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Janos Rado: Desmopressin may counteract polyuria in lithium-induced nephrogenic diabetes insipidus

(Review of the literature)

 

ABSTRACT

          Lithium is a simple ion that remains the best, safest and least expensive treatment for the prevention of recurrent episodes of bipolar disorder. However, in many patients administration of lithium is associated with renal side effects. The most frequent side effect is a defect in urinary concentration, wich may lead to permanent lithium-induced nephrogenic diabetes insipidus. In the older literature this problem was treated with great attention, in the most recent publications, however, lithium-induced nephrogenic insipidus is hardly mentioned. Patients suffer from the disturbed night, therefore it is an eminent goal to secure them some rest. In our previous works administration of excessive doses of desmopressin resulted in clinically relevant antidiuresis, enhanced by indomethacine and abolished by calcitonine. The purpose of the present paper is to review of the literature concerning the use of desmopressin in nephrogenic diabetes insipidus

INTRODUCTION

          Lithium is a simple ion that remains the best, safest and least expensive treatment for the prevention of recurrent episodes of bipolar disorder. (Barry Blackwell 2018) This concept is supported by many workers in psychiatry, among them Ban 2017; Gupta, Kripafani, Khastgir,Reilly 2013; Rybakovski 2017; and Severus 2014. However, its use has gradually declined and many less-established drugs are preferred (Gupta Kripafani, Khastgir,Reilly 2013) It is underused because of its low therapeutic index, the need for regular blood tests and perceptions about its adverse effects, including renal problems (Gupta, Kripafani, Khastgir, Reilly 2013)

          The most frequent renal problem is the disturbance in water metabolism, due to lithium-induced insufficiency in renal concentrating operation resulting in polyuria and polydipsia. Daily urine volume increases, in many cases it is more than 3-5 liters a day (Johnson 2018; Walker 2019), but we have seen a patient, in whom in a stage of her long history it was more than 10 liters. Patients suffer from the disturbed night, therefore it is an eminent goal to secure them some rest. In the older literature this problem seemed to be very important (Johnson G, Glenn E, Hunt G, Duggin G, Horvath JS, Tiller DJ 1984, Johnson 1998; Radó and Zdravkova 1991) and treated with great attention, in the most recent publications, however, lithium-induced nephrogenic insipidus is hardly mentioned (Gupta, Khastgear 2017; Davis, Desmond and Berk 2018) The recommanded drugs are mostly a thiazide diuretic (Mizuno et al 2003), indomethacine (Weinstock, Moses, 1984) and amiloride (Croft et al 2018).

          In our previous works administration of excessive doses of desmopressin resulted in clinically relevant antidiuresis in lithium-induced nephrogenic insipidus enhanced by indomethacine (Radó 1991;1993; 2018ab; 2019a).The purpose of the present paper is to review the literature concerning the use of desmopressin in lithium-induced nephrogenic diabetes insipidus.

SHORT PHARMACOLOGY OF DESMOPRESSIN

          Structural alterations of the vasopressin molecule resulted in 1-Deamino-8-D-Arginine Vasopressin or desmopressin, with increased antidiuretic potency, longer duration of action and lacking pressor effect due to decreased vasoconstrictor activity. In our studies carried out over 40 years we have demonstrated a relationship between the dose and both the magnitude and the duration of the antidiuretic effect (Radó et al. 1975a, 1976c). Robertson and his coworkers (Oiso et al. 2013) wrote about our early investigations that “in patients with neurohypophyseal diabetes insipidus rapid infusion of 1 micgr desmopressin increased urine osmolality to a maximum of 700-800 mOm/Kg; further increases in dosage only prolonged the duration of action from an average of 26 hours after 1 micgr to 46 hours after 8 micgr.” Our further studies revealed large interindividual variability in the magnitude and duration of the antidiuretic response of desmopressin, which was contributed -at least in part- to the interindividual differences in renal concentrating power (Radó et al. 1976a). The long duration of action of desmopressin is attributed mainly to its slow metabolic (enzymatic) degradation, and both shortened duration of action (Radó et al. 1976b) and lengthened duration of action (Radó et al 1975b) were reported under varying pharmacological circumstances. Effect of desmopressin was inhibited by glyburide, an antidiabetic compound probably by competetive antagonism (Radó et al 1974a;1974b) A similar antagonism by calcitonine was discovered later (Radó and Zdravkova 1993). Comparison of the antidiuretic effects of single intravenous and intranasal doses of desmopressin in diabetes insipidus was also an important part of our investigations (Radó, Marosi and Fischer 1977). Intranasal administration of desmopressin was at that time a comfortable way of administration and proved to be reliable. (Walle et al 2007) Today desmopressin therapy can be carried out by oral melting tablets. (Walle et al 2007). We have elaborated a diagnostic procedure for the differentiation of the various concentrating defects by intranasal administration of desmopressin, the “desmopressin concentrating test” (Radó 1978).  When we started our studies with desmopressin a „supramaximal” dose was 300 microgr given intranasally. In these early human pharmacology investigations 320 mcg was given as a quasi „single dose” during one hour to patients with neurohypophyseal (central) diabetes insipidus. (Radó 1975b) When we used desmopressin for nephrogenic diabetes insipidus 300 microgr was given during 24 hrs. (Radó and Zdravkova 1991,1993) In the meantime, however, it became known desmopresin may be effective also in hematologic disorders. In these disorders in certain cases desmopressin was given in really extreme doses The industry produced desmopressin preparations containing very high concentrations of desmopressin acting on the blood clotting mechanism for bleeding disorders. By using such a preparation (Octim Nasal Spray Ferring Pharmaceuticals Ltd) administration of 300 micrgr (150 micrgr into both nostrils) as a single dose is easily feasible. To the best of my knowledge this preparation has not been tried, up to now in the therapy of the lithium-induced permanent nephrogenic diabetes insipidus (Radó 2019c).

DESMOPRESSIN ADMINISTERED ALONE IN NEPHROGENIC DIABETES INSIPIDUS

          Although nephrogenic diabetes insipidus is said to be “vasopressin resistant,” on the basis of ours and others’ previous investigations we did not exclude the use of certain vasopressin derivatives in this condition, because vasopressine resistance in many cases is not absolute (Canfield MC et al 1997; Fujiwara , Bichet 2005; 16:2836-2846 Khanna A. 2006; Oiso et al. 2013; Moses, Scheinman and Oppenheim 1984). Large doses of desmopressin was succesfully given to patients with congenital nephrogenic diabetes insipidus for antidiuretic purposes (Boccalandro 2004; Canfield MC, Tamarappoo BK, Moses AM, Verkman AS, Holtzman EJ. 1997; Khanna A. 2006; Oiso et al. 2013; Moses 1984) The effectiveness of relatively large doses of vasopressin (and also excessive doses of desmopressin) can be significantly different even within one family with congenital nephrogenic diabetes insipidus (Radó JP, Szende L. 1995; Radó 2019a). Probably, the degree of resistance to vasopressin (desmopressin) may differ among the family members. One member of this family was treated succesfully with desmopressin for decades and the case was published because the (congenital nephrogenic) diabetes insipidus was later associated with diabetes mellitus (Radó 2011). In our previous work we found that in a patient with lithium-induced permanent nephrogenic diabetes insipidus, in response to excessive desmopressin doses free water excretion (expressed in the percentage of glomerular filtration rate (CH2Ox100/GFR)) significantly decreased and urine osmolality significantly increased (Radó 2018 a).

          Finally, a very special observation. Müller, Marr, Deen (2002) investigated two unrelated families, in which two children had inherited primary nocturnal enuresis, and nephrogenic diabetes insipidus. They had mutations in the aquaporin-2 gene. The mutant proteins were inactive, suggesting that administration of desmopressin could not concentrate the urine in these patients. However, treatment with desmopressin resolved primary nocturnal enuresis completely.

COMBINATION OF DESMOPRESSIN WITH OTHER ANTIDIURETIC AGENTS IN NEPHROGENIC DIABETES INSIPIDUS

          Mizuno et al treated a 7-year-old boy suffering from congenital nephrogenic diabetes insipidus, who had demonstrated a partial response to desmopressin. (2013). Neither a low salt diet and a thiazide nor a large dose of desmopressin was effective in reduction of daily urine volume. However combination of thiazide and a large dose of desmopressin resulted in a decrease in urine volume and disappearance of nocturia.

          Indomethacine and desmopressin was used for the first time in lithium induced nephrogenic diabetes insipidus in 1990 by Weinstock and Moses. They found in their two patients that indomethacine alone was practically ineffective, but in combination with large doses of desmopressin urine volume decreased by 47% and 63% respectively, while urine osmolalities inceased by200% and 227% respectively.

          Stasior, Kikeri, Duel and Seifter in 1991 reported a patient with lithium induced nephrogenic diabetes insipidus who was responsive to desmopressin in the presence of indomethacine, but not to desmopressin or indomethacine alone. A single dose of 6 micgr desmopressin subcutaneosly (not a too large dose!) without indomethacine caused an increase in urine osmolality from 187 mOsm/Kg to 270 mOsm/Kg (44%). However, in response to the same dose of desmopressin in the presence of indomethacine urine osmolality increased from106 mOsm/Kg to 384 mOsm/Kg. (262%).

          In our patient urine volume and free water clearance significantly decreased while urine osmolality significantly increased after administration of the combination of indomethacine and desmopressin as compared to desmopressin administered alone (Radó 2018a).

          In our further studies piroxicam plus desmopressin as compared to desmopressin (administered alone) was also antidiuretic : urine volume and free water excretion decreased while urine osmolality increased without any consistent change in osmolal clearance, glomerular filtration rate and serum osmolality. These results support the contention that indomethacine is not the only nonsteroidal anti-inflammatory compound which can be used in the antidiuretic therapy. However, piroxicam seemed to be less antidiuretic than indomethacine, by ca 20-30 %.

          Antidiuretic properties has been demonstrated for chlorpropamide, carbamazepine and clofibrate which potentiated the effect of desmopressin (Radó 2019a). From these compounds probably only carbamazepine may be useful in a limited extent in the treatment of the lithium-induced nephrogenic insipidus. Statins (Bonfrate et al 2015; Milano 2017), metformin (Efe et al 2016) sildenafil (Milano et al 2017) and calcitonine (Milano et al 2017) were also shown to have some antidiuretic capabilities. Only calcitonine was combined with desmopressin (Radó 2018 a,b). In our hands, however, it was not an antidiuretic factor. Administration of excessive doses of desmopressin resulted in clinically relevant antidiuresis, enhanced by indomethacine and abolished by calcitonine (Radó 2018a). Calcitonine is a “tricky” hormone, having both diuretic and antidiuretic properties. Diuretic effect of calcitonine was an observation mainly in the older literature and is in harmony with our published data on a water mobilizing action (Radó 1991, 1993, 2018a). On the other hand, a water retaining action was found (Elalouf, Roinel and de Rouffignac 1986) in response to human calcitonine in rats during micropuncture studies simulating the changes induced by desmopressin. Calcitonin was recommended as a possible treatment for hereditary nephrogenic diabetes insipidus by Milano et al (2017).

          Combinations of hydrochlorothizide with indomethacine, amiloride with thiazide diuretics have additive antidiuretic effects (Milano et al 2017). All could have been combined -at least theoretically- with desmopressin to have a really potentiated antidiuretic intervention for the treatment of lithium-induced nephrogenic diabetes insipidus.

CONCLUSION

          It is important to save lithium treatment for millions of people suffering from bipolar disorder and other psychiatric abnormalities in an age when, its use has gradually declined and many less-established drugs are preferred (Gupta, Kripafani, Khastgir,Reilly 2013.) This can be done (at least partly) by demonstrating that treatment of lithium induced permanent nephrogenic diabetes insipidus is not so hopeless as it appeares from some recent articles dealing with lithium induced nephrotoxicity. Our therapeutic armamentarium include several drugs, thiazide diuretics, nonsteroid antiinflammatory drugs, amiloride and desmopressin. In this article we dealt with desmopressin administered alone and in combinations with other drugs in the treatment of congenital as well as lithium-induced nephrogenic diabetes insipidus. On the basis of the available literature desmopressin alone and in combinations with other antidiuretic drugs seemed to be an effective mean in counteracting lithium-induced polyuria.

 

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July 18, 2019