Cleveland Clinic Journal of Medicine 2006 Makaryus 65 71

CLEVELAND CL IN IC JOURNAL OF MEDICINE VOLUME 73 • NUMBER 1 JANUARY 2006 65

AMGAD N. MAKARYUS, MDNorth Shore University Hospital, New York UniversitySchool of Medicine, Manhasset, NY

SAMY I. McFARLANE, MD, MPHState University of New York-Downstate and KingsCounty Hospital Center, Brooklyn, NY

Diabetes insipidus:Diagnosis and treatmentof a complex disease

REVIEW

■ ABSTRACT

Diabetes insipidus, characterized by excretion of copiousvolumes of dilute urine, can be life-threatening if notproperly diagnosed and managed. It can be caused bytwo fundamentally different defects: inadequate orimpaired secretion of antidiuretic hormone (ADH) fromthe posterior pituitary gland (neurogenic or centraldiabetes insipidus) or impaired or insufficient renalresponse to ADH (nephrogenic diabetes insipidus). Thedistinction is essential for effective treatment.

■ KEY POINTS

Urine osmolality is easy to measure and helps indetermining whether polyuria is due to diabetes insipidusor another condition.

The water deprivation test can help in distinguishingcentral diabetes insipidus from nephrogenic diabetesinsipidus.

ADH preparations are used in treating central diabetesinsipidus but do not help in nephrogenic diabetesinsipidus.

Nephrogenic diabetes insipidus is treated by correctinghypokalemia and hypercalcemia and by discontinuing anydrugs that may be causing it. Thiazide diuretics are alsoused.

ATIENTS WHO PRESENT with diabetesinsipidus need immediate care because

the body’s delicate water and electrolyte bal-ance is threatened. It is essential to perform aknowledgeable assessment based on character-izing features, intervene rapidly with the prop-er treatment, and continue to reevaluate thepatient’s condition.

Complicating matters, the proper treat-ment depends on the cause in the individualpatient. Therefore, the physician must deter-mine whether the defect is in the brain or inthe kidney.

■ INABILITY TO CONSERVE WATER

Diabetes insipidus is caused by the inability toconserve water and maintain an optimumfree water level. The kidneys pass largeamounts of dilute urine regardless of thebody’s hydration state, leading to symptoms ofextraordinary thirst, copious water intake (upto 20 liters per day), dry skin, and constipa-tion.

Two very different mechanisms can causediabetes insipidus (FIGURE 1):• Inadequate release of antidiuretic hor-

mone (ADH, also called vasopressin)from the hypothalamus (central diabetesinsipidus) and

• Inadequate response of the kidney toADH (nephrogenic diabetes insipidus).The distinction is essential, since the

treatment is different for the two causes, and isbest achieved by a combination of hormonaland clinical observations.1–3

P

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66 CLEVELAND CL IN IC JOURNAL OF MEDICINE VOLUME 73 • NUMBER 1 JANUARY 2006

■ EVALUATING POLYURIA,DIAGNOSING DIABETES INSIPIDUS

Polyuria is defined as urine volume of morethan 3 liters in 24 hours. The history is essen-tial in differentiating diabetes insipidus fromother causes of polyuria and in determiningthe cause of diabetes insipidus.

Urine osmolality is an easy differentiatingtest. A urine osmolality of 300 mOsmol/kg ormore plus a high serum glucose level points tothe diagnosis of diabetes mellitus; high urineosmolality plus high serum urea points to renaldisease. If the urine osmolality is less than 200mOsmol/kg in the presence of polyuria, thendiabetes insipidus is present. A water depriva-tion test, although not required for the diag-nosis of diabetes insipidus, is helpful in differ-entiating between central and nephrogenicdiabetes insipidus.

The water deprivation test, which shouldbe done only by experienced physicians,involves withholding all fluids until the patientis sufficiently dehydrated to provide a potentstimulus for ADH secretion. Deprivation lasts 4to 18 hours, with hourly measurements of bodyweight and urine osmolality, until two or threeconsecutive samples vary by less than 30mOsm/kg (or < 10%) or until the patient loses5% of his or her body weight. At this point, theserum ADH level is measured, and then 5 unitsof ADH or 1 µg of desmopressin (DDAVP, asynthetic analogue of ADH) is injected. Urine

osmolality is then measured 30 and 60 minuteslater. Plasma osmolality is also measured at var-ious points during the test.

In normal subjects and patients with psy-chogenic diabetes insipidus (ie, due to mentaldisturbances that lead to excess fluid intake,which suppresses ADH secretion), the urineosmolality is greater than the plasma osmolal-ity following fluid restriction, and the urineosmolality increases only minimally (< 10%)after ADH injection.

In central diabetes insipidus, urine osmo-lality remains less than plasma osmolality afterdehydration. After ADH injection, urineosmolality increases by more than 50%.

In nephrogenic diabetes insipidus, urineosmolality remains less than plasma osmolali-ty; after giving ADH, urine osmolality increas-es by less than 50%.2,3

■ CENTRAL DIABETES INSIPIDUS

Central diabetes insipidus results from anycondition that impairs the synthesis, trans-port, and release of ADH. It occurs in bothsexes equally and affects all ages, with themost frequent age of onset between 10 and 20years.

The main evidence of ill health is polyuriaand polydipsia (besides the symptoms from theunderlying disease that damaged the neurohy-pophyseal system in the first place). Waterdeprivation for even a short time results inrapid dehydration and compulsive thirst. Thethirst is so extreme that it even awakens thepatient during the night.

The complete form of the disease is lesscommon than a more moderate partial formwith only moderately excessive diuresis. Aslong as the thirst center remains intact andthe patient can seek water, the osmotic con-centration of plasma usually remains aroundvalues only slightly exceeding 290 mOsm/kg(normal value 280–295 mOsm/kg).1

Causes of central diabetes insipidusThe causes of central diabetes insipidus(TABLE 1) can be divided into three major cat-egories.

Damage to the hypothalamo-neurohy-pophyseal region due to head trauma, surgery,or primary or metastatic tumors.1–3

In centraldiabetesinsipidus, thirstis so extremeit wakens thepatient at night

DIABETES INSIPIDUS MAKARYUS AND McFARLANE

Causes of centraldiabetes insipidus

Injury to the central nervous systemNeoplastic/autoimmune diseaseHypothalamic or pituitary surgery or ischemiaRadiation to the brainInfection: meningitis, encephalitisCerebral edemaIntracranial hemorrhage

Familial diseaseIdiopathic*

*Some cases may be due to autoimmune or geneticdisorders or psychogenic polydipsia

T A B L E 1




FIGURE 1

CCF©2006

■ Two different mechanisms of diabetes insipidus

Medical Illustrator: Beth Halasz

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

Central diabetes insipidus results from anycondition (injury, genetic defect, or idiopathiccause) that impairs the synthesis, transport, orrelease of antidiuretic hormone (ADH; TABLE 1).

ADH is normally produced inthe hypothalamus and travels alongnerve fibers to the posterior pituitary,where it is stored and released.

Increased plasma osmolality normallystimulates release of ADH. If urineosmolality remains lower than plasmaosmolality during fluid restriction, thepatient may have central diabetesinsipidus.

ADH normally promotes reabsorptionof water in the collecting duct of nephrons.If urine osmolality does not increase afterinjection of exogenous ADH, the patient mayhave nephrogenic diabetes inispidus.

Nephrogenic diabetes insipidus results frominability of the kidneys to respond to ADH, owingto kidney disease, drug toxicity, or other causes(TABLE 2).

H2O

Posteriorpituitary

Collectingduct




Damage to the proximal part of this sensi-tive region kills more neurons of the hypo-thalamo-neurohypophyseal tract than do dis-tal injuries. Proximal lesions account for 30%to 40% of all cases of posttraumatic and post-operative diabetes insipidus, whereas distallesions (below the median eminence) accountfor 50% to 60%. With the low (distal) lesions,only a small proportion of magnocellular neu-rons degenerate, and intact cell bodies areable, over weeks to months, to regenerate newaxonal terminals at the level of the portal ves-sels of the median eminence.4

Identification of the anatomical locationin the brain of the area of neuronal damage isoften helpful and necessary in the assessmentof the functional significance of the lesion.This is performed with magnetic resonanceimaging of the hypothalamus and pituitary.

Idiopathic cases may actually have anidentifiable cause. In the few autopsy seriesperformed in patients with this form of centraldiabetes insipidus, there were reports ofatrophic neurohypophyses as well as supraop-tic and paraventricular nuclei. Other reportshave noted circulating antibodies againstADH-secreting hypothalamic neurons, sug-gesting an autoimmune variant of this dis-ease.4

Genetic. Some of the idiopathic forms ofcentral diabetes insipidus have recently beenascribed to a newly discovered mutation in theneurophysin II coding region of the ADHgene.5,6 Exons 1 and 3 are normal, but in exon2, thymine is substituted for guanine atnucleotide 1884. This in turn induces a substi-tution of a glycine for a valine in the ADHmolecule. Affected patients have both normaland mutant alleles, indicating that this muta-tion is heterozygous. Accumulation of abnor-mal ADH in the posterior pituitary cells leadsto destruction of the entire cell and the clini-cal syndrome of diabetes insipidus.

Another form of familial central diabetesinsipidus may be due to a substitution ofvaline for alanine in the gene for the signalpeptide for ADH-neurophysin II/copeptideprecursor.7

Hereditary forms account for only 1% to2% of all cases of central diabetes insipidus,and autopsy findings in these cases have con-sistently shown neuronal degeneration and

gliosis of variable numbers of supraoptic andparaventricular nuclei, usually accompaniedby a small posterior pituitary gland.4

Treatment of central diabetes insipidusWater is essential: in sufficient quantity, it

will correct any metabolic abnormality due toexcessive dilute urine.

ADH replacement. The earliest availablepreparation of ADH was a crude acetone driedextract from bovine or porcine posterior pitu-itary, given by nasal insufflation. Problemswith this preparation included variable dura-tion of activity and local irritation of the nasalmucosa.

Subsequently, a more purified preparationof ADH was developed, known as Pitressin(vasopressin tannate in oil). This is given intra-muscularly every 2 to 4 days and provides relieffor 24 to 72 hours. Its side effects includeabdominal cramping, hypertension, and angina.

The disadvantages of these preparationsprompted the development of oral agents toaid in antidiuresis.

Desmopressin (1-deamino-8-D-argininevasopressin, DDAVP) is the current drug ofchoice for long-term therapy of central dia-betes insipidus.8 It can be given parenterally,orally, or intranasally. For all dosage forms, thestarting dosage is 10 µg at night to relieve noc-turia. A morning dose can be added if symp-toms persist during the day. The duration ofeffect of this synthetic peptide is well repro-ducible in an individual. Therefore, desmo-pressin dosage and scheduling should beadjusted individually according to the degreeof polyuria.

Chlorpropamide (Diabinese), an antidi-abetes drug, decreases the clearance of solute-free water, but only if the neurohypophysishas some residual secretory capacity. Its anti-diuretic effect is likely due to raising the sen-sitivity of the epithelium of the collectingduct to low concentrations of circulatingADH.

Carbamazepine (Tegretol), an anticon-vulsant, reduces the sensitivity of theosmoregulatory system of ADH secretion andsimultaneously raises the sensitivity of the col-lecting duct to the hydro-osmotic action ofthe hormone.

Clofibrate (Atromid-S), a lipid-lowering

Desmopressinis the currentdrug ofchoice forcentraldiabetesinsipidus




agent, stimulates residual ADH production inpatients with partial central diabetesinsipidus. Chlorpropamide, carbamazepine,and clofibrate all can be used in cases of par-tial central diabetes insipidus.9,10

Thiazide diuretics paradoxically can beused for treating central diabetes insipidus.They exert their effect by decreasing sodiumand chloride absorption in the distal tubule,therefore allowing more sodium absorption—and therefore water absorption—in the proxi-mal tubule.9,10

After starting one of the above agents, itis important to monitor the efficacy of thetherapy. This is easily performed by follow-upof electrolyte values.

■ NEPHROGENIC DIABETES INSIPIDUS

In nephrogenic diabetes insipidus, the poste-rior pituitary is hyperstimulated because ofincreased plasma osmolality and produces asufficient amount of ADH, but the kidneyscannot produce maximally concentratedurine in response to it.

Nephrogenic diabetes insipidus can becharacterized by three main disturbances inkidney function:• Disturbance of the generation or mainte-nance (or both) of the corticomedullaryosmotic gradient, which is the driving forcefor the osmotic water flow from collectingducts into the interstitial tissue• Disturbance of osmotic equilibrationbetween the tubular contents and themedullary interstitium due to a defect of theproximal component of the ADH-cyclicadenosine monophosphate system or the dis-tal component or both• Osmotic diuresis, which produces rapidflow of the tubular fluid and thus prevents itscomplete osmotic equilibration with themedullary interstitium.1,4

The degree of disease varies amongpatients. In patients with the complete form,the urine osmolality remains consistentlylower than the plasma osmolality, while inpartial forms of the syndrome the urine osmo-lality can be considerably higher.4

The many causes of nephrogenic diabetesinsipidus can be divided into two categories:acquired and familial (TABLE 2).

Acquired formsof nephrogenic diabetes insipidusAcquired forms are more common than familialforms. The kidney is structurally or functionallyaltered, either permanently or transiently, by dis-ease (the most common cause), drugs, or otherconditions so that it is less sensitive to ADH.

Among the systemic circumstances lead-ing to acquired nephrogenic diabetes insipidusare hypokalemia, hypercalcemia, various typesof renal disease, and sickle cell anemia.

Hypokalemia. Potassium depletion due toinsufficient dietary intake or due to losses (eg,in gastroenteritis) is usually associated withthe development of polyuria, polydipsia, and arenal concentrating defect that is resistant toADH.

Two mechanisms have been proposed toexplain the diuresis seen in potassium deple-tion: an alteration of the generation and


Mutationsthat causediabetesinsipidushave beendiscovered

Causes of nephrogenicdiabetes insipidus

AcquiredRenal disease

Chronic renal failureChronic renal medullary diseasePyelonephritisObstructive uropathyPolycystic kidney diseaseRenal transplantation

Electrolyte disturbancesChronic hypokalemiaChronic hypercalcemia

DrugsAmphotericin BColchicineDemeclocyclineGentamicinLithiumLoop diureticsMethoxyflurane

PregnancyMultiple myelomaSickle cell diseaseProtein starvation

FamilialV2 receptor mutation (X-linked)Aquaporin-2 mutation (autosomal-recessive)

T A B L E 2




maintenance of the medullary osmotic gradi-ent and resistance of the collecting ducts tothe hydro-osmotic effect of ADH.

Chronic hypercalcemia may result inrenal interstitial calcification and fibrosis withsecondary anatomic disruption of the renalconcentrating mechanism, which thereforeproduces large amounts of dilute urine.

Advanced chronic renal failure in most ofits forms features a defect in the renal concen-trating capacity, as does sickle cell anemia.2–4

Pregnancy is yet another cause: duringpregnancy, vasopressinase produced by theplacenta can destroy ADH too rapidly. Thistype of ADH deficiency often disappears 4 to6 weeks after delivery, but often recurs withsubsequent pregnancies.

Drug-induced diabetes insipidusA variety of widely used drugs can causeacquired nephrogenic diabetes insipidus.

Lithium salts cause polydipsia andpolyuria at the start of treatment in as many as60% of patients, and these side effects persist in20% to 25% even if plasma lithium levels arewithin the therapeutic range. In one reportedcase, a patient undergoing chronic lithiumtherapy presented with transient central dia-betes insipidus on top of underlying chronicnephrogenic diabetes insipidus.11 Lithium saltshave been proposed as a treatment for thechronic syndrome of inappropriate secretion ofADH, but another agent, demeclocycline, hasbeen proven to be more effective.4

Demeclocycline, an antibiotic of thetetracycline group, is commonly used by der-matologists to treat acne. In high doses(900–1,200 mg/day), demeclocycline inducespolyuria and polydipsia. These side effectsmight not manifest themselves in the first daysor weeks of use, and complete restoration ofrenal function usually requires several weeksafter the drug is stopped.

Both lithium salts and demeclocycline arethought to affect renal function by disturbingsome aspect of the proximal component of theADH-cyclic adenosine monophosphate sec-ond-messenger system.4

Amphotericin B, a potent antifungalagent, is nephrotoxic. It disturbs the genera-tion and maintenance of the medullary osmot-ic gradient in the kidney.

Gentamicin seems to impair the cellularresponse to ADH.

Colchicine inhibits the action of the sec-ond messenger by disrupting microtubulefunction.

Loop diuretics have been shown to wors-en renal function in some cases.1

Foscarnet, which is used to treatcytomegalovirus infection, has recently beenshown to cause nephrogenic diabetes insipidusin certain patients.12

Familial nephrogenic diabetes insipidusFamilial nephrogenic diabetes insipidus is rareand can be caused by two different geneticdefects.

V2 receptor mutations. Mutations in thegene encoding the ADH type 2 receptor (V2receptor) cause an X-linked form of the dis-ease. More than 60 different disease-causingmutations have been identified throughoutthe V2 receptor gene.13

Aquaporin-2 mutations. Mutations inthe gene encoding the ADH-dependentwater channel aquaporin-2 are responsiblefor an autosomal-recessive form, and in somecases an autosomal-dominant type of the dis-ease. The conformational change in theaquaporin-2 channel leads to improper fluidexchange in the distal collecting system andpolyuria.13 Autosomal-recessive nephrogenicdiabetes insipidus appears in 10% of families.In these patients, a normal extrarenalresponse to ADH is observed, indicatingunresponsiveness to ADH restricted to thekidney.

Earm et al14 examined the effect of hyper-calcemia on the expression of aquaporin-2 inrat kidneys. They found that hypercalcemiadecreased the expression of aquaporin-2 in theinner medulla and cortex of the kidneys, andthey concluded that aquaporin-2 downregula-tion and reduced plasma membrane deliveryof aquaporin-2 play important roles in thedevelopment of polyuria in association withhypercalcemia.

The way to distinguish between patientswith a V2 receptor defect and those with anaquaporin-2 defect is with a trial of desmo-pressin therapy: those with an aquaporin-2defect will have a response to desmopressin,but those with a V2 receptor defect will not.13

Thiazidediuretics canparadoxicallyimprovediabetesinsipidus




Treatment of nephrogenic diabetes insipidusTreating nephrogenic diabetes insipidusinvolves a different regimen than for centraldiabetes insipidus. Nephrogenic diabetesinsipidus does not respond to ADH; instead, itis treated by correcting hypokalemia andhypercalcemia and by discontinuing any drugsthat may be causing it.

Thiazide diuretics are used along withmodest salt restriction to reduce the deliveryof filtrate to the diluting segments of thenephron. They exert their effect by decreasingsodium and chloride absorption in the distaltubule, thereby allowing more sodium absorp-tion and therefore more water absorption inthe proximal tubule.10,15


■ REFERENCES1. Cagno JM. Diabetes insipidus. Crit Care Nurse 1989; 9:86–93.2. Singer I, Oster JR, Fishman LM. The management of diabetes

insipidus in adults. Arch Intern Med 1997; 157:1293–1301.3. Adam P. Evaluation and management of diabetes insipidus. Am Fam

Physician 1997; 55:2146–2153.4. Kovacs L, Lichardus B. Vasopressin, Disturbed Secretion and Its Effects.

Prague: Kluwer Academic Publishers, 1989.5. Ueta Y, Taniguchi S, Yoshida A, et al. A new type of familial central

diabetes insipidus caused by a single base substitution in the neuro-physin II coding region of the vasopressin gene. J Clin EndocrinolMetab 1996; 81:1787–1790.

6. Rauch F, Lenzner C, Nurnberg P, Frommel C, Vetter U. A novel muta-tion in the coding region for neurophysin-II is associated with autoso-mal dominant neurohypophyseal diabetes insipidus. Clin Endocrinol(Oxf) 1996; 44:45–51.

7. Repaske DR, Medlej R, Gultekin EK, et al. Heterogeneity in clinicalmanifestation of autosomal dominant neurohypophyseal diabetesinsipidus caused by a mutation encoding Ala-1 —> Val in the signalpeptide of the arginine vasopressin/neurophysin II/copeptin precursor.J Clin Endocrinol Metab 1997; 82:51–56.

8. Lam KS, Wat MS, Choi KL, Ip TP, Pang RW, Kumana CR.Pharmacokinetics, pharmacodynamics, long-term efficacy, and safetyof oral 1-deamino-8-D-arginine vasopressin in adult patients with cen-tral diabetes insipidus. Br J Clin Pharmacol 1996; 42:379–385.

9. Gregerman RI. Selected endocrine problems. In: Barker LR, Burton JR,Zieve PD, editors. Principles of Ambulatory Medicine, 3rd edition.Baltimore, MD: Williams and Wilkins Publishers, 1991:997–998.

10. Seckl JR, Dunger DB. Diabetes insipidus. Current treatment recom-mendations. Drugs 1992; 44:216–224.

11. Posner L, Mokrzycki MH. Transient central diabetes insipidus in thesetting of underlying nephrogenic diabetes insipidus associated withlithium use. Am J Nephrol 1996; 16:339–343.

12. Navarro JF, Quereda C, Quereda C, et al. Nephrogenic diabetesinsipidus and renal tubular acidosis secondary to foscarnet therapy.Am J Kidney Dis 1996; 27:431–434.

13. Knoers NV, van Os CH. Molecular and cellular defects in nephrogenicdiabetes insipidus. Curr Opin Nephrol Hypertens 1996; 5:353–358.

14. Earm JH, Christensen BM, Frokiaer J, et al. Decreased aquaporin-2expression and apical plasma membrane delivery in kidney collectingducts of polyuric hypercalcemic rats. J Am Soc Nephrol 1998;9:2181–2193.

15. Kim GH, Lee JW, Oh YK, et al. Antidiuretic effect of hydrochloro-thiazide in lithium-induced nephrogenic diabetes insipidus is associat-ed with upregulation of aquaporin-2, Na-Cl co-transporter, andepithelial sodium channel. J Am Soc Nephrol 2004; 15:2836–2843.

ADDRESS: Samy I. McFarlane, MD, Department of Medicine, Box 50, StateUniversity of New York Health Science Center at Brooklyn, Kings CountyHospital Center, 450 Clarkson Avenue, Brooklyn, NY 11203; [email protected].

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Cleveland Clinic Journal of Medicine 2006 Makaryus 65 71