Syndrome of inappropriate antidiuretic hormone associated with eosinophilic granulomatosis and polyangiitis.

A 62-year-old man presented with classic signs and symptoms of eosinophilic granulomatosis and polyangiitis (EGPA, also known as Churg-Strauss syndrome)-mononeuritis multiplex, palpable purpura, hypereosinophilia, positive P-ANCA (perinuclear anti-neutrophil cytoplasmic antibodies) developed diffuse alveolar haemorrhage. The patient had longstanding mild hyponatraemia, but developed moderate and symptomatic hyponatraemia characteristic of the syndrome of inappropriate antidiuretic hormone. The patient's serum sodium returned to his baseline- mildly hyponatraemic, after initiation of treatment targeted towards EGPA.

Molecular structure-function relationship in the slit diaphragm.

The past 5 years have witnessed an exponential increase in our understanding of the structure and function of the glomerular slit diaphragm. The identification of nephrin as the first transmembrane slit diaphragm protein was a watershed event in slit diaphragm biology. This article correlates some of the observations of the prenephrin era with more recent studies, and elaborates on the individual characteristics of each slit diaphragm protein. Recent studies on protein-protein interactions related to slit diaphragm permeability and cell signaling are elaborated, along with observations on their expression in human disease and experimental models of proteinuria. Developmental expression of components of the slit diaphragm in normal and knockout mice also is discussed. Finally, some areas of future investigation are proposed.

Neph1 and nephrin interaction in the slit diaphragm is an important determinant of glomerular permeability.

Neph1-deficient mice develop nephrotic syndrome at birth, indicating the importance of this protein in the development of a normal glomerular filtration barrier. While the precise subcellular localization of Neph1 remains unknown, its relationship with other components of the glomerular filtration barrier is of great interest in this field. In this paper, we localize the expression of Neph1 to the glomerular slit diaphragm by immunogold electron microscopy in rodents and describe its direct interaction with two other components of the slit diaphragm, nephrin and ZO-1. Both native and recombinant Neph1 associate with each other as dimers and multimers and interact with nephrin via their extracellular segments. Disruption of the Neph1-nephrin interaction in vivo by injecting combinations of individual subnephritogenic doses of anti-Neph1 and anti-nephrin results in complement- and leukocyte-independent proteinuria with preserved foot processes. This disruption modestly reduces Neph1 and nephrin protein expression in podocytes and dramatically reduces ZO-1 protein expression via the interaction of ZO-1 PDZ domains with the cytoplasmic tail of Neph1, independent of changes in mRNA expression of all three genes. The interaction between nephrin and Neph1 is specific and not shared by either protein with P-cadherin, another integral slit diaphragm protein. The interaction between nephrin and Neph1 therefore appears to be an important determinant of glomerular permeability.