2002 Global Researcher Conference Proceeding
April 26 - 28, 2002
| Conference: | 2002 Global Researcher Conference |
|---|---|
| Title: | Clinical presentation of the polyuric and hyperprostaglandinuric salt losing tubulopathies (HPS/aBS) and the therapeutic option with COX inhibitors |
| Authors: | Seyberth, M.D., Hannsjorg W.; Peters, Melanie; Reinalter, Stefan; Jeck, Nikola; Konrad, Martin; Komhoff, Martin |
| Institutions: | Philipps University, Philipps University Marburg, Universitatskinderklinik, University Children's Hospital, Children Hospital at the Philipps University |
Inherited salt losing tubulopathies due to defective salt reabsorption in the TAL have been termed antenatal Bartter syndrome (aBS) or hyper-PGE2 syndrome (HPS). The later designation emphasize the role of prostaglandin E2 in both pathogenesis and treatment of this salt losing tubulopathy. Patients affected by HPS/aBS show excessive renal and systemic production of PGE2, thereby causing and/or aggravating both renal salt and water wasting and systemic disturbances such as diarrhea, vomiting, fever, osteopenia, and failure to thrive. The major clinical characteristics are polyhydramnios, nephrocalcinosis and hypo- or isosthenuria. Thus these tubulopathies are clinically and genetically distingue inherited renal disorders, which can be clearly differentiated from the classical Bartter syndrome and its variant, the Gitelman syndrome, which are hypokalemic salt losing tubulopathies without gross abnormality in concentrating capacity indicating the tubulodefect in the distal convoluted tubule. Loss of function in the furosemide sensitive sodium potassium chloride cotransporter NKCC2 or the potassium channel ROMK are the primary molecular defects in HPS/aBS while the chloride channel CLC-Kb and the thiazide-sensitive sodium chloride cotransporter NCCT are the molecular defects for the Bartter/Gitelman syndromes. Only the first group is associate with the hyperprostaglandin E syndrome, in which non-steroidal anti-inflammatory drugs such as indomethacin has been proven as a very effective symptomatic treatment.
As renal salt loss has been shown to be associate with induced expression of COX-2 in the macula densa, leading to hyperreninemia, a more specific pharmacotherapeutic intervention with COX-2 selective inhibitors has been tested in patients with HBP/aBS. Concomitantly COX-2 selectivity of nimesulide and rofecoxibe has been investigated in vivo and ex vivo. Both indomethacin and the COX-2 inhibitors ameliorated clinical symptoms, the typical laboratory findings, and significantly suppressed renal and systemic prostaglandin E2 activity to normal values.
Thus excessive PGE2 synthesis and hyperreninemia are dependent on COX-2 activity. This observation has led to a new therapeutic option with less gastrointestinal side effects which are the major therapeutic drawbacks of the symptomatic treatment with non-steroidal anti-inflammatory drugs in patients with HPS/aBS.
Supported by grants of the DFG
Antenatal Bartter Syndrome (aBS) and hyper PGE2 syndrome (HPS) are disorders of the small tubes in the kidneys that result in excessive loss of salt. Patients with these disorders have excessive amounts of prostaglandin E2 (PGE2) and manifest symptoms such as diarrhea, vomiting, fever, reduced bone mass and failure to thrive. The major clinical signs of these disorders are excessive amniotic fluid, urine that is dilute or has the same concentration as that of plasma, and an excess of calcium phosphate in the little tubes of the kidney.
A substance called COX-2 is associated with the creation of excessive PGE2 and excessive renin in the blood. When patients with aBS/HPS are treated with COX-2 selective inhibitors, their clinical symptoms are reduced and kidney and PGE2 activity tend toward normal. Thus, COX-2 inhibitors are seen as a promising therapeutic option for people with aBS/HPS.