[Kidney involvement in sarcoidosis]. / Atteintes rénales de la sarcoïdose.

Sarcoidosis is a chronic multisystemic inflammatory disorder of unknown etiology, characterized by the presence of non-necrotizing epithelioid and giant cell granulomas. Various renal manifestations have been reported in patients with sarcoidosis. Disorders of bone and mineral metabolism related to the overexpression of 25-hydroxyvitamin-D1α-hydroxylase by alveolar and granuloma macrophages are frequently associated with sarcoidosis. Hypercalcemia and hypercalciuria are a major cause of renal injury predisposing to pre renal azotemia, acute tubular necrosis, nephrolithiasis and nephrocalcinosis. Therapeutic management of hypercalcemia includes preventive measures (limited sunlight exposure, limited vitamin D and calcium intakes, and adequate hydration) and specific treatment in cases of severe hypercalcemia (corticosteroid therapy, chloroquine or ketoconazole). Granulomatous tubulointerstitial nephritis is the most common renal lesion associated with sarcoidosis leading to end stage renal disease in some patients. In these cases, interstitial fibrosis seems to appear early in the course of sarcoidosis and is a major prognostic factor requiring rapid corticosteroid therapy to reduce the risk of severe renal impairment. Membranous nephropathy seems to be the most frequent glomerular disease that may occur in association with sarcoidosis. Among kidney allograft recipients, the risk of recurrence of granulomatous tubulointerstitial nephritis is high and may have a negative impact on the graft survival.

Successful long-term outcome of the first combined heart and kidney transplant in a patient with systemic Al amyloidosis.

Simultaneous cardiac and renal involvement is associated with a particularly poor prognosis in patients with AL amyloidosis (AL-A). We report the first case of a successful long-term outcome of combined heart and kidney transplantation not followed by autologous stem cell transplantation in a patient with systemic AL-A. The recipient was a 46-year-old man with end-stage renal failure associated with serious cardiac involvement in the context of AL-A. Before transplantation, two courses of oral melphalan plus prednisone induced partial hematologic remission, as shown by the decrease in circulating free light chain with no improvement of renal or heart function. The patient underwent combined heart and kidney transplantation as a rescue treatment. During the follow-up period (36 months), plasma cell dyscrasia remains in complete remission, with normal free lambda light chain levels and no recurrence of amyloid deposition on heart and kidney grafts. This case report demonstrates that combined heart and kidney transplantation not systematically associated with stem cell transplantation may be considered an additional therapeutic option in AL-A patients with severe organ dysfunction and partial hematologic remission.

Minimal change nephrotic syndrome and classical Hodgkin's lymphoma: report of 21 cases and review of the literature.

Minimal change nephrotic syndrome (MCNS) is described as a paraneoplastic manifestation of classical Hodgkin's lymphoma (cHL). We reassessed the pathophysiological and clinical significance of this association. A retrospective study was performed to evaluate a cohort of adult patients who developed MCNS and cHL. Twenty-one patients recruited in 15 French centers were analyzed. cHL was associated with inflammatory and general symptoms in most cases. The morphological subtype was predominantly nodular sclerosis (71.4%). MCNS appeared before the diagnosis of lymphoma in eight patients (38.1%) and in this case, it was characterized by a nephrotic syndrome (NS) frequently resistant (50%) or dependent (12.5%) to steroid treatment. Interestingly, diagnosis (3-120 months after MCNS) and effective treatment of the hemopathy were associated with the disappearance of the MCNS. cHL was diagnosed before MCNS in nine patients (42.9%), and in this case, glomerulopathy was associated with cHL relapse in 55.5% of cases. In four patients (19%), the two diseases occurred simultaneously. Extensive immunohistochemical study of lymph nodes was performed in eight patients and did not reveal particular features. In conclusion, MCNS associated with cHL is frequently dependent or resistant to steroid regimen, but remission of NS is obtained with the cure of lymphoma.

[Recent approaches to the pathogenesis of minimal change nephrotic syndrome]. / Nouvelles approaches dans l'étude de la pathogénie de la néphrose lipoïdique.

Clinical and experimental observations suggest that lipoid nephrosis (Minimal change nephrotic syndrome) results from T cell dysfunction due to still unknown mechanisms. By substractive screening library, we identified 84 transcripts, of which 42 correspond to known genes, 12 match with proteins of yet unknown function and 30 are unknown clones. Among the 42 known transcripts, at least 18 are closely involved in the T-Cell Receptor mediated signaling cascades. This includes genes encoding components of the T-Cell Receptor and proteins associated with the cytoskeleton scaffold, as well as transcription factors. During the relapse phase, we have detected very low levels of IL12R beta 2 mRNA suggesting that the T-cell activation evolves toward a Th2 phenotype. Thus, the combination of substractive cloning and differential screening constitutes an efficient approach to identify genes likely involved in the pathophysiology of MCNS.

Isolation of cDNAs encoding immunogenic regions of gp330, the autoantigen involved in Heymann nephritis.

Active Heymann nephritis is an organ-specific autoimmune disease of the rat kidney, characterized by the formation of immune complexes located subepithelially in the glomerulus. The T cell-mediated humoral immune response is directed to gp330, a large renal epithelial glycoprotein which is expressed both in the proximal tubule and on glomerular podocytes. In this study polyclonal rabbit antibodies raised against affinity-purified rat gp330 were used to screen a lambda-gt11 expression library of the rat kidney. One cDNA clone that was recognized by the antibodies coded for a 2.7-kb protein that is not described in the sequence database of GenBank/EMBL. Two other groups of cDNA clones were identified that displayed similarity with several members of the low-density lipoprotein (LDL)-receptor gene family to which gp330 belongs. By comparison with the gp330-cDNA sequence, these two clones could be mapped to two remote areas on the extracellular domain of gp330. The antigenicity of these two areas is in accordance with their location in highly hydrophilic regions on the extracellular domain of gp330. The cDNA clones described in this study may represent two main immunodominant regions on rat gp330.

Comparative immunochemistry and ontogeny of two closely related coated pit proteins. The 280-kd target of teratogenic antibodies and the 330-kd target of nephritogenic antibodies.

We have previously shown that monoclonal antibodies specific for a 280-kd protein (gp280) concentrated within the coated pits of renal and yolk sac brush border-induced fetal malformations, whereas antibodies specific for gp330, another coated pit protein with a similar distribution, had no deleterious effect on embryonic development. In this study, we show that gp280 and gp330 are closely related proteins, as indicated by: 1) similarities in peptide maps obtained after cyanogen bromide cleavage, 2) immunological cross-reactivity related to a minor contingent of antibodies that do not have teratogenic activity, and 3) asynchronous but related expressions during ontogenesis. During the early stages of development, the expression of the two glycoproteins was limited to (gp330) or predominant in (gp280) the clathrin-coated pits and intermicrovillar areas. In the pre-implantation embryo, gp330 was expressed by trophectodermal cells, which became negative in day-6 embryos trapped in endometrial infoldings. At this stage, gp280 and gp330 were both simultaneously detectable at the apical pole of the first entoblastic cells and remained expressed by the brush border of visceral yolk sac epithelial cells until the end of pregnancy. In addition, gp330 was expressed by amniotic cells and neurectodermal structures. During nephrogenesis, in contrast, the expression of gp280 and gp330 by the intermicrovillar areas of the proximal tubule cell was the result of a complex maturation process. gp280 and gp330 were diffusely distributed in S-shaped bodies in the presumptive areas of the glomerulus, proximal tubule, and distal tubule (gp330). During development of the nephron, the pattern of expression became progressively restricted to the proximal tubule and glomerulus (gp330), and selective localization in the intermicrovillar areas was only achieved in filtrating nephrons.

[Teratogenesis and autoimmunity: significance of an experimental murine model for human pathology]. / Tératogenèse et auto-immunité: signification en pathologie humaine d'un modèle expérimental murin.

Fetal malformations constitute a major problem of public health. Unfortunately the known causes do not account for more than 50% of the cases observed. The potential role of immune mechanisms is suggested by experimental studies in the rat indicating that antibodies reactive with the yolk sac induce fetal malformations. In this study we show that these antibodies are specific for a 280 kDa protein expressed only in the kidney and the yolk sac by cell structures associated with the formation of endocytic vesicles. We further show that a similar protein is expressed in man by the yolk sac, the kidney and the trophoblasts. The possible role in pathology of antibodies against the human protein is discussed.

Coexpression in humans by kidney and fetal envelopes of a 280 kDa-coated pit-restricted protein. Similarity with the murine target of teratogenic antibodies.

Experimental studies performed in the rat over the last three decades have shown that antibodies raised against kidney or yolk sac, which, in the rat, surrounds the embryo and serves as a placenta during the major part of pregnancy, induced fetal resorptions or malformations. It is generally considered that the teratogenic antibodies decrease internalization and degradation of maternal proteins by yolk sac epithelial cells leading to an inadequate supply of nutriments to the embryo. These observations demonstrating the pathogenic role of antibodies to fetal envelopes are of great potential interest in clinical pathology since most cases of fetal malformations in humans are of unknown cause. The authors have recently shown that the key teratogenic antibodies in the murine system were directed against a 280 kDa-coated pit protein (gp280) specific for the brush border of epithelial cells lining the renal proximal tubule and the yolk sac. This observation allows for the unique opportunity to search for a similar system in humans. In this study, the presence in humans of a protein closely related to murine gp280 is shown, as indicated by extensive immunologic crossreactivity, close apparent molecular weights, strong homology of bidimensional peptide maps, and restricted distribution at the organ and subcellular level. In addition to kidney and yolk sac, human gp280 was also detected within the coated pits of the placental syncytiotrophoblastic cells. When introduced in an in vitro rat embryo culture system, antibodies to human gp280-induced developmental anomalies in a dose-dependent manner. These observations indicate that the antigenic component of the murine model is present in humans and can give rise to heterologous antibodies that cause developmental anomalies, suggesting that the experimental model might be of significance in human pathology.

Gallium67 scintigraphy in the diagnosis of glomerulonephritis.

To assess the role of gallium-67 (67Ga) scintigraphy in the diagnosis of glomerular diseases, we performed the following technique in 39 patients with glomerulonephritis (GN) who underwent simultaneous Ga scan and histologic examination. 72 hours after IV injection of Ga citrate (2 mCi), isotopic kidney activity (normally undetectable) was compared to the activity of the liver and quantified as follows: less than (1+), equal to (2+) or greater than (3+) that of the liver. Renal biopsy was performed at the same time to evaluate the type of the GN and to quantify interstitial cellular infiltration. Proteinuria, serum albumin and creatinine were measured. There was a significant correlation between the level of 67Ga kidney activity and the degree of proteinuria and hypoalbuminemia. On the contrary, no correlation was found between isotopic activity and the degree of renal failure or the degree of interstitial cellular infiltration. Increased kidney 67Ga activity did not appear characteristic of a specific histologic type of GN. Increased glomerular permeability may alter renal uptake of Ga; therefore 67Ga scanning does not appear to contribute significantly to the diagnosis and the follow-up of either primary or secondary GN.

Characterization of a 280-kD protein restricted to the coated pits of the renal brush border and the epithelial cells of the yolk sac. Teratogenic effect of the specific monoclonal antibodies.

Intermicrovillar areas and apical vesicles characterized by an extensive clathrin coat can be identified in some epithelial cell types. We describe a 280-kD protein, characteristic of these areas in the proximal tubule brush border and epithelial cells of the visceral yolk sac. When injected to 9-d pregnant rats, mAbs to the 280-kD protein regularly induced fetal resorption and/or malformations. Antibodies to a 330-kD protein that is also coated-pit-restricted had no effect. Our observations point to a key function for p280 and suggest that immunity to specific constituents of the receptor-mediated endocytotic system may be involved in the induction of fetal abnormalities.

Immunological segmentation of the rabbit distal, connecting, and collecting tubules.

To obtain monoclonal antibodies (MAB) specific for the different cell types of distal and collecting tubules, BALB/c mice were immunized with cell suspensions highly enriched in cells from the distal segments of the rabbit nephron. Nine MAB were selected and cloned. Four groups could be identified on the basis of double-labeling immunofluorescence (IF) on frozen kidney sections and on microdissected tubules. In addition, binding specificity at the cellular level was studied by immunoelectronmicroscopy (IEM) for selected MAB. A single MAB (group 1) was specific for distal bright cells and a subpopulation of cortical ascending limb cells. Six MAB (group 2) reacted with connecting and collecting tubules. Five of these (group 2A) had similar binding patterns and reacted identically with the two tubular segments. The MAB studied by IEM was specific for connecting and principal cells. One antibody (group 2B) reacted with only a fraction of the cells associated with the connecting tubule (CNT), but with all cells of the cortical collecting tubule (CCT). By IEM, this antibody was found to be specific for intercalated cells in CNT and bound both principal and intercalated cells of the CCT. Two MAB (group 3) reacted with antigen(s) expressed by the various terminal segments of renal tubule. MAB of groups 1 and 2A, which define distal bright cells and connecting-principal cells from the CNT-CCT, respectively, were used for cell fractionation experiments. Heterogeneous rabbit cortical cells were first incubated with the selected MAB. MAB-bearing renal cells were separated on plastic dishes previously coated with an affinity-purified goat anti-mouse immunoglobulin. Using these procedures it was possible to obtain highly purified subpopulations of distal, bright, or connecting-principal cells.