyroidism and chronic renal failure. Other therapeutic implications are possible.

[Comparative study of heparin and a very low molecular-weight heparin in hemodialysis in chronic renal insufficiency]. / Etude comparative de l'héparine et d'une héparine de très faible masse moléculaire en hémodialyse dans l'insuffisance rénale chronique.

In the course of dialysis sessions, we have compared the antithrombotic effect of two heparinization regimens: low molecular weight heparin (CY 222, mean molecular weight: 2,500, Institute Choay, France): 90 anti-Xa units/kg bodyweight as a bolus injection followed by a continuous infusion of 1,000 anti-Xa units/hour (regimen 1); or 300 anti-Xa units/kg as a bolus injection (regimen 3), with a standard heparinization regimen (100 IU/kg regimen 2). Eight patients received the 3 regimens successively. Factor IIa and factor Xa inactivation was measured by a method that uses chromogenic substrates. The frequency of adverse effects, ultrafiltration rates, creatinine and BUN clearances of the 3 regimens were similar, whereas dialyser blood loss was higher in the first regimen. At the dose of 300 anti-Xa units of CY 222 (regimen 3), inactivation of factor Xa was similar to Xa inhibition reached through the conventional treatment (regimen 2) but IIa inhibition was less pronounced.

[Septicemic cutaneous localization of cryptococcosis following renal transplantation in a female]. / Localisations cutanées septicémiques d'une cryptococcose chez une greffée rénale.

Cryptococcosis is a systemic disease caused by the yeast-like fungus Cryptococcus neoformans. Cutaneous manifestations, although rare, may precede other organ involvements. A case of cutaneous cryptococcosis is described herein. The skin lesions in our patient (a 47-year old female with renal transplant) consisted of acute cellulitis over her left and right thighs, revealing a septicemic infection. The patient received immunosuppressive drugs (prednisone, azathioprine). Clinical, mycological and histopathological data are described in details. Amphotericin B and fluconazole were initially successful, but a relapse with Cryptococcus meningitis required the adjunction of itraconazole to treatment. This case report underlines the insufficient effectiveness of fluconazole and the success of itraconazole.

[Hereditary angioneurotic edema: an underestimated medical emergency. Apropos of 33 cases]. / L'oedème angio-neurotique héréditaire: une urgence médicale sous-estimée. A propos de 33 cas.

INTRODUCTION: Hereditary angio-oedema is a poorly understood disease. In more than 70 p. 100 of the cases, diagnosis is made 5 to 10 years after the first manifestations despite their typical nature. PATIENTS AND METHODS: We examined retrospectively 33 cases of hereditary angio-neurotic oedema treated at the Besançon University Hospital from 1973 to 1990. RESULTS: Laryngeal oedema was the most dangerous complication causing a critical episode in 22 cases. Ten patients were given danazol. DISCUSSION: This study emphasizes that preventive treatment is essential, based on danazol which should be prescribed at the lowest dose which gives a 50 p. 100 rise in the C2 complement fraction (usually 50 to 200 mg/day). Life-threatening attacks should be treated with purified C1 INH, although there are still problems with drug supply.

[Aneurysm of the abdominal aorta following renal transplantation. Surgical repair with extracorporeal circulation of the graft]. / Anévrysme de l'aorte abdominale après transplantation rénale. Cure chirurgicale sous CEC du greffon.

The authors report a case of abdominal aortic aneurysm, revealed three years after a renal transplantation in left hypogastric position. A pump-oxygenator was utilised to protect the renal transplant during the aortic aneurysmectomy. The renal function is normal three years after the aneurysmectomy, and the patient presented not prosthesis infection, despite the corticoid and immunosuppressive treatment.