Fibrinolytic Responses to 1-desamino-8-D-arginine-vasopressin in Patients with Congenital Nephrogenic Diabetes Insipidus
| Title: | Fibrinolytic Responses to 1-desamino-8-D-arginine-vasopressin in Patients with Congenital Nephrogenic Diabetes Insipidus |
|---|---|
| Authors: | Monnens, Leo A.H.; Brommer, E.J.P.; van Oost, Bernard A.; Willems, J.; Knoers, Nine |
| Publisher: | Nephron |
| Date Published: | January 01, 1990 |
| Reference Number: | 256 |
Fibrinolytic responses to infusion of 1-desamino-8-D-arginine-vasopressin (DDAVP) were assessed in 6 males with congenital nephrogenic diabetes insipidus (NDI), 6 carriers of the NDI gene and 6 normal control subjects. Tissue-type plasminogen activator (t-PA) activity and antigen increased significantly in normal subjects, while plasminogen activator inhibitor (PAI) activity decreased. None of these changes were observed in patients with NDI. In 2 female carriers, normal fibrinolytic responses were seen, while in the other carriers responses were delayed. These findings are consistent with the concept of a general V-2 receptor defect in congenital NDI. DDAVP tests are of limited use in NDI carrier detection.
This translation by the NDI Foundation is to assist the lay reader. To provide a clear, accessible interpretation of the original article, we eliminated or simplified some technical detail and complicated scientific language. We concentrated our translation on those aspects of the article dealing directly with NDI. The NDI Foundation thanks the researchers for their work toward understanding and more effectively treating this disorder.
© Copyright NDI Foundation 2007 (JC)
The X-linked form of congenital nephrogenic diabetes insipidus (NDI) is a disorder in which the kidney does not respond to the antidiuretic actions of AVP. Thus the kidneys cannot reabsorb the water flowing through the CD, cannot concentrate urine, and cannot balance body water. The primary symptoms of NDI are polyuria (the chronic passage of large volumes of urine) and polydipsia (chronic, excessive thirst). A body of evidence suggests that X-linked NDI is caused by a defect of the vasopressin-2 receptors located in the kidney CD.
1-desamino-8-D-arginine-vasopressin (DDAVP) is a synthetically modified form of AVP that binds with V2R but not with V1R. Thus it does not promote the increase of blood pressure and it does promote antidiuresis. DDAVP also exerts a dilatory action on the blood vessels which is manifested by facial flushing, a fall in diastolic blood pressure and a rise in the pulse rate. DDAVP also has other effects on the dynamics and chemistry of the blood: it increases the levels of factor VIII coagulant activity(FVIII:C), von Willebrand factor antigen (vWF: Ag), and fibrinolytic activity (the dissolution of fibrin - a protein that forms an essential portion of blood clots). The reason DDAVP increases fibrinolytic activity is because it causes the body to rapidly release plasminogen activator (t-PA), a substance which converts plasminogen into plasmin. Plasmin dissolves fibrin. Thus, DDAVP exerts a number of vasodilatory effects by binding with the V2R.
Kobrinsky discovered that people with X-linked NDI do not respond to DDAVP in terms of either allowing the kidney to concentrate urine or releasing of blood factors FVIII:C or vWF:Ag. Bichet, et al., discovered that NDI patients also do not vasodilate in response to DDAVP. These findings have led researchers to propose that people with X-linked NDI also have faulty V2Rs outside the kidney. This prompted the authors, Knoers, et al., to measure the response to DDAVP of the fibrinolytic parameters (t-PA antigen, t-PA activator, and PAI -plasminogen activator inhibitor)in six NDI patients, six female carriers of the NDI-causing gene, and six normal subjects.
In the normal subjects, the infusion of DDAVP produced a 15-fold rise in t-PA activity and a two-fold rise in t-PA antigen within 10 minutes, while PAI activity decreased slightly within 20 minutes. In contrast, none of the patients with congenital NDI showed any significant change in t-PA activity, t-PA antigen or PAI values. DDAVP infusion was followed by a decrease in diastolic blood pressure and a significant rise in pulse rate in the normal subjects but not in the NDI patients. In short, the NDI patients did not show increased fibrinolytic activity after infusions of DDAVP, whereas normal subjects did. Since research has demonstrated that NDI patients do not concentrate urine, do not evidence hemodynamic, blood coagulation responses, or fibrinolytic changes in response to DDAVP, Knoers, et al., suggests that this indicates that people with X-linked NDI have a general V2R defect.
In this study, four of the six female NDI carriers showed a diminished fibrinolytic response 10 minutes after DDAVP administration. However, after 20 minutes the majority of carriers demonstrated fibrinolytic responses similar to normal controls. Two of the carriers showed a completely normal response at all points in the test. This finding acts as a caution against assuming that all NDI carriers can be identified by means of their fibrinolytic response to DDAVP.