- Email: [email protected]
A 39-year-old pregnant woman with polyuria and hypomagnesemia
the renal consult
http://www.kidney-international.org & 2006 International Society of Nephrology
A 39-year-old pregnant woman with polyuria and hypomagnesemia SB Ahmed1, JM Abi Rached2, AK Singh1 and DM Charytan1 1
Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA; and 2American University of Beirut, Beirut, Lebanon
CASE PRESENTATION A 39-year-old Caucasian G4P2 woman at 27 weeks gestation was admitted to the hospital with newly diagnosed dilated cardiomyopathy and non-sustained ventricular tachycardia. Her urine output was 2.5–7 l/24 h. Serum magnesium levels were low despite repletion with up to 160 mEq of oral and i.v. magnesium daily. She had completed two prior pregnancies uneventfully, but complained of thirst, polyuria, and nocturia predating the current pregnancy by approximately 2 years. There was no history of lithium or diuretic use, head trauma, or neurological deficits. Past medical and family history was otherwise unremarkable. Physical examination revealed a well-appearing pregnant woman. Blood pressure was 80/60, jugular venous pressure was flat, and there was minimal peripheral edema. Laboratory values are shown in Table 1. Responses to 1-deamino-8-arginine vasopressin (dDAVP) and a water-deprivation test are shown in Figures 1 and 2.
Correspondence: SB Ahmed, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, PBB-3, RA126E, Boston, Massachusetts 02115, USA. E-mail: [email protected] Kidney International (2006) 69, 938–941. doi:10.1038/sj.ki.5000256; published online 8 February 2006 Received 13 October 2005; revised 14 November 2005; accepted 30 November 2006; published online 8 February 2006 938
DIAGNOSIS
Decreased osmotic threshold for sensation of thirst, unmasked by pregnancy and exacerbated by a high osmolar load. CLINICAL FOLLOW-UP
Serum magnesium levels remained stable and urinary collections suggested that the majority of exogenous magnesium supplementation was being excreted in the urine. This was consistent with normal physiologic responses of pregnancy and further suggested that the persistent osmotic losses were exacerbating the polyuria. Magnesium supplementation was tapered and ultimately discontinued, and serum magnesium levels remained in the 1.5–1.8 mg/dl range: reference range 1.8–2.5 mg/dl (0.6–0.7 mmol/l: reference range 0.7–1.0). Urine output decreased to 2–5 l/24 h but remained high and the patient continued to complain of severe thirst. The possibility of a baseline or pregnancy-induced diabetes insipidus (DI) was considered. The patient was challenged with ddAVP and a water deprivation test was performed (Figures 1 and 2). In both tests, the patient demonstrated an ability to concentrate the urine to X600 mOsm/kg. These results confirmed the presence of intact central production of and nephrogenic response to vasopressin (AVP) and ruled out the possibility of clinically significant DI. Conversely, the patient complained of extreme thirst at serum osmolalities p285 mOsm/kg, which confirmed the suspicion of a reduced osmotic threshold for thirst. Following the water deprivation test, the patient was allowed ad-lib access to water. Hospitalization continued without any evidence of hypernatremia or volume depletion. Labor was induced and a healthy male infant was delivered uneventfully at 35 weeks. At 2 weeks post-partum, the patient continued to complain of thirst and palpitations but was otherwise well. Blood pressure was 90/50, and JVP flat. Laboratory values were as follows: serum sodium 140 mmol/l: reference range 136–142 mmol/l; potassium 4 mmol/l: reference range 3.5–5 mmol/l; chloride 107 mmol/l: reference range 98–108 mmol/l; bicarbonate 23 mmol/l: reference range 23–32 mmol/l; calcium 8.4 mg/dl: reference range 8.8–10.5 mg/dl (2.1 mmol/l: reference range 2.2–2.6 mmol/l); magnesium Kidney International (2006) 69, 938–941
the renal consult
SB Ahmed et al.: Pregnancy, polyuria, and hypomagnesemia
Table 1 | Laboratory values Value (reference range) Serum/blood Sodium Potassium Chloride Bicarbonate Glucose Urea nitrogen Creatinine Calcium Ionized calcium Magnesium Albumin Osmolality Antidiuretic hormone Diuretic screen
Serum osmolality (mOsm/kg)
sodium potassium calcium magnesium phosphate
H2O
Serum sodium 600
500
400 mmol/l
pH 5, specific gravity 1.008, neg blood, protein, glucose 247 mOsm/kg (390–1093) 5575 ml (600–1600) 1578 mg (800–1800) (139495 mmol (70 720–159 120)) 156 mmol (75–200) 127 mmol (40–80) 502 mmol (50–400) 797 mg (121–243) (32.8 mmol (5.0–10)) 931 mg (500–1200) (9.8 mmol (5.3–12))
Osmolality 24 h volume 24 h creatinine 24 h 24 h 24 h 24 h 24 h
700
136 mmol/l (136–142) 4.0 mmol/l (3.5–5.0) 105 mmol/l (98–108) 27 mmol/l (23–32) 74 mg/dl (54–118) (4.1 mmol/l (3.0–6.6)) 8 mg/dl (9–25) (2.9 mmol/l (3.2–8.9)) 0.5 mg/dl (0.7–1.3) (44.2 mmol/l (62–115)) 8.0 mg/dl (8.8–10.5) (2.0 mmol/l (2.2–2.6)) 1.14 mmol/l (1.13–1.32) 1.6 mg/dl (1.8–2.5) (0.7 mmol/l (0.78–1.2)) 3.4 g/dl (3.7–5.4) (34 g/l(37–54)) 283 mOsm/kg (278–297) oassay (0.0–4.7) Negative
Urine Urinalysis
Urine osmolality (mOsm/kg)
300
200
100 Urine osmolality (mOsm/kg)
700
Serum osmolality (mOsm/kg) 600
0 0
Serum sodium
1
2
3
4
5
Hours
Figure 2 | Response to H2O deprivation. 500
Table 2 | Osmoregulation in normal pregnancy Plasma sodium Plasma osmolarity AVP Metabolic clearance of AVP 24 h urine volume
mmol/l
400 DDAVP
Decreased by approximately 5 mEq/l Decreased by approximately 10 mOsm/kg 1–8 pg/ml (unchanged from nongravid state) 4-fold increase Unchanged from nongravid state
300
2.0 mg/dl: reference range 1.8–2.5 mg/dl (0.8 mmol/l: reference range 0.72–1.0 mmol/l); albumin 3.9 mg/dl: reference range 3.7–5.4 g/dl (39 g/l: reference range 37–54 g/l).
200
DISCUSSION
100
Figure 1 | Response to dDAVP.
The syndrome of DI is characterized by polyuria and polydipsia, and is associated with intense thirst due to the loss of concentrating ability by the kidney. If the patient has free access to water, the rise in the serum osmolality and serum sodium is often mitigated by the thirst sensation, but the urinary loss of water is obligate. The cause of the syndrome is due either to impaired secretion of AVP by the
Kidney International (2006) 69, 938–941
939
0 0
1
2
3 Hours
4
5
6
the renal consult
pituitary gland (central DI) or to an impaired renal response to AVP (nephrogenic DI). AVP activates the V2 receptor on the collecting duct cells in the kidney to stimulate water absorption. The first reports of transient polyuria and polydipsia associated with pregnancy appeared over 60 years ago,1,2 and it has since been estimated that DI complicates approximately 1/300 000 pregnancies.3 The occurrence of DI during pregnancy is not surprising, given the profound alterations in the regulation of plasma osmolality and thirst that occur during normal gestation (Table 2). Both serum sodium and plasma osmolality are known to drop by approximately 5 mEq/l and 10 mOsm/kg, respectively, during pregnancy.4 Similarly, in both rats and humans, the thresholds for vasopressin (AVP) release and thirst are reset in the normal gravid state. Human chorionic gonadotrophin may play a role in these osmoregulatory changes,5 but placental production of vasopressinase plays an important role during the third trimester.6 Davison et al.7 demonstrated that vasopressinase levels were measurable starting at week 10 of gestation and reached peak levels by 22–24 weeks. At 22–24 weeks of normal pregnancy, the metabolic clearance of AVP increases fourfold. Plasma levels of AVP remain in the normal range, indicating that an increased compensatory secretion of AVP by the pituitary gland matches the rate of its degradation. These changes in thirst, AVP release and AVP metabolism typically result in a self-limited decrease of approximately 10 mOsm/kg in serum osmolarity by the third trimester. However, in some cases, the changes can be profound. Barron et al.8 published a report of previously healthy women developing polyuria in the immediate puerperium unresponsive to large amounts of exogenously administered AVP. Because all symptoms resolved later on in the post-partum period, the authors termed the condition ‘transient vasopressin-resistant DI of pregnancy’, recognizing that increased destruction of AVP may have occurred, rather than simply increased renal resistance to the hormone. Durr et al.9 later reported a study on a patient with significant polyuria (up to 25 l/day) and hypernatremia in the puerperium who failed to concentrate her urine after administration of AVP. However, her urine osmolality increased to 800 mOsm/kg when dDAVP, an endogenous AVP analogue resistant to inactivation by vasopressinase that selectively activates the nonpressor V2 vasopressor receptor, was administered.7 High levels of circulating vasopressinase in the post-partum period suggested increased destruction of AVP by placental vasopressinase, although alterations in the kinetics of the enzyme has been offered as another explanation.4 Another disorder has been described where women with partial central DI, asymptomatic when nongravid, manifest polyuria after midpregnancy, coincident with the normal four-fold increase in AVP catabolism. This disorder remits postpartum.10 In addition, Iwasaki et al.11 studied two women in whom overt polyuria and polydipsia developed during the third trimester of pregnancy and disappeared 940
SB Ahmed et al.: Pregnancy, polyuria, and hypomagnesemia
after delivery. They reported not only an increase in the degradation of vasopressin during pregnancy but also an increased resistance at the level of the kidney to the action of AVP. They concluded that pregnancy may unmask subclinical forms of both nephrogenic and neurogenic DI. This exacerbation may result from both increased vasopressinase activity and diminished renal responsiveness to AVP. Regardless of its cause, DI during pregnancy is suggested by the output of large volumes (42.5 l/day) of hypotonic urine. If urine osmolarity is Xserum osmolarity, osmotic diuresis should be considered in the differential. A water deprivation test should be conducted to confirm the diagnosis of DI. The failure to decrease urinary volume or to increase urine osmolarity above 600 mOsm/l when serum osmolarity exceeds 295–300 mOsm/kg confirms the diagnosis of DI. Central DI can be distinguished from nephrogenic DI by the absence of biologically active AVP in vivo, although care must be taken in measuring AVP levels, as vasopressinase is extremely active in vitro,4 which may confuse the diagnosis. DI of pregnancy induced by placental vasopressinase is confirmed when the urine is concentrated in response to dDAVP but not in response to AVP.12 When DI of pregnancy is diagnosed, limited data suggest that dDAVP can be used safely to control urine output.13 Careful attention should be paid to serum osomolarity after administration of general anesthesia when access to water may be restricted. In this case, the normal responses to both dDAVP and water deprivation ruled out both nephrogenic and central DI and suggested a more unusual cause. Polydipsia, likely exacerbated by pregnancy-induced resetting of the thirst threshold, was ultimately felt to be the etiology and the patient was treated simply by allowing free access to water. Several studies have reported hypomagnesemia associated with pregnancy.14–18 Standley et al.19 followed 22 healthy women throughout their pregnancies and found that both total and ionized serum magnesium levels decreased with increasing gestational age, while sodium, potassium, total and ionized calcium levels remained unchanged. Handwerker et al.16 noted that healthy women in the latter stages of pregnancy had lower levels of both total and ionized magnesium compared to women in their first trimester. Many hypotheses have been proposed as a cause for this gestational ‘hypomagnesemia’, including hemodilution,19 extracellular volume expansion causing reduced magnesium resorption,20 and fetal consumption of magnesium.15 CLINICAL PERSPECTIVE AND CONCLUSIONS
Nephrologists caring for pregnant patients must be aware of the normal physiologic changes in the handling of water and electrolytes that occur during gestation. Osmotic disorders during pregnancy are simple to both diagnose and treat with water deprivation tests and vasopressin challenges as the cornerstones of diagnosis. Patients with a reset threshold for thirst can be reassured, while dDAVP can be administered to patients with vasopressinase-induced DI. Serum sodium should be carefully monitored when access to water is Kidney International (2006) 69, 938–941
the renal consult
SB Ahmed et al.: Pregnancy, polyuria, and hypomagnesemia
restricted as ongoing water losses in this setting of can be lifethreatening if unrecognized. Finally, a low serum magnesium level is not a cause for alarm as this appears to be physiologic in the setting of pregnancy.
10.
REFERENCES
13.
1. Blotner H, Kunkel P. Diabetes insipidus and pregnancy: report of two cases. N Engl J Med 1942; 227: 287–292. 2. McLaren CH, McLeod M. A case of diabetes insipidus in pregnancy. J Obstet Gynaecol Br Emp 1942; 49: 51–58. 3. Hime MC, Richardson JA. Diabetes insipidus and pregnancy. Case report, incidence and review of literature. Obstet Gynecol Surv 1978; 33: 375–379. 4. Lindheimer MD. Polyuria and pregnancy: its cause, its danger. Obstet Gynecol 2005; 105: 1171–1172. 5. Davison JM, Shiells EA, Philips PR, Lindheimer MD. Serial evaluation of vasopressin release and thirst in human pregnancy. Role of human chorionic gonadotrophin in the osmoregulatory changes of gestation. J Clin Invest 1988; 81: 798–806. 6. Hooper KC. The preparation of soluble vasopressinase from human placenta. Biochem J 1960; 74: 297–300. 7. Davison JM, Sheills EA, Philips PR et al. Metabolic clearance of vasopressin and an analogue resistant to vasopressinase in human pregnancy. Am J Physiol 1993; 264: F348–F353. 8. Barron WM, Cohen LH, Ulland LA et al. Transient vasopressin-resistant diabetes insipidus of pregnancy. N Engl J Med 1984; 310: 442–444. 9. Durr JA, Hoggard JG, Hunt JM, Schrier RW. Diabetes insipidus in pregnancy associated with abnormally high circulating vasopressinase activity. N Engl J Med 1987; 316: 1070–1074.
Kidney International (2006) 69, 938–941
11. 12.
14. 15.
16.
17.
18.
19.
20.
Lindheimer MD, Davison JM. Osmoregulation, the secretion of arginine vasopressin and its metabolism during pregnancy. Eur J Endocrinol 1995; 132: 133–143. Iwasaki Y, Oiso Y, Kondo K et al. Aggravation of subclinical diabetes insipidus during pregnancy. N Engl J Med 1991; 324: 522–526. Lindheimer MD, Barron WM, Davison JM. Osmoregulation of thirst and vasopressin release in pregnancy. Am J Physiol 1989; 257: F159–F169. Ray JG. DDAVP use during pregnancy: an analysis of its safety for mother and child. Obstet Gynecol Surv 1998; 53: 450–455. Kurzel RB. Serum magnesium levels in pregnancy and preterm labor. Am J Perinatol 1991; 8: 119–127. Handwerker SM, Altura BT, Royo B, Altura BM. Ionized serum magnesium levels in umbilical cord blood of normal pregnant women at delivery: relationship to calcium, demographics, and birthweight. Am J Perinatol 1993; 10: 392–397. Handwerker SM, Altura BT, Altura BM. Serum ionized magnesium and other electrolytes in the antenatal period of human pregnancy. J Am Coll Nutr 1996; 15: 36–43. Borella P, Szilagyi A, Than G et al. Maternal plasma concentrations of magnesium, calcium, zinc and copper in normal and pathological pregnancies. Sci Total Environ 1990; 99: 67–76. Seydoux J, Girardin E, Paunier L, Beguin F. Serum and intracellular magnesium during normal pregnancy and in patients with pre-eclampsia. Br J Obstet Gynaecol 1992; 99: 207–211. Standley CA, Whitty JE, Mason BA, Cotton DB. Serum ionized magnesium levels in normal and preeclamptic gestation. Obstet Gynecol 1997; 89: 24–27. de Rouffignac C, Morel F, Moss N, Roinel N. Micropuncture study of water and electrolyte movements along the loop of Henle in psammomys with special reference to magnesium, calcium and phosphorus. Pflugers Arch 1973; 344: 309–326.
941
http://www.kidney-international.org & 2006 International Society of Nephrology
A 39-year-old pregnant woman with polyuria and hypomagnesemia SB Ahmed1, JM Abi Rached2, AK Singh1 and DM Charytan1 1
Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA; and 2American University of Beirut, Beirut, Lebanon
CASE PRESENTATION A 39-year-old Caucasian G4P2 woman at 27 weeks gestation was admitted to the hospital with newly diagnosed dilated cardiomyopathy and non-sustained ventricular tachycardia. Her urine output was 2.5–7 l/24 h. Serum magnesium levels were low despite repletion with up to 160 mEq of oral and i.v. magnesium daily. She had completed two prior pregnancies uneventfully, but complained of thirst, polyuria, and nocturia predating the current pregnancy by approximately 2 years. There was no history of lithium or diuretic use, head trauma, or neurological deficits. Past medical and family history was otherwise unremarkable. Physical examination revealed a well-appearing pregnant woman. Blood pressure was 80/60, jugular venous pressure was flat, and there was minimal peripheral edema. Laboratory values are shown in Table 1. Responses to 1-deamino-8-arginine vasopressin (dDAVP) and a water-deprivation test are shown in Figures 1 and 2.
Correspondence: SB Ahmed, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, PBB-3, RA126E, Boston, Massachusetts 02115, USA. E-mail: [email protected] Kidney International (2006) 69, 938–941. doi:10.1038/sj.ki.5000256; published online 8 February 2006 Received 13 October 2005; revised 14 November 2005; accepted 30 November 2006; published online 8 February 2006 938
DIAGNOSIS
Decreased osmotic threshold for sensation of thirst, unmasked by pregnancy and exacerbated by a high osmolar load. CLINICAL FOLLOW-UP
Serum magnesium levels remained stable and urinary collections suggested that the majority of exogenous magnesium supplementation was being excreted in the urine. This was consistent with normal physiologic responses of pregnancy and further suggested that the persistent osmotic losses were exacerbating the polyuria. Magnesium supplementation was tapered and ultimately discontinued, and serum magnesium levels remained in the 1.5–1.8 mg/dl range: reference range 1.8–2.5 mg/dl (0.6–0.7 mmol/l: reference range 0.7–1.0). Urine output decreased to 2–5 l/24 h but remained high and the patient continued to complain of severe thirst. The possibility of a baseline or pregnancy-induced diabetes insipidus (DI) was considered. The patient was challenged with ddAVP and a water deprivation test was performed (Figures 1 and 2). In both tests, the patient demonstrated an ability to concentrate the urine to X600 mOsm/kg. These results confirmed the presence of intact central production of and nephrogenic response to vasopressin (AVP) and ruled out the possibility of clinically significant DI. Conversely, the patient complained of extreme thirst at serum osmolalities p285 mOsm/kg, which confirmed the suspicion of a reduced osmotic threshold for thirst. Following the water deprivation test, the patient was allowed ad-lib access to water. Hospitalization continued without any evidence of hypernatremia or volume depletion. Labor was induced and a healthy male infant was delivered uneventfully at 35 weeks. At 2 weeks post-partum, the patient continued to complain of thirst and palpitations but was otherwise well. Blood pressure was 90/50, and JVP flat. Laboratory values were as follows: serum sodium 140 mmol/l: reference range 136–142 mmol/l; potassium 4 mmol/l: reference range 3.5–5 mmol/l; chloride 107 mmol/l: reference range 98–108 mmol/l; bicarbonate 23 mmol/l: reference range 23–32 mmol/l; calcium 8.4 mg/dl: reference range 8.8–10.5 mg/dl (2.1 mmol/l: reference range 2.2–2.6 mmol/l); magnesium Kidney International (2006) 69, 938–941
the renal consult
SB Ahmed et al.: Pregnancy, polyuria, and hypomagnesemia
Table 1 | Laboratory values Value (reference range) Serum/blood Sodium Potassium Chloride Bicarbonate Glucose Urea nitrogen Creatinine Calcium Ionized calcium Magnesium Albumin Osmolality Antidiuretic hormone Diuretic screen
Serum osmolality (mOsm/kg)
sodium potassium calcium magnesium phosphate
H2O
Serum sodium 600
500
400 mmol/l
pH 5, specific gravity 1.008, neg blood, protein, glucose 247 mOsm/kg (390–1093) 5575 ml (600–1600) 1578 mg (800–1800) (139495 mmol (70 720–159 120)) 156 mmol (75–200) 127 mmol (40–80) 502 mmol (50–400) 797 mg (121–243) (32.8 mmol (5.0–10)) 931 mg (500–1200) (9.8 mmol (5.3–12))
Osmolality 24 h volume 24 h creatinine 24 h 24 h 24 h 24 h 24 h
700
136 mmol/l (136–142) 4.0 mmol/l (3.5–5.0) 105 mmol/l (98–108) 27 mmol/l (23–32) 74 mg/dl (54–118) (4.1 mmol/l (3.0–6.6)) 8 mg/dl (9–25) (2.9 mmol/l (3.2–8.9)) 0.5 mg/dl (0.7–1.3) (44.2 mmol/l (62–115)) 8.0 mg/dl (8.8–10.5) (2.0 mmol/l (2.2–2.6)) 1.14 mmol/l (1.13–1.32) 1.6 mg/dl (1.8–2.5) (0.7 mmol/l (0.78–1.2)) 3.4 g/dl (3.7–5.4) (34 g/l(37–54)) 283 mOsm/kg (278–297) oassay (0.0–4.7) Negative
Urine Urinalysis
Urine osmolality (mOsm/kg)
300
200
100 Urine osmolality (mOsm/kg)
700
Serum osmolality (mOsm/kg) 600
0 0
Serum sodium
1
2
3
4
5
Hours
Figure 2 | Response to H2O deprivation. 500
Table 2 | Osmoregulation in normal pregnancy Plasma sodium Plasma osmolarity AVP Metabolic clearance of AVP 24 h urine volume
mmol/l
400 DDAVP
Decreased by approximately 5 mEq/l Decreased by approximately 10 mOsm/kg 1–8 pg/ml (unchanged from nongravid state) 4-fold increase Unchanged from nongravid state
300
2.0 mg/dl: reference range 1.8–2.5 mg/dl (0.8 mmol/l: reference range 0.72–1.0 mmol/l); albumin 3.9 mg/dl: reference range 3.7–5.4 g/dl (39 g/l: reference range 37–54 g/l).
200
DISCUSSION
100
Figure 1 | Response to dDAVP.
The syndrome of DI is characterized by polyuria and polydipsia, and is associated with intense thirst due to the loss of concentrating ability by the kidney. If the patient has free access to water, the rise in the serum osmolality and serum sodium is often mitigated by the thirst sensation, but the urinary loss of water is obligate. The cause of the syndrome is due either to impaired secretion of AVP by the
Kidney International (2006) 69, 938–941
939
0 0
1
2
3 Hours
4
5
6
the renal consult
pituitary gland (central DI) or to an impaired renal response to AVP (nephrogenic DI). AVP activates the V2 receptor on the collecting duct cells in the kidney to stimulate water absorption. The first reports of transient polyuria and polydipsia associated with pregnancy appeared over 60 years ago,1,2 and it has since been estimated that DI complicates approximately 1/300 000 pregnancies.3 The occurrence of DI during pregnancy is not surprising, given the profound alterations in the regulation of plasma osmolality and thirst that occur during normal gestation (Table 2). Both serum sodium and plasma osmolality are known to drop by approximately 5 mEq/l and 10 mOsm/kg, respectively, during pregnancy.4 Similarly, in both rats and humans, the thresholds for vasopressin (AVP) release and thirst are reset in the normal gravid state. Human chorionic gonadotrophin may play a role in these osmoregulatory changes,5 but placental production of vasopressinase plays an important role during the third trimester.6 Davison et al.7 demonstrated that vasopressinase levels were measurable starting at week 10 of gestation and reached peak levels by 22–24 weeks. At 22–24 weeks of normal pregnancy, the metabolic clearance of AVP increases fourfold. Plasma levels of AVP remain in the normal range, indicating that an increased compensatory secretion of AVP by the pituitary gland matches the rate of its degradation. These changes in thirst, AVP release and AVP metabolism typically result in a self-limited decrease of approximately 10 mOsm/kg in serum osmolarity by the third trimester. However, in some cases, the changes can be profound. Barron et al.8 published a report of previously healthy women developing polyuria in the immediate puerperium unresponsive to large amounts of exogenously administered AVP. Because all symptoms resolved later on in the post-partum period, the authors termed the condition ‘transient vasopressin-resistant DI of pregnancy’, recognizing that increased destruction of AVP may have occurred, rather than simply increased renal resistance to the hormone. Durr et al.9 later reported a study on a patient with significant polyuria (up to 25 l/day) and hypernatremia in the puerperium who failed to concentrate her urine after administration of AVP. However, her urine osmolality increased to 800 mOsm/kg when dDAVP, an endogenous AVP analogue resistant to inactivation by vasopressinase that selectively activates the nonpressor V2 vasopressor receptor, was administered.7 High levels of circulating vasopressinase in the post-partum period suggested increased destruction of AVP by placental vasopressinase, although alterations in the kinetics of the enzyme has been offered as another explanation.4 Another disorder has been described where women with partial central DI, asymptomatic when nongravid, manifest polyuria after midpregnancy, coincident with the normal four-fold increase in AVP catabolism. This disorder remits postpartum.10 In addition, Iwasaki et al.11 studied two women in whom overt polyuria and polydipsia developed during the third trimester of pregnancy and disappeared 940
SB Ahmed et al.: Pregnancy, polyuria, and hypomagnesemia
after delivery. They reported not only an increase in the degradation of vasopressin during pregnancy but also an increased resistance at the level of the kidney to the action of AVP. They concluded that pregnancy may unmask subclinical forms of both nephrogenic and neurogenic DI. This exacerbation may result from both increased vasopressinase activity and diminished renal responsiveness to AVP. Regardless of its cause, DI during pregnancy is suggested by the output of large volumes (42.5 l/day) of hypotonic urine. If urine osmolarity is Xserum osmolarity, osmotic diuresis should be considered in the differential. A water deprivation test should be conducted to confirm the diagnosis of DI. The failure to decrease urinary volume or to increase urine osmolarity above 600 mOsm/l when serum osmolarity exceeds 295–300 mOsm/kg confirms the diagnosis of DI. Central DI can be distinguished from nephrogenic DI by the absence of biologically active AVP in vivo, although care must be taken in measuring AVP levels, as vasopressinase is extremely active in vitro,4 which may confuse the diagnosis. DI of pregnancy induced by placental vasopressinase is confirmed when the urine is concentrated in response to dDAVP but not in response to AVP.12 When DI of pregnancy is diagnosed, limited data suggest that dDAVP can be used safely to control urine output.13 Careful attention should be paid to serum osomolarity after administration of general anesthesia when access to water may be restricted. In this case, the normal responses to both dDAVP and water deprivation ruled out both nephrogenic and central DI and suggested a more unusual cause. Polydipsia, likely exacerbated by pregnancy-induced resetting of the thirst threshold, was ultimately felt to be the etiology and the patient was treated simply by allowing free access to water. Several studies have reported hypomagnesemia associated with pregnancy.14–18 Standley et al.19 followed 22 healthy women throughout their pregnancies and found that both total and ionized serum magnesium levels decreased with increasing gestational age, while sodium, potassium, total and ionized calcium levels remained unchanged. Handwerker et al.16 noted that healthy women in the latter stages of pregnancy had lower levels of both total and ionized magnesium compared to women in their first trimester. Many hypotheses have been proposed as a cause for this gestational ‘hypomagnesemia’, including hemodilution,19 extracellular volume expansion causing reduced magnesium resorption,20 and fetal consumption of magnesium.15 CLINICAL PERSPECTIVE AND CONCLUSIONS
Nephrologists caring for pregnant patients must be aware of the normal physiologic changes in the handling of water and electrolytes that occur during gestation. Osmotic disorders during pregnancy are simple to both diagnose and treat with water deprivation tests and vasopressin challenges as the cornerstones of diagnosis. Patients with a reset threshold for thirst can be reassured, while dDAVP can be administered to patients with vasopressinase-induced DI. Serum sodium should be carefully monitored when access to water is Kidney International (2006) 69, 938–941
the renal consult
SB Ahmed et al.: Pregnancy, polyuria, and hypomagnesemia
restricted as ongoing water losses in this setting of can be lifethreatening if unrecognized. Finally, a low serum magnesium level is not a cause for alarm as this appears to be physiologic in the setting of pregnancy.
10.
REFERENCES
13.
1. Blotner H, Kunkel P. Diabetes insipidus and pregnancy: report of two cases. N Engl J Med 1942; 227: 287–292. 2. McLaren CH, McLeod M. A case of diabetes insipidus in pregnancy. J Obstet Gynaecol Br Emp 1942; 49: 51–58. 3. Hime MC, Richardson JA. Diabetes insipidus and pregnancy. Case report, incidence and review of literature. Obstet Gynecol Surv 1978; 33: 375–379. 4. Lindheimer MD. Polyuria and pregnancy: its cause, its danger. Obstet Gynecol 2005; 105: 1171–1172. 5. Davison JM, Shiells EA, Philips PR, Lindheimer MD. Serial evaluation of vasopressin release and thirst in human pregnancy. Role of human chorionic gonadotrophin in the osmoregulatory changes of gestation. J Clin Invest 1988; 81: 798–806. 6. Hooper KC. The preparation of soluble vasopressinase from human placenta. Biochem J 1960; 74: 297–300. 7. Davison JM, Sheills EA, Philips PR et al. Metabolic clearance of vasopressin and an analogue resistant to vasopressinase in human pregnancy. Am J Physiol 1993; 264: F348–F353. 8. Barron WM, Cohen LH, Ulland LA et al. Transient vasopressin-resistant diabetes insipidus of pregnancy. N Engl J Med 1984; 310: 442–444. 9. Durr JA, Hoggard JG, Hunt JM, Schrier RW. Diabetes insipidus in pregnancy associated with abnormally high circulating vasopressinase activity. N Engl J Med 1987; 316: 1070–1074.
Kidney International (2006) 69, 938–941
11. 12.
14. 15.
16.
17.
18.
19.
20.
Lindheimer MD, Davison JM. Osmoregulation, the secretion of arginine vasopressin and its metabolism during pregnancy. Eur J Endocrinol 1995; 132: 133–143. Iwasaki Y, Oiso Y, Kondo K et al. Aggravation of subclinical diabetes insipidus during pregnancy. N Engl J Med 1991; 324: 522–526. Lindheimer MD, Barron WM, Davison JM. Osmoregulation of thirst and vasopressin release in pregnancy. Am J Physiol 1989; 257: F159–F169. Ray JG. DDAVP use during pregnancy: an analysis of its safety for mother and child. Obstet Gynecol Surv 1998; 53: 450–455. Kurzel RB. Serum magnesium levels in pregnancy and preterm labor. Am J Perinatol 1991; 8: 119–127. Handwerker SM, Altura BT, Royo B, Altura BM. Ionized serum magnesium levels in umbilical cord blood of normal pregnant women at delivery: relationship to calcium, demographics, and birthweight. Am J Perinatol 1993; 10: 392–397. Handwerker SM, Altura BT, Altura BM. Serum ionized magnesium and other electrolytes in the antenatal period of human pregnancy. J Am Coll Nutr 1996; 15: 36–43. Borella P, Szilagyi A, Than G et al. Maternal plasma concentrations of magnesium, calcium, zinc and copper in normal and pathological pregnancies. Sci Total Environ 1990; 99: 67–76. Seydoux J, Girardin E, Paunier L, Beguin F. Serum and intracellular magnesium during normal pregnancy and in patients with pre-eclampsia. Br J Obstet Gynaecol 1992; 99: 207–211. Standley CA, Whitty JE, Mason BA, Cotton DB. Serum ionized magnesium levels in normal and preeclamptic gestation. Obstet Gynecol 1997; 89: 24–27. de Rouffignac C, Morel F, Moss N, Roinel N. Micropuncture study of water and electrolyte movements along the loop of Henle in psammomys with special reference to magnesium, calcium and phosphorus. Pflugers Arch 1973; 344: 309–326.
941