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Home , Antidiuretic, Demeclocycline, Diabetes insipidus

REVIEW

AMGAD N. MAKARYUS, MD SAMY I. McFARLANE, MD, MPH CME North Shore University Hospital, New York University State University of New York-Downstate and Kings CREDIT School of Medicine, Manhasset, NY County Hospital Center, Brooklyn, NY

Diabetes insipidus: Diagnosis and treatment of a complex

■ ABSTRACT ATIENTS WHO PRESENT with P insipidus need immediate care because , characterized by of copious the body’s delicate water and bal- volumes of dilute urine, can be life-threatening if not ance is threatened. It is essential to perform a properly diagnosed and managed. It can be caused by knowledgeable assessment based on character- two fundamentally different defects: inadequate or izing features, intervene rapidly with the prop- impaired secretion of hormone (ADH) from er treatment, and continue to reevaluate the the posterior (neurogenic or central patient’s condition. diabetes insipidus) or impaired or insufficient renal Complicating matters, the proper treat- response to ADH (nephrogenic diabetes insipidus). The ment depends on the cause in the individual distinction is essential for effective treatment. patient. Therefore, the must deter- mine whether the defect is in the brain or in ■ KEY POINTS the . ■ Urine osmolality is easy to measure and helps in INABILITY TO CONSERVE WATER determining whether is due to diabetes insipidus or another condition. Diabetes insipidus is caused by the inability to conserve water and maintain an optimum free water level. The kidneys pass large The water deprivation test can help in distinguishing amounts of dilute urine regardless of the central diabetes insipidus from nephrogenic diabetes body’s hydration state, leading to symptoms of insipidus. extraordinary , copious water intake (up to 20 liters per day), dry skin, and constipa- ADH preparations are used in treating central diabetes tion. insipidus but do not help in nephrogenic diabetes Two very different mechanisms can cause insipidus. diabetes insipidus (FIGURE 1): • Inadequate release of antidiuretic hor- Nephrogenic diabetes insipidus is treated by correcting mone (ADH, also called ) and hypercalcemia and by discontinuing any from the (central diabetes drugs that may be causing it. are also insipidus) and • Inadequate response of the kidney to used. ADH (nephrogenic diabetes insipidus). The distinction is essential, since the treatment is different for the two causes, and is best achieved by a combination of hormonal and clinical observations.1–3

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T ABLE 1 osmolality is then measured 30 and 60 minutes later. Plasma osmolality is also measured at var- Causes of central ious points during the test. diabetes insipidus In normal subjects and patients with psy- Injury to the central nervous system chogenic diabetes insipidus (ie, due to mental Neoplastic/autoimmune disease disturbances that lead to excess fluid intake, Hypothalamic or pituitary surgery or ischemia which suppresses ADH secretion), the urine Radiation to the brain osmolality is greater than the plasma osmolal- : meningitis, encephalitis ity following fluid restriction, and the urine Cerebral edema osmolality increases only minimally (< 10%) Intracranial hemorrhage after ADH injection. Familial disease In central diabetes insipidus, urine osmo- Idiopathic* lality remains less than plasma osmolality after . After ADH injection, urine *Some cases may be due to autoimmune or genetic osmolality increases by more than 50%. disorders or psychogenic In nephrogenic diabetes insipidus, urine osmolality remains less than plasma osmolali- ty; after giving ADH, urine osmolality increas- es by less than 50%.2,3 ■ EVALUATING POLYURIA, DIAGNOSING DIABETES INSIPIDUS ■ CENTRAL DIABETES INSIPIDUS

Polyuria is defined as urine volume of more Central diabetes insipidus results from any than 3 liters in 24 hours. The history is essen- condition that impairs the synthesis, trans- tial in differentiating diabetes insipidus from port, and release of ADH. It occurs in both other causes of polyuria and in determining sexes equally and affects all ages, with the the cause of diabetes insipidus. most frequent age of onset between 10 and 20 In central Urine osmolality is an easy differentiating years. diabetes test. A urine osmolality of 300 mOsmol/kg or The main evidence of ill health is polyuria more plus a high serum glucose level points to and polydipsia (besides the symptoms from the insipidus, thirst the diagnosis of diabetes mellitus; high urine underlying disease that damaged the neurohy- is so extreme osmolality plus high serum points to renal pophyseal system in the first place). Water disease. If the urine osmolality is less than 200 deprivation for even a short time results in it wakens the mOsmol/kg in the presence of polyuria, then rapid dehydration and compulsive thirst. The patient at night diabetes insipidus is present. A water depriva- thirst is so extreme that it even awakens the tion test, although not required for the diag- patient during the night. nosis of diabetes insipidus, is helpful in differ- The complete form of the disease is less entiating between central and nephrogenic common than a more moderate partial form diabetes insipidus. with only moderately excessive . As The water deprivation test, which should long as the thirst center remains intact and be done only by experienced , the patient can seek water, the osmotic con- involves withholding all fluids until the patient centration of plasma usually remains around is sufficiently dehydrated to provide a potent values only slightly exceeding 290 mOsm/kg stimulus for ADH secretion. Deprivation lasts 4 (normal value 280–295 mOsm/kg).1 to 18 hours, with hourly measurements of body weight and urine osmolality, until two or three Causes of central diabetes insipidus consecutive samples vary by less than 30 The causes of central diabetes insipidus mOsm/kg (or < 10%) or until the patient loses (TABLE 1) can be divided into three major cat- 5% of his or her body weight. At this point, the egories. serum ADH level is measured, and then 5 units Damage to the hypothalamo-neurohy- of ADH or 1 µg of (DDAVP, a pophyseal region due to head trauma, surgery, synthetic analogue of ADH) is injected. Urine or primary or metastatic tumors.1–3

66 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 73 • NUMBER 1 JANUARY 2006 ■ Two different mechanisms of diabetes insipidus

Diabetes insipidus, characterized by excretion of copious volumes of dilute urine, can be caused by a variety of defects that fall into two broad categories: central and nephrogenic.

Central diabetes insipidus results from any condition (injury, genetic defect, or idiopathic cause) that impairs the synthesis, transport, or release of antidiuretic hormone (ADH; TABLE 1). ADH is normally produced in the hypothalamus and travels along nerve fibers to the , where it is stored and released.

Increased plasma osmolality normally Posterior stimulates release of ADH. If urine pituitary osmolality remains lower than plasma osmolality during fluid restriction, the patient may have central diabetes insipidus.

ADH normally promotes reabsorption of water in the collecting duct of nephrons. If urine osmolality does not increase after injection of exogenous ADH, the patient may have nephrogenic diabetes inispidus.

Nephrogenic diabetes insipidus results from inability of the kidneys to respond to ADH, owing to , drug toxicity, or other causes H2O (TABLE 2).

Collecting duct

CCF Medical Illustrator: Beth Halasz ©2006 FIGURE 1

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Damage to the proximal part of this sensi- gliosis of variable numbers of supraoptic and tive region kills more neurons of the hypo- paraventricular nuclei, usually accompanied thalamo-neurohypophyseal tract than do dis- by a small posterior pituitary gland.4 tal injuries. Proximal lesions account for 30% to 40% of all cases of posttraumatic and post- Treatment of central diabetes insipidus operative diabetes insipidus, whereas distal Water is essential: in sufficient quantity, it lesions (below the median eminence) account will correct any metabolic abnormality due to for 50% to 60%. With the low (distal) lesions, excessive dilute urine. only a small proportion of magnocellular neu- ADH replacement. The earliest available rons degenerate, and intact cell bodies are preparation of ADH was a crude acetone dried able, over weeks to months, to regenerate new extract from bovine or porcine posterior pitu- axonal terminals at the level of the portal ves- itary, given by nasal insufflation. Problems sels of the median eminence.4 with this preparation included variable dura- Identification of the anatomical location tion of activity and local irritation of the nasal in the brain of the area of neuronal damage is mucosa. often helpful and necessary in the assessment Subsequently, a more purified preparation of the functional significance of the lesion. of ADH was developed, known as Pitressin This is performed with magnetic resonance (vasopressin tannate in oil). This is given intra- imaging of the hypothalamus and pituitary. muscularly every 2 to 4 days and provides relief Idiopathic cases may actually have an for 24 to 72 hours. Its side effects include identifiable cause. In the few autopsy series abdominal cramping, hypertension, and angina. performed in patients with this form of central The disadvantages of these preparations diabetes insipidus, there were reports of prompted the development of oral agents to atrophic neurohypophyses as well as supraop- aid in antidiuresis. tic and paraventricular nuclei. Other reports Desmopressin (1-deamino-8-D-arginine have noted circulating antibodies against vasopressin, DDAVP) is the current drug of ADH-secreting hypothalamic neurons, sug- choice for long-term therapy of central dia- Desmopressin gesting an autoimmune variant of this dis- betes insipidus.8 It can be given parenterally, is the current ease.4 orally, or intranasally. For all dosage forms, the Genetic. Some of the idiopathic forms of starting dosage is 10 µg at night to relieve noc- drug of central diabetes insipidus have recently been turia. A morning dose can be added if symp- choice for ascribed to a newly discovered mutation in the toms persist during the day. The duration of neurophysin II coding region of the ADH effect of this synthetic peptide is well repro- central gene.5,6 Exons 1 and 3 are normal, but in exon ducible in an individual. Therefore, desmo- diabetes 2, thymine is substituted for guanine at pressin dosage and scheduling should be insipidus nucleotide 1884. This in turn induces a substi- adjusted individually according to the degree tution of a glycine for a valine in the ADH of polyuria. molecule. Affected patients have both normal Chlorpropamide (Diabinese), an antidi- and mutant alleles, indicating that this muta- abetes drug, decreases the clearance of solute- tion is heterozygous. Accumulation of abnor- free water, but only if the neurohypophysis mal ADH in the posterior pituitary cells leads has some residual secretory capacity. Its anti- to destruction of the entire cell and the clini- effect is likely due to raising the sen- cal syndrome of diabetes insipidus. sitivity of the epithelium of the collecting Another form of familial central diabetes duct to low concentrations of circulating insipidus may be due to a substitution of ADH. valine for alanine in the gene for the signal (Tegretol), an anticon- peptide for ADH-neurophysin II/copeptide vulsant, reduces the sensitivity of the precursor.7 osmoregulatory system of ADH secretion and Hereditary forms account for only 1% to simultaneously raises the sensitivity of the col- 2% of all cases of central diabetes insipidus, lecting duct to the hydro-osmotic action of and autopsy findings in these cases have con- the hormone. sistently shown neuronal degeneration and Clofibrate (Atromid-S), a lipid-lowering

68 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 73 • NUMBER 1 JANUARY 2006 agent, stimulates residual ADH production in TABLE 2 patients with partial central diabetes insipidus. Chlorpropamide, carbamazepine, Causes of nephrogenic and clofibrate all can be used in cases of par- diabetes insipidus 9,10 tial central diabetes insipidus. Acquired Thiazide diuretics paradoxically can be Renal disease used for treating central diabetes insipidus. Chronic renal failure They exert their effect by decreasing Chronic renal medullary disease and chloride absorption in the distal tubule, therefore allowing more sodium absorption— Obstructive uropathy and therefore water absorption—in the proxi- Polycystic kidney disease mal tubule.9,10 Renal transplantation After starting one of the above agents, it Electrolyte disturbances is important to monitor the efficacy of the Chronic hypokalemia Chronic hypercalcemia therapy. This is easily performed by follow-up of electrolyte values. Drugs Amphotericin B ■ NEPHROGENIC DIABETES INSIPIDUS Colchicine In nephrogenic diabetes insipidus, the poste- rior pituitary is hyperstimulated because of Loop diuretics increased plasma osmolality and produces a Methoxyflurane sufficient amount of ADH, but the kidneys cannot produce maximally concentrated Multiple myeloma urine in response to it. Sickle cell disease Nephrogenic diabetes insipidus can be Protein starvation characterized by three main disturbances in Familial kidney function: V2 receptor mutation (X-linked) Mutations • Disturbance of the generation or mainte- -2 mutation (autosomal-recessive) that cause nance (or both) of the corticomedullary osmotic gradient, which is the driving force diabetes for the osmotic water flow from collecting insipidus ducts into the interstitial tissue Acquired forms • Disturbance of osmotic equilibration of nephrogenic diabetes insipidus have been between the tubular contents and the Acquired forms are more common than familial discovered medullary interstitium due to a defect of the forms. The kidney is structurally or functionally proximal component of the ADH-cyclic altered, either permanently or transiently, by dis- adenosine monophosphate system or the dis- ease (the most common cause), drugs, or other tal component or both conditions so that it is less sensitive to ADH. • Osmotic diuresis, which produces rapid Among the systemic circumstances lead- flow of the tubular fluid and thus prevents its ing to acquired nephrogenic diabetes insipidus complete osmotic equilibration with the are hypokalemia, hypercalcemia, various types medullary interstitium.1,4 of renal disease, and sickle cell anemia. The degree of disease varies among Hypokalemia. depletion due to patients. In patients with the complete form, insufficient dietary intake or due to losses (eg, the urine osmolality remains consistently in gastroenteritis) is usually associated with lower than the plasma osmolality, while in the development of polyuria, polydipsia, and a partial forms of the syndrome the urine osmo- renal concentrating defect that is resistant to lality can be considerably higher.4 ADH. The many causes of nephrogenic diabetes Two mechanisms have been proposed to insipidus can be divided into two categories: explain the diuresis seen in potassium deple- acquired and familial (TABLE 2). tion: an alteration of the generation and

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maintenance of the medullary osmotic gradi- Gentamicin seems to impair the cellular ent and resistance of the collecting ducts to response to ADH. the hydro-osmotic effect of ADH. Colchicine inhibits the action of the sec- Chronic hypercalcemia may result in ond messenger by disrupting microtubule renal interstitial calcification and fibrosis with function. secondary anatomic disruption of the renal Loop diuretics have been shown to wors- concentrating mechanism, which therefore en renal function in some cases.1 produces large amounts of dilute urine. Foscarnet, which is used to treat Advanced chronic renal failure in most of cytomegalovirus infection, has recently been its forms features a defect in the renal concen- shown to cause nephrogenic diabetes insipidus trating capacity, as does sickle cell anemia.2–4 in certain patients.12 Pregnancy is yet another cause: during pregnancy, vasopressinase produced by the Familial nephrogenic diabetes insipidus can destroy ADH too rapidly. This Familial nephrogenic diabetes insipidus is rare type of ADH deficiency often disappears 4 to and can be caused by two different genetic 6 weeks after delivery, but often recurs with defects. subsequent . V2 receptor mutations. Mutations in the gene encoding the ADH type 2 receptor (V2 Drug-induced diabetes insipidus receptor) cause an X-linked form of the dis- A variety of widely used drugs can cause ease. More than 60 different disease-causing acquired nephrogenic diabetes insipidus. mutations have been identified throughout Lithium salts cause polydipsia and the V2 receptor gene.13 polyuria at the start of treatment in as many as Aquaporin-2 mutations. Mutations in 60% of patients, and these side effects persist in the gene encoding the ADH-dependent 20% to 25% even if plasma lithium levels are water channel aquaporin-2 are responsible within the therapeutic range. In one reported for an autosomal-recessive form, and in some case, a patient undergoing chronic lithium cases an autosomal-dominant type of the dis- Thiazide therapy presented with transient central dia- ease. The conformational change in the diuretics can betes insipidus on top of underlying chronic aquaporin-2 channel leads to improper fluid nephrogenic diabetes insipidus.11 Lithium salts exchange in the distal collecting system and paradoxically have been proposed as a treatment for the polyuria.13 Autosomal-recessive nephrogenic improve chronic syndrome of inappropriate secretion of diabetes insipidus appears in 10% of families. ADH, but another agent, demeclocycline, has In these patients, a normal extrarenal diabetes been proven to be more effective.4 response to ADH is observed, indicating insipidus Demeclocycline, an of the unresponsiveness to ADH restricted to the group, is commonly used by der- kidney. matologists to treat . In high doses Earm et al14 examined the effect of hyper- (900–1,200 mg/day), demeclocycline induces calcemia on the expression of aquaporin-2 in polyuria and polydipsia. These side effects rat kidneys. They found that hypercalcemia might not manifest themselves in the first days decreased the expression of aquaporin-2 in the or weeks of use, and complete restoration of inner medulla and cortex of the kidneys, and renal function usually requires several weeks they concluded that aquaporin-2 downregula- after the drug is stopped. tion and reduced plasma membrane delivery Both lithium salts and demeclocycline are of aquaporin-2 play important roles in the thought to affect renal function by disturbing development of polyuria in association with some aspect of the proximal component of the hypercalcemia. ADH-cyclic adenosine monophosphate sec- The way to distinguish between patients ond-messenger system.4 with a V2 receptor defect and those with an Amphotericin B, a potent antifungal aquaporin-2 defect is with a trial of desmo- agent, is nephrotoxic. It disturbs the genera- pressin therapy: those with an aquaporin-2 tion and maintenance of the medullary osmot- defect will have a response to desmopressin, ic gradient in the kidney. but those with a V2 receptor defect will not.13

70 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 73 • NUMBER 1 JANUARY 2006 Treatment of nephrogenic diabetes insipidus Thiazide diuretics are used along with Treating nephrogenic diabetes insipidus modest salt restriction to reduce the delivery involves a different regimen than for central of filtrate to the diluting segments of the diabetes insipidus. Nephrogenic diabetes nephron. They exert their effect by decreasing insipidus does not respond to ADH; instead, it sodium and chloride absorption in the distal is treated by correcting hypokalemia and tubule, thereby allowing more sodium absorp- hypercalcemia and by discontinuing any drugs tion and therefore more water absorption in that may be causing it. the .10,15

■ REFERENCES 9. Gregerman RI. Selected endocrine problems. In: Barker LR, Burton JR, Zieve PD, editors. Principles of Ambulatory Medicine, 3rd edition. 1. Cagno JM. Diabetes insipidus. Crit Care Nurse 1989; 9:86–93. Baltimore, MD: Williams and Wilkins Publishers, 1991:997–998. 2. Singer I, Oster JR, Fishman LM. The management of diabetes 10. Seckl JR, Dunger DB. Diabetes insipidus. Current treatment recom- insipidus in adults. Arch Intern Med 1997; 157:1293–1301. mendations. Drugs 1992; 44:216–224. 3. Adam P. Evaluation and management of diabetes insipidus. Am Fam 11. Posner L, Mokrzycki MH. Transient central diabetes insipidus in the Physician 1997; 55:2146–2153. setting of underlying nephrogenic diabetes insipidus associated with 4. Kovacs L, Lichardus B. Vasopressin, Disturbed Secretion and Its Effects. lithium use. Am J Nephrol 1996; 16:339–343. Prague: Kluwer Academic Publishers, 1989. 12. Navarro JF, Quereda C, Quereda C, et al. Nephrogenic diabetes 5. Ueta Y, Taniguchi S, Yoshida A, et al. A new type of familial central insipidus and secondary to foscarnet therapy. diabetes insipidus caused by a single base substitution in the neuro- Am J Kidney Dis 1996; 27:431–434. physin II coding region of the vasopressin gene. J Clin Endocrinol 13. Knoers NV, van Os CH. Molecular and cellular defects in nephrogenic Metab 1996; 81:1787–1790. diabetes insipidus. Curr Opin Nephrol Hypertens 1996; 5:353–358. 6. Rauch F, Lenzner C, Nurnberg P, Frommel C, Vetter U. A novel muta- 14. Earm JH, Christensen BM, Frokiaer J, et al. Decreased aquaporin-2 tion in the coding region for neurophysin-II is associated with autoso- expression and apical plasma membrane delivery in kidney collecting mal dominant neurohypophyseal diabetes insipidus. Clin Endocrinol ducts of polyuric hypercalcemic rats. J Am Soc Nephrol 1998; (Oxf) 1996; 44:45–51. 9:2181–2193. 7. Repaske DR, Medlej R, Gultekin EK, et al. Heterogeneity in clinical 15. Kim GH, Lee JW, Oh YK, et al. Antidiuretic effect of hydrochloro- manifestation of autosomal dominant neurohypophyseal diabetes thiazide in lithium-induced nephrogenic diabetes insipidus is associat- insipidus caused by a mutation encoding Ala-1 —> Val in the signal ed with upregulation of aquaporin-2, Na-Cl co-transporter, and peptide of the arginine vasopressin/neurophysin II/ precursor. epithelial sodium channel. J Am Soc Nephrol 2004; 15:2836–2843. J Clin Endocrinol Metab 1997; 82:51–56. 8. Lam KS, Wat MS, Choi KL, Ip TP, Pang RW, Kumana CR. ADDRESS: Samy I. McFarlane, MD, Department of Medicine, Box 50, State , pharmacodynamics, long-term efficacy, and safety University of New York Health Science Center at Brooklyn, Kings County of oral 1-deamino-8-D-arginine vasopressin in adult patients with cen- Hospital Center, 450 Clarkson Avenue, Brooklyn, NY 11203; e-mail tral diabetes insipidus. Br J Clin Pharmacol 1996; 42:379–385. [email protected].

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