Engagement of transferrin receptor by polymeric IgA1: evidence for a positive feedback loop involving increased receptor expression and mesangial cell proliferation in IgA nephropathy

IgA nephropathy (IgAN), the most common primary glomerulonephritis in the world, is characterized by IgA immune complex-mediated mesangial cell proliferation. The transferrin receptor (TfR) was identified previously as an IgA1 receptor, and it was found that, in biopsies of patients with IgAN, TfR is overexpressed and co-localizes with IgA1 mesangial deposits. Here, it is shown that purified polymeric IgA1 (pIgA1) is a major inducer of TfR expression (three- to four-fold increase) in quiescent human mesangial cells (HMC). IgA-induced but not cytokine-induced HMC proliferation is dependent on TfR engagement as it is inhibited by both TfR1 and TfR2 ectodomains as well as by the anti-TfR mAb A24. It is dependent on the continued presence of IgA1 rather than on soluble factors released during IgA1-mediated activation. In addition, pIgA1-induced IL-6 and TGF-beta production from HMC was specifically inhibited by mAb A24, confirming that pIgA1 triggers a TfR-dependent HMC activation. Finally, upregulation of TfR expression induced by sera from patients with IgAN but not from healthy individuals was dependent on IgA. It is proposed that deposited pIgA1 or IgA1 immune complexes could initiate a process of auto-amplification involving hyperexpression of TfR, allowing increased IgA1 mesangial deposition. Altogether, these data unveil a functional cooperation between pIgA1 and TfR for IgA1 deposition and HMC proliferation and activation, features that are commonly implicated in the chronicity of mesangial injuries observed in IgAN and that could explain the recurrence of IgA1 deposits in the mesangium after renal transplantation.     

Recombinant coagulation factor VIIa in major liver resection: a randomized, placebo-controlled, double-blind clinical trial

BACKGROUND: Prevention of bleeding episodes in noncirrhotic patients undergoing partial hepatectomy remains unsatisfactory in spite of improved surgical techniques. The authors conducted a randomized, placebo-controlled, double-blind trial to evaluate the hemostatic effect and safety of recombinant factor VIIa (rFVIIa) in major partial hepatectomy. METHODS: Two hundred four noncirrhotic patients were equally randomized to receive either 20 or 80 microg/kg rFVIIa or placebo. Partial hepatectomy was performed according to local practice at the participating centers. Patients were monitored for 7 days after surgery. Key efficacy parameters were perioperative erythrocyte requirements (using hematocrit as the transfusion trigger) and blood loss. Safety assessments included monitoring of coagulation-related parameters and Doppler examination of hepatic vessels and lower extremities. RESULTS: The proportion of patients who required perioperative red blood cell transfusion (the primary endpoint) was 37% (23 of 63) in the placebo group, 41% (26 of 63) in the 20-microg/kg group, and 25% (15 of 59) in the 80-microg/kg dose group (logistic regression model; P = 0.09). Mean erythrocyte requirements for patients receiving erythrocytes were 1,024 ml with placebo, 1,354 ml with 20 microg/kg rFVIIa, and 1,036 ml with 80 microg/kg rFVIIa (P = 0.78). Mean intraoperative blood loss was 1,422 ml with placebo, 1,372 ml with 20 microg/kg rFVIIa, and 1,073 ml with 80 microg/kg rFVIIa (P = 0.07). The reduction in hematocrit during surgery was smallest in the 80-microg/kg group, with a significant overall effect of treatment (P = 0.04). CONCLUSIONS: Recombinant factor VIIa dosing did not result in a statistically significant reduction in either the number of patients transfused or the volume of blood products administered. No safety issues were identified.     

The blood-air barrier in desquamative interstitial pneumonia (D.I.P.)

Summary Two biopsies of lung diagnosed as D.I.P. were studied by electrom microscopy to ascertain the type of cells lining the alveoli and of those lying free in the alveolar spaces. The alveoli were lined predominantly by granular pneumocytes that were P.A.S.-negative after diastase digestion. In contrast, the free intraluminal cells were mostly phagocytic pneumocytes mixed with desquamated granular pneumocytes and were diastase resistant P.A.S.-positive. Sometimes the phagocytic pneumocytes were joined by intertwining pseudopodial-like processes. In addition to that dual cellular reaction (hyperplasia and desquamation of granular pneumocytes, with groups of phagocytic pneumocytes in the alveolar spaces), there were ultrastructural changes in capillaries and infiltrates of lymphocytes, plasma cells and eosinophils in the interstitial tissue of the alveolar wall. We believe that these alterations in the blood-air barrier are one of the factors responsible for the reduced pulmonary diffusing capacity recorded in the two cases presented.

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Der Blut-Luft-Weg bei desquamativer interstitieller Pneumonie

Zusammenfassung Zwei als diffuse interstitielle Pneumonie (D.I.P.) diagnostizierte Lungenbiopsien wurden elektronenmikroskopisch untersucht zwecks Bestimmung der die Alveolarwand bekleidenden und der frei im Alveolarraum liegenden Zellen. Die Alveolarwände waren vorwiegend mit granulären Pneumocyten besetzt. Diese waren nach Diastaseein wirkung PAS-negativ. Die frei im Alveolarraum liegenden Zellen waren hauptsächlich Diastase-resistente, PAS-positive phagocytäre Pneumocyten, untermischt mit abgelösten granulären Pneumocyten. Manchmal waren die phagocytären Pneumocyten durch verflochtene pseudopodienartige Fortsätze miteinander verbunden. Außer der zweifachen Zellreaktion (Hyperplasie und Ablösung von granulären Pneumocyten, Gruppen von phagocytären Pneumocyten in den Alveolarräumen), waren feinstrukturelle Veränderungen an den Capillaren nachweisbar sowie lymphocytäre, plasmacytäre und eosinophile Infiltrate im interstitiellen Gewebe der Alveolarwände. Die dadurch hervorgerufene Verbreiterung der Blut-Luftschranke scheint einer der für die in beiden Fällen nachgewiesene verringerte Lungendiffusionskapazität verantwortlichen Faktoren zu sein.

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Supported by the Illinois Tuberculosis Association.

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Presented at the Sixty-Fourth Annual Meeting of the American Association of Pathologists and Bacteriologists, Washington, D.C., March 1967.     

Existence and anatomic distribution of double parathyroid adenoma

BACKGROUND: Double parathyroid adenomas occur in 2% to 15% of primary hyperparathyroidism cases, but the very existence of double adenomas has been controversial. This study was conducted to evaluate the clinical significance and anatomic distribution of parathyroid double adenomas. STUDY DESIGN: Mono-institutional retrospective study of the medical records of 183 unselected consecutive patients who underwent intervention for primary hyperparathyroidism between 1996 and 2003. RESULTS: A total of 14 (7.65%) patients were found to have double parathyroid adenomas. Intraoperative parathyroid hormone (PTH) levels were measured in every case. Two enlarged parathyroid glands were identified in four possible configurations: two both superior, one both inferior, two both right, three both left, two right superior and left inferior, and three left superior and right inferior. There was a preferential crossed bilateral distribution of double adenomas. In all patients, intraoperative PTH levels dropped by at least 50% from baseline after removal of both abnormal parathyroid glands. In this series, no patient developed persistent hypoparathyroidism or had recurrent laryngeal nerve injuries or neck hematoma. All patients remained normocalcemic 9 to 96 months postoperatively. One patient had persistently elevated PTH values with normal serum calcium levels. CONCLUSION: The drop in intraoperative PTH levels and maintenance of normocalcemia postoperatively confirm previous reports that double adenomas do exist and are not simply missed cases of four-gland hyperplasia. There was a preferential crossed bilateral distribution of double adenomas in this series.     

Prosthetic joint infections

Success in the treatment of infected orthopedic prosthesis requires the best surgical approach in combination with prolonged optimum targeted antimicrobial therapy. In choosing the surgical option, one must consider the type of infection, condition of the bone stock and soft tissue, the virulence and antimicrobial susceptibility of the pathogen, the general health and projected longevity of the patient, and the experience of the surgeon. If surgery is not possible, an alternative is long-term oral antimicrobial suppression to maintain a functioning prosthesis. Treatment must be individualized for a specific infection in a specific patient.