WATER METABOLISM

Our total body water content is about 35 liters, of which 60% (21 L) is extracellular and 40% (14 L) is intracellular. The
extracellular water is further distributed as plasma (about 2.5 L) and interstitial fluid (about 18.5 L). The intracellular water is
mainly in the cytoplasm of the cells. The approximate input of water per day is 2.4 L. Of this, water intake as fluids is 1.5 L; water
content of food consumed is 0.5 L and water from biological oxidation is 0.4 L. Solutes are substances dissolved in body water such
as sodium chloride, glucose. Solvent is the liquid in which solutes are dissolved and mostly this solvent is water. We need to be
familiar with the two expressions namely “Osmolality” and “Osmolarity”. When the solutes are expressed as milliosmoles/
kilogram (mOsm/kg) of the solvent, it is referred to as “Osmolality” and when expressed as milliosmoles/liter (mOsm/L) of the
solvent, we refer it as “Osmolarity”. Our plasma osmolality depends on the number of particles in solution. Normally it is
maintained within a very narrow range of about 285 mOsm/kg H2O. Sodium is the principle determinant of the osmolality of the
plasma as can be seen by the formula given below.
Osmolality is calculated as follows: 2(Na + K) + (Glucose/ 18) + (BUN/2.8), which is 2(132 + 4) + (108/18) + (14/2.8) and that is
equal to (2 × 136) + 6 + 5 = 272 + 11 = 283.

HYPOTHALAMIC PITUITARY ENDOCRINE AXIS

Antidiuretic hormone (ADH), also known as vasopressin, is synthesized and secreted by the posterior pituitary gland or
neurohypophysis. It is also known as arginine vasopressin (AVP). Plasma osmolality is always maintained in a very narrow
physiological range of about 285 mOsm/kg H2O by the plasma ADH concentration of 4 pg/mL. Release of ADH is immediately
stopped and water is excreted, if the plasma osmolality reaches 280 mOsm/kg H 2O (just five points less than normal). This is called
the threshold for ADH release. Secretion of ADH is immediately doubled and thirst is stimulated if the plasma osmolality increases
to 290 mOsm/kg H2O (just five points more than normal). This is called the threshold for thirst.
Renal handling of water excretion is very fascinating. A primary urine of about 170 liters is filtered [glomerular filtration rate (GFR)
of 120 mL/minute x 60 minutes x 24 hours = 170 L)]. Such a large volume of water is needed to flush out all the solutes and waste
molecules through the microfilters of the glomeruli. But we cannot afford to lose even a small fraction of that filtered primary urine
(as our total water in the body is itself 65 liters and plasma volume is mere 2.5 liters). Hence, all the filtered 170 mL should almost
be reabsorbed back into the system. The final urine volume is only about 1.5 liters, which means 99% of the filtered primary urine is
reabsorbed and only 1% is finally excreted. This is made possible by both passive and active reabsorption in the renal tubules.
About 70% of water is reabsorbed in the proximal convoluted tubule (PCT) by the aquaporin-1 (AQP-1) channels. Rest of the 29%
is reabsorbed by AQP-2, 3 and 4 channels in the loop of Henle and distal convoluted tubule (DCT). (Prof. Peter Agre, the winner of
Nobel prize in Chemistry for 2003, has characterized these AQP channels). Reabsorption of water in the collecting tubules (CT) is
mediated by the ADH.
Decrease in plasma volume triggers secretion of renin, which initiates angiotensin formation. Angiotensin II is a powerful
dipsinogen and stimulates thirst and also AVP release. Increase in plasma osmolality stimulates AVP release, which reduces the
urine output and balances the increase in osmolality. If there is deficiency of AVP, we will have a water diuresis. The countercurrent
multiplier and countercurrent exchange mechanisms in the renal tubules and renal parenchyma maintain this delicate and tricky
balance of water and solutes. Complex interactions of plasma osmolality, plasma volume, thirst center, kidney, neurohypophysis
and the bandmaster—the hypothalamus regulate the fine and delicate water and solute balance. Dysfunction in any of these areas
results in polyuria and polydipsia.
The clinical disorders of water balance include cardiac failure, cirrhosis of liver, renal failure, hyper and hypothyroidism, Addison’s
disease, central diabetes insipidus (CDI), nephrogenic diabetes insipidus (NDI), psychogenic polydipsia (PPD) or compulsive water
drinking (CWD) and pregnancy.

Gambar 1. Abbas
MW et al. Diabetes insipidus: the basic and clinical review.Int J Res Med Sci.
2016;4(1):5-11

ADIPSIA

Adipsia is a disease in which there is an absence of thirst although body has dehydration and
high plasma osmolality. Any lesion of thirst center in hypothalamus leads to the loss of thirst
 causing adipsia. Adipsia is often associated with CDI because the lesion of hypothalamus
also affects the supraoptic and pavaventricular region (the releasing sites of ADH). Hence,
adipsia and CDI are collectively known as Adipsic diabetes insipidus (ADI). It is very rare
disease. In the world only 200 cases have been reported till now.
Abbas MW et al. Diabetes insipidus: the basic and clinical review.Int J Res Med Sci.
2016;4(1):5-11

PSIKOGENIK

Psychogenic diabetes Insipidus (PDI) is also a sub-variety of PP. It is mainly caused by psychiatric
disorders like schizophrenia. Such psychiatric disorders lead a person to increase fluid intake and
person then excretes highly dilute urine

POLIURI
Polyuria is the passage of excessive quantity of urine and it implies water or solute diuresis of at least 2.5–3 L/day or urine
volume of more than 40 mL/kg/day. Polyuria is usually associated with polydipsia. Polydipsia is defined as water intake of
more than 100 mL/kg/day (6 L/day).
There are four mechanisms, which can cause polyuria. One or more of these will be operating.
1. Increased intake of fluids as in psychogenic causes, stress and anxiety
2. Increased GFR as in hyperthyroidism, fever, hypermetabolic states
3. Increased output of solutes as occurs in DM, hyperthyroidism, hyperparathyroidism, use of diuretics (which present more
solute at the DCT)
4. Inability of the kidney to reabsorb water in DCT as in CDI, NDI, drugs and chronic renal failure (CRF).
PENDAHULUAN

Diabetes insipidus (DI) is characterized by profuse diuresis, usually greater than 3L/24h of urine, with
osmolality below 300mOsm/kg. It has two main forms: Central (also known asneurogenic) DI is characterized by low
levels of antidiuretic hormone, also known as vasopressin (AVP); nephrogenic DI is characterized by difficulties
concentrating urine due to resistance to AVP action in the kidneys. AVP is the main determiner of free water
clearance in the body. It acts mainly in the kidneys where it alters water permeability in the cortical tubules and the
medulla. Water is reabsorbed by osmosisdue to hypertonicity within the medullary interstitium, and then taken back
into systemic circulation. Two other forms of DI are gestational DI and primary polydipsia (dipsogenic DI). Neither of
these results from a defect in the neurohypophysis or the kidneys, but both participate in differential diagnoses of
diabetes. The predominant manifestations of DI are polyuria, polydipsia, and nocturia, which also indicate diabetes
mellitus (DM), another important differential diagnosis.
Laboratory tests, particularly 24-hour urine collection to determine the volume of urine and concentration
of serum electrolytes, urine and plasma osmolality, and glucose and AVP levels, must be carefully analyzed,as small
differences are crucial to a correct diagnosis. We report a case of central diabetes insipidus (CDI), accompanied by a
literary review. CDI has many possible causes. According to the literature, the main causes of CDI and their
frequencies are: idiopathic-30%; malign or benign tumors of the brain or neurohypophysis-25%; cranial surgery 0-
20%; and cranial trauma-16%. As this disease is often undiagnosed, we will stress the importance of noting discrete
abnormalities in laboratory results to make a differential, early diagnosis so that appropriate therapy can be started
to improve the patient’s quality of life.

Mara C, Ana R S, Sabrina P F, Moacir B, Larissa B P C d S, et al. Key points in Diabetes Insipidus´ Diagnosis. Biomed J Sci
&Tech Res 2(1)- 2018. BJSTR. MS.ID.000684. DOI : 10.26717/BJSTR.2018.02.000684

DEFINISI

The word “Diabetes Insipidus” is a combination of two words “Diabetes” and “Insipidus”. Diabetes is a word
of Greek origin which means “siphon” and Insipidus is a word of Latin origin which means “without taste”. 1 DI
is actually inability of body to conserve water due to pathophysiology of production of antidiuretic hormone
(ADH) and its action

Abbas MW et al. Diabetes insipidus: the basic and clinical review.Int J Res Med Sci.
2016;4(1):5-11

Diabetes insipidus is a disease in which large volumes of dilute urine (polyuria) are excreted
due to vasopressin (AVP) deficiency [central diabetes insipidus (CDI)], AVP resistance
[nephrogenic diabetes insipidus (NDI)], or excessive water intake (primary polydipsia).
Polyuria is characterized by a urine volume in excess of 2 l/m 2 /24 h or approximately 150
ml/kg/24 h at birth, 100–110 ml/kg/24 h until the age of 2 years and 40–50 ml/kg/24 h in the
older child and adult.

Di Iorgi N, Napoli F, Allegri AEM, Olivieri I, Bertelli A, Gallizia A.Diabetes Insipidus – Diagnosis and
Management.Horm Res Paediatr 2012;77:69–84

PATOF
Irrespective of the cause of diabetes insipidus,whether central or nephrogenic, hereditary or acquired,
the consequences are similar as shown in the chart above with loss of free water. This leads to
dehydration if the patient is not able to keep up with urinary loss and may cause hypernatremia.

4.1. Central Diabetes Insipidus. The central causes of diabetes insipidus are either due to decreased
secretion of vasopressin or secretion of partially functional form of vasopressin. The causes of central
diabetes insipidus are hereditary, congenital or acquired. The hereditary form includes an autosomal
dominant disorder with mutation of the AVP-neurophysin II gene. One of the forms of the disease, the
X-linked recessive and autosomal recessive forms due to mutations of the WFS 1 gene responsible
for Wolfram’s syndrome can also cause diabetes insipidus. Deficiency of vasopressin can occur
during pregnancy from increased breakdown by an N-terminal aminopeptidase that is usually
produced in the placenta. There are many acquired causes of diabetes insipidus as described above.

4.2. Nephrogenic Diabetes Insipidus. The nephrogenic causes of diabetes insipidus are due to
abnormalities of the vasopressin receptorV2R and aquaporin-2 proteinwater channels. The
mechanism of lithium in causation of diabetes insipidus is still debated and there are many
hypotheses. Lithium causes decreased AQP2 and AQP3 expression and thus free water loss in the
collecting duct. Electrolyte abnormalities like hypokalemia and hypercalcemia can cause resistance to
vasopressin. Chronic bilateral ureteral obstruction can cause decreased aquaporin protein expression.
In nephrogenic diabetes insipidus, the posterior pituitary is hyperstimulated because of increased
plasma osmolality and produces a sufficient amount of ADH, but the kidneys cannot produce
maximally concentrated urine in response to it. Nephrogenic diabetes insipidus can be characterized
by three main disturbances in kidney function:
• Disturbance of the generation or maintenance (or both) of the corticomedullary osmotic gradient,
which is the driving force for the osmotic water flow from collecting ducts into the interstitial tissue
• Disturbance of osmotic equilibration between the tubular contents and the medullary interstitium
due to a defect of the proximal component of the ADH-cyclic adenosine monophosphate system or
the distal component or both
• Osmotic diuresis, which produces rapid flow of the tubular fluid and thus prevents its complete
osmotic equilibration with the medullary interstitium.
Acquired forms
of nephrogenic diabetes insipidus
Acquired forms are more common than familial forms. The kidney is structurally or functionally
altered, either permanently or transiently, by disease (the most common cause), drugs, or other
conditions so that it is less sensitive to ADH. Among the systemic circumstances leading to acquired
nephrogenic diabetes insipidus are hypokalemia, hypercalcemia, various types of renal disease, and
sickle cell anemia.
Hypokalemia. Potassium depletion due to insufficient dietary intake or due to losses (eg, in
gastroenteritis) is usually associated with the development of polyuria, polydipsia, and a renal
concentrating defect that is resistant to ADH.
Two mechanisms have been proposed to explain the diuresis seen in potassium depletion: an
alteration of the generation and maintenance of the medullary osmotic gradient
and resistance of the collecting ducts to
the hydro-osmotic effect of ADH.
Chronic hypercalcemia may result in renal interstitial calcification and fibrosis with
secondary anatomic disruption of the renal concentrating mechanism, which therefore produces large
amounts of dilute urine.
Advanced chronic renal failure in most of its forms features a defect in the renal concentrating
capacity, as does sickle cell anemia.
Pregnancy is yet another cause: during pregnancy, vasopressinase produced by the
placenta can destroy ADH too rapidly. This type of ADH deficiency often disappears 4 to 6 weeks
after delivery, but often recurs with subsequent pregnancies

Drug-induced diabetes insipidus

A variety of widely used drugs can cause acquired nephrogenic diabetes insipidus.
Lithium salts cause polydipsia and polyuria at the start of treatment in as many as 60% of patients,
and these side effects persist in 20% to 25% even if plasma lithium levels are within the therapeutic
range. In one reported case, a patient undergoing chronic lithium therapy presented with transient
central diabetes insipidus on top of underlying chronic nephrogenic diabetes insipidus. Lithium salts
have been proposed as a treatment for the chronic syndrome of inappropriate secretion of ADH, but
another agent, demeclocycline, has been proven to be more effective.
Demeclocycline, an antibiotic of the tetracycline group, is commonly used by dermatologists
to treat acne. In high doses (900–1,200 mg/day), demeclocycline induces polyuria and polydipsia.
These side effects might not manifest themselves in the first days or weeks of use, and complete
restoration of renal function usually requires several weeks after the drug is stopped. Both lithium
salts and demeclocycline are thought to affect renal function by disturbing
some aspect of the proximal component of the ADH-cyclic adenosine monophosphate second-
messenger system.4
Amphotericin B, a potent antifungal agent, is nephrotoxic. It disturbs the generation and maintenance
of the medullary osmotic gradient in the kidney.
Gentamicin seems to impair the cellular response to ADH.
Colchicine inhibits the action of the second messenger by disrupting microtubule function.
Loop diuretics have been shown to worsen renal function in some cases.
Foscarnet, which is used to treat cytomegalovirus infection, has recently been shown to cause
nephrogenic diabetes insipidus in certain patients

Familial nephrogenic diabetes insipidus

Familial nephrogenic diabetes insipidus is rare and can be caused by two different genetic defects.
V2 receptor mutations. Mutations in the gene encoding the ADH type 2 receptor (V2 receptor) cause
an X-linked form of the disease. More than 60 different disease-causing mutations have been
identified throughout the V2 receptor gene.
Aquaporin-2 mutations. Mutations in the gene encoding the ADH-dependent water channel
aquaporin-2 are responsible for an autosomal-recessive form, and in some cases an autosomal-
dominant type of the disease.
The conformational change in the aquaporin-2 channel leads to improper fluid exchange in the distal
collecting system and polyuria.13 Autosomal-recessive nephrogenic diabetes insipidus appears in 10%
of families. In these patients, a normal extrarenal response to ADH is observed, indicating
unresponsiveness to ADH restricted to the kidney.
Earm et al14 examined the effect of hypercalcemia on the expression of aquaporin-2 in rat kidneys.
They found that hypercalcemia decreased the expression of aquaporin-2 in the inner medulla and
cortex of the kidneys, and they concluded that aquaporin-2 downregulation and reduced plasma
membrane delivery of aquaporin-2 play important roles in the development of polyuria in association
with hypercalcemia.
The way to distinguish between patients with a V2 receptor defect and those with an aquaporin-2
defect is with a trial of desmopressin therapy: those with an aquaporin-2 defect will have a response to
desmopressin, but those with a V2 receptor defect will not.

Saifan C, Nasr R, Mehta S, Acharya PS, Perrera I, Faddoul G, et al. Diabetes Insipidus: A
Challenging Diagnosis with New Drug Therapies. ISRN Nephrology Volume 2013, Article
ID 797620,

MANIFESTASI KLINIS
The age of presentation is dependent on the etiology, it can present at any age, and the prevalence is
equal among males and females although there is one study showing higher prevalence in the males.
In an alert and conscious patient, diabetes insipidus presents with intense thirst (polydipsia),
craving for ice water together with polyuria. The volume of fluid ingested may range from 2 L to even
20 L a day. Less-severe cases may present with persistent enuresis. Most patients with an intact
hypothalamic thirst centre maintain their fluid balance by drinking water. But patient who are unable to
access free water as seen in neonates and elderly present with clinical features of hypernatremia and
dehydration. Lethargy, altered mental status, hyperreflexia, seizure, or, may be other presenting
symptoms especially in the older age group, neonates and infants. Dehydration may lead to
contraction of intravascular volume which in severe cases causes traction of dural veins and sinuses
leading to intracranial hemorrhage. During pregnancy, diabetes insipidus is associated with
oligohydramnios, preeclampsia, and even hepatic dysfunction
Saifan C, Nasr R, Mehta S, Acharya PS, Perrera I, Faddoul G, et al. Diabetes Insipidus: A
Challenging Diagnosis with New Drug Therapies. ISRN Nephrology Volume 2013, Article
ID 797620,
KESIMPULAN

Diabetes insipidus (DI) is a complex disease. DI is inability of the body to conserve water. Polydipsia and
polyuria are the major manifestations of DI. DI has various variants including central diabetes insipidus (due to
defect in ADH secretion), nephrogenic diabetes insipidus (due to defect in ADH receptors or urea receptors),
gestational diabetes insipidus (due to catabolism of ADH by placental vasopressinase) and primary polydipsia
(due to massive fluid intake). The cause of various variants of DI is either acquired or congenital. High plasma
osmolality due to hypotonic urine excretion can be fatal because it can cause psychosis, lethargy, seizures, coma
or even death. Polyuria and polydipsia help in the diagnosis of DI. Differential diagnosis of various variants of
DI can be carried out on the basis of water deprivation test, MRI and other radiological techniques. The proper
management of DI is the replenishment of water loss and correction of clinical presentations produced as a
result of DI, major is hypernatremia. The best management for primary polydipsia is fluid restriction while fluid
intake is used for adipsic diabetes insipidus. ADH replacement therapy is widely used to treat DI. DDAVP or
desmopressin is mostly preferred ADH analogue because it has less side effects and resistant to placental
vasopressinase.

DIAGNOSIS

Polyuria is generally defined as urine output exceeding 3 liters per day in adults. Usually polyuria
could be caused by other conditions such as primary polydipsia, osmotic diuresis, and prostatic
hypertrophy. It is crucial to identify the cause of diabetes insipidus and to implement therapy as early
as possible to prevent the electrolyte disturbances and the associated morbidity and mortality. In
order to distinguish diabetes insipidus from other forms of polyuria, several blood tests have to be
ordered including the blood glucose, plasma osmolality, bicarbonate levels, electrolytes, and
urinalysis along with urine osmolality.
High blood glucose levels along with an osmolar excretion rate, which is equal to urine output
multiplied by urine osmolality, above 1000 mosm/d indicates osmotic diuresis secondary to
hyperglycemia.Other causes of osmotic diuresis could be due to urea as in post-AKI and mannitol and
giving high intravenous sodium loads causing iatrogenic osmotic diuresis.
When the osmolar excretion rate is less than 1000mOsm/d, two conditions have to be examined
including primary polydipsia which is associated with a serum sodium of <140meq/L and a dilute urine
with urine osmolality of <100mOsm/Kg on the one hand and diabetes insipidus on the other hand. It is
associated with a serum sodium above 140meq/L and a urine osmolality above 100mOsm/Kg. The
water deprivation test helps to distinguish between the different causes of polyuria. It should be done
by experienced physicians. It entails withholding any fluid intake from the patient. The normal
physiologic response to water deprivation test leads to increase in antidiuretic hormone as the plasma
osmolality increases and subsequently an increase in urine osmolality.The effect of antidiuretic
hormone would be maximal when the plasma osmolality reaches 295–300 mOsmol/Kg or when the
serum sodium is above 145 meq/L. At this point, administering desmopressin will not further increase
the urine osmolality only if we have deficient endogenous arginine vasopressin as in central diabetes
insipidus.

The water restriction test helps to determine the cause of polyuria. First, it could be due to excessive
drinking as in primary polydipsia. Second, it could be due to insufficient endogenous antidiuretic
hormone, hence it is called central diabetes insipidus. And third, it could be due to resistance of the
kidney to antidiuretic hormone, called nephrogenic diabetes insipidus.
Patients should stop drinking. After 2 to 3 hours of cessation of fluid intake, the urine volume and
osmolality should be measured every hour and the plasma sodium and plasma osmolality every 2
hours. The test is continued till we reach one of the following endpoints.
(1) The urine osmolality increases to reach a value above 600mOsmol/Kg, it means that this is an
appropriate response, and endogenous antidiuretic hormone is intact. The urine osmolality remains
steady on 2 subsequent measurements and the plasma osmolality is rising. The plasma sodium level
rises to reach a level above 145meq/L or a plasma osmolality become between 295 and
300mOsmol/Kg. Desmopressin is then given in the last two conditions either subcutaneously or
intravenously as 4 mcg or intranasally as 10 mcg. The urine volume and osmolality and plasma
osmolality are followed closely and the variations should be recorded. Different patterns to water
restriction and desmopressin administration will help to discriminate between the different causes of
polyuria.

(2) The urine osmolality increases in complete central diabetes insipidus with water deprivation test,
usually to more than 300mOsmol/Kg.Desmopressin leads to an increase in urine osmolality to more
than 100% in complete central diabetes insipidus and 15–50% in partial central diabetes insipidus. In
nephrogenic diabetes insipidus, water deprivation test leads to a rise in urine osmolality but usually
less than 300mOsmol/Kg and desmopressin produces little or no change in urine osmolality. In
primary polydipsia, water deprivation test produces a rise in urine osmolality but desmopressin
administration produces no change since the endogenous arginine vasopressin function and
secretion are intact.
Saifan C, Nasr R, Mehta S, Acharya PS, Perrera I, Faddoul G, et al. Diabetes Insipidus: A
Challenging Diagnosis with New Drug Therapies. ISRN Nephrology Volume 2013, Article
ID 797620,
The diagnosis of DI is made on the basis of the patient’s clinical history, laboratory tests, and imagingresults [21].The main
clinical symptoms of DI are polyuria and polydipsia, which manifest regardless of thetime period.The laboratory findings
that indicate DI are persistent hyposthenuria, with specific density below 1010g/mL, and urinary osmolality (UOSM) below
300mOsm/kg. Plasma osmolality (POSM) is normal or slightly high, according to the patient’s thirst and the amount of water
ingested. Determining POSM or basal serum sodium is not diagnostically useful because values in patients with CDI, NDI and
primary polydipsia (PP) are normal and may overlap. Nonetheless, if these values are clearly above normal levels (P OSM>295
mOsm/kg and Na>143mEq/L) in conditions where ingestion of water is unrestricted, a diagnosis of PP is excluded.
Consequently, a differential diagnosis must be made between CDI and serious NDI. For a differential diagnosis, DDAVP
(10μg subcutaneously) is administered, and after one and two hours assessment, non-concentrated urine indicates NDI,
and concentrated urine, CDI. In cases where a cause for polyuria cannot be found, water deprivation is advised. Water
deprivation is carried out in two stages: First, during a period of water fasting, the patient’s weight (after hourly urine
elimination) and urine osmolality are checked every hour, and plasma osmolality and serum sodium every two hours

Figure 3: Water Deprivation Test. Note: a. DDAVP:desmopressin acetate b. OsmU: Urinary osmolality c. CDI: central
diabetes insipidus d. NDI: nephrogenic diabetes insipidus

Second, 40 μg of intranasal desmopressin is administered, free fluids given orally, and plasma osmolality and urinary
osmolality checked one and two hours, respectively, after administration of desmopressin. This is illustrated in (Figure 3).
In CDI cases, the gold standard imaging techniqueto search for tumors or other pathologies in the hypothalamic-
hypophyseal region is MRI. MRI may also reveal expanding lesions in the sella turcica region (e.g., tumors, abscesses,
infiltrative diseases, hypophysitis, etc.) and thickening of the pituitary stalk. In up to 80% of CDI cases, the posterior
pituitary bright spot is visualized on MRI. However, this is also observed in up to 20% of normal people or people who have
NDI, which may be secondary to depletion of AVP caused by chronic, excessive secretion. Patients with a diagnosis of
idiopathic CDI with no evidence of tumors, infiltrative diseases, infectious diseases or metastatic diseases on initial MRI
images should have subsequent MRIs because, in some cases, tumors may appear a few years after diagnosis
Mara C, Ana R S, Sabrina P F, Moacir B, Larissa B P C d S, et al. Key points in Diabetes Insipidus´ Diagnosis. Biomed J Sci
&Tech Res 2(1)- 2018. BJSTR. MS.ID.000684. DOI : 10.26717/BJSTR.2018.02.000684

DD
According to the definition of DI, polyuria and hypotonic urine should be present. For the confirmation of
polyuria, the urine output should be greater than 40ml/kg/24hrs. For the confirmation of DI urine osmolality
should be <300 mOsm/kg. Polyuria can be confirmed by the history of patient. For differential diagnosis of
various variants of DI, Water Deprivation Test is performed. In order to perform this test person should be
sufficiently dehydrated to stimulate ADH production and measure the volume and osmolality with each
discharge until the weight decreases by 3% or plasma sodium level reaches 145mmol/L. Now, treat with
desmopressin or DDAVP. If the concentration of urine rises by 50% or more then person is suffering from CDI if
it increases by <10% then the diagnosis is NDI. If the osmolality of urine increases more than 750 mOsm then
the patient is suffering from either CDI or PP. PP can be distinguished from CDI by the ability of a person to
concentrate urine in response to dehydration while this concentrating ability is absent in CDI patients. CDI can
also be diagnosed with the help of MRI showing bright spot in sella turcica. MRI and other radiological
techniques help in the conformation of ADI.

Abbas MW et al. Diabetes insipidus: the basic and clinical review.Int J Res Med Sci.
2016;4(1):5-11
Natascia DI, Flavia N, Anna Elsa MA. Diabetes Insipidus – Diagnosis and Management. Horm Res Paediatr.
2012;77:69-84

Differential diagnoses could be PP, CDI or NDI [21]. PP includes psychiatric diseases, absence of nocturia, or episodic
polyuria. A urinary volume greater than 18L is highly suggestive of PP. However, most CDI patients have moderate
dehydration, a decrease in urine volume (6 to 12L), and a decrease in the glomerular filtration rate. In CDI, patients develop
polyuria after cranial trauma or neurosurgery; it is also found in patients with clinical evidence of sella turcica or metastatic
tumors (lung and breast), granulomatous diseases (Langerhans cell histiocytosis, sarcoidosis, and tuberculosis), and
infectious diseases (pituitary abscesses, meningitis, encephalitis, and neurosyphilis). NDI is characterized by the kidney’s
inabilityto concentrate urine despite normal concentrations of AVP. It may be caused by hydroelectrolytic disorders
(hypopotassemia, hypercalcemia), chronic renal disease or ingestion of DI-inducing substances (lithium, amphotericin B,
methotrexate, etc.). A rare form is familial CDI, caused by mutation of the receptor gene V2

Mara C, Ana R S, Sabrina P F, Moacir B, Larissa B P C d S, et al. Key points in Diabetes Insipidus´ Diagnosis. Biomed J Sci
&Tech Res 2(1)- 2018. BJSTR. MS.ID.000684. DOI : 10.26717/BJSTR.2018.02.000684

TATALAKSANA

Management of diabetes insipidus

The proper management of DI involves the replenishment of water loss and correction of
manifestations like hypernatremia produced as a result of DI. Thirst mechanism plays an important
role in management of DI because water intake in response to thirst immediately corrects water loss
but thirst mechanism is not much effective in unconscious patients and infants. Hypernatremia should
not be corrected too quickly because it can cause cerebral edema, seizures and death.The rate at which
hypernatremia is corrected should not be greater than 0.5mEq.The best management for psychogenic
and dipsogenic DI is fluid restriction while adequate fluid intake is best proper management for
adipsic diabetes insipidus.

Therapeutic approaches
Neurogenic diabetes insipidus
ADH replacement is best therapeutic approach for CDI. Pitressin is purified form of ADH given
intramuscularly for treatment of CDI. But now-a-days it is not frequently used due to its side effects
including angina, hypertension and abdominal cramping The most preferred replacement therapy is
DDAVP (1-desamino-8-arginine vasopressin). It is also known as Desmopressin. It is preffered over
pitressin and is resistant to placental vasopressinase. Chlorpropamide also decreases the Polyuria by
upto 75% and is used to treat the patients with mild CDI. The other drugs which are used for
treatment of mild form of CDI are Carbamazepine and Clofibrate. Prostaglandin synthase inhibitors
and thiazides are also used for treatment of CDI.
Nephrogenic diabetes insipidus
Patients of NDI do not respond to ADH and desmopressin. The best therapeutic approach is to remove
the causing agent like lithium etc, if causative agent of NDI is of acquired form. Thiazides and
amiloride are used for the treatment of lithium induced NDI. Prostaglandin synthase inhibitors are
used because they increase the AQP-2 channels at apical membrane by increasing intracellular cAMP
level. The main side effect of these drugs is that they cause kidney damage and gastric problems.
Recent studies have shown that long term treatment with thiazides can cause renal carcinoma.
Another treatment of NDI is the release of trapped V2 receptors from endoplasmic reticulum. This
can be done with the help of chemicals known as nonpeptide chaperones. Recent studies have shown
that gene therapy can be the better option for treatment of NDI but it is highly speculative. Recent
investigations have revealed that statins also increase the expression of AQP2 in apical membrane.
Gestational Diabetes Insipidus
The best possible treatment of GDI is replacement of ADH by DDAVP. DDAVP or desmopressin is
resistant to placental vasopressinase. DDAVP is frequently preferable because of its minute effect on
maternal vascular tone but the recent studies have shown that the quantity of amniotic fluid may
change. Another treatment of GDI is by hydrochlorothiazide but it is usually not preferred because of
its side effects including neonatal hypoglycemia and neonatal DI.
Adipsic diabetes insipidus
DDAVP therapy is used to decrease the urine output in the patients of ADI. Moreover behavioral
therapy is also required because the thirst mechanism fails to perform its function in patients of ADI.
Primary polydipsia
Clozapine is an effective drug because it reduces the water intake but it is generally not preferred
because of its side effects. Therefore fluid restriction is best management.

Abbas MW et al. Diabetes insipidus: the basic and clinical review.Int J Res Med Sci.
2016;4(1):5-11
Sinha A, Ball S, Jenkins A, Hale J, Cheetham T. Objective assessment of thirst recovery in patients with adipsic
diabetes insipidus. Pituitary. 2011;14(4):307-11.

Treatment of central diabetes insipidus

Water is essential: in sufficient quantity, it will correct any metabolic abnormality due to excessive
dilute urine.
ADH replacement. The earliest available preparation of ADH was a crude acetone dried extract from
bovine or porcine posterior pituitary, given by nasal insufflation. Problems with this preparation
included variable duration of activity and local irritation of the nasal mucosa. Subsequently, a more
purified preparation of ADH was developed, known as Pitressin (vasopressin tannate in oil). This is
given intramuscularly every 2 to 4 days and provides relief for 24 to 72 hours. Its side effects include
abdominal cramping, hypertension, and angina. The disadvantages of these preparations prompted the
development of oral agents to aid in antidiuresis.
Desmopressin (1-deamino-8-D-arginine vasopressin, DDAVP) is the current drug of choice for long-
term therapy of central diabetes insipidus. It can be given parenterally, orally, or intranasally. For all
dosage forms, the starting dosage is 10 g at night to relieve nocturia. A morning dose can be added if
symptoms persist during the day. The duration of effect of this synthetic peptide is well reproducible
in an individual. Therefore, desmopressin dosage and scheduling should be adjusted individually
according to the degree of polyuria.
Chlorpropamide (Diabinese), an antidiabetes drug, decreases the clearance of solutefree water, but
only if the neurohypophysis has some residual secretory capacity. Its antidiuretic effect is likely due
to raising the sensitivity of the epithelium of the collecting duct to low concentrations of circulating
ADH.
Carbamazepine (Tegretol), an anticonvulsant, reduces the sensitivity of the osmoregulatory system
of ADH secretion and simultaneously raises the sensitivity of the collecting duct to the hydro-osmotic
action of the hormone.
Clofibrate (Atromid-S), a lipid-lowering agent, stimulates residual ADH production in
patients with partial central diabetes insipidus. Chlorpropamide, carbamazepine, and clofibrate all can
be used in cases of partial central diabetes insipidus.
Thiazide diuretics paradoxically can be used for treating central diabetes insipidus.
They exert their effect by decreasing sodium and chloride absorption in the distal tubule,
therefore allowing more sodium absorption— and therefore water absorption—in the proximal
tubule.
After starting one of the above agents, it is important to monitor the efficacy of the therapy. This is
easily performed by follow-up of electrolyte values.

Treatment Of Nephrogenic Diabetes Insipidus

Treating nephrogenic diabetes insipidus involves a different regimen than for central diabetes
insipidus. Nephrogenic diabetes insipidus does not respond to ADH; instead, it is treated by correcting
hypokalemia and hypercalcemia and by discontinuing any drugs that may be causing it.
Thiazide diuretics are used along with modest salt restriction to reduce the deliver of filtrate to the
diluting segments of the nephron. They exert their effect by decreasing sodium and chloride
absorption in the distal tubule, thereby allowing more sodium absorption and therefore more water
absorption in the proximal tubule

Makaryus AM, McFarlane SI. Diabetes insipidus: Diagnosis and treatment of a complex
disease. Cleveland Clinic Journal Of Medicine.2006;73:65-71

PROGNOSIS

Central DI occurring after pituitary surgery usually remits within days to weeks but if structural damage
has occurred to the stalk, it may even be permanent. The clinical course of chronic central DI is more
of inconvenience to daily life than a diremedical condition. Currently available treatments do a good
job to control symptoms but patients must be watched closely for side effects, water intoxication, and
hypernatremia.
Saifan C, Nasr R, Mehta S, Acharya PS, Perrera I, Faddoul G, et al. Diabetes Insipidus: A
Challenging Diagnosis with New Drug Therapies. ISRN Nephrology Volume 2013, Article
ID 797620,

BEDAIN DM DAN DI

Diabetes Insipidusrepresentsa small part of diabetes cases in our population. DM2 account for the great majority
of cases of Diabetes. Complaints of polydipsia and polyuria are common in patients with uncontrolled DM2. In our
patient’s case, his complaints at the initial consultations suggested likely uncontrolled DM2. However, continuous
monitoring of capillary glycemia and glycosylated hemoglobin showed that the patient did not have significant
enough discomfort to reportfurther symptoms. Other important causes of polyuria and polydipsia are DI and PP.
Measuring urine volume for 24 h and urine density via a simple urine test were key to diagnosing the type of diabetes.
The patient spent two years receiving treatment for DM2, and experienced frequent episodes of hypoglycemia. In
such cases, it is also important to exclude adrenal insufficiency; the basal cortisol level was greater than 10μg/L,
which helped exclude adrenal insufficiency. We did not investigate possible insulinoma because there was no classic
Whipple’s triad of hypoglycemic symptoms and no significant weight gain, both of which are typical of insulinomas.
Differential analysis depends on exclusion criteria that compare symptoms and laboratory anomalies to diseases that
are similar to NDI.

Urine density analysis is a differential criterion. In DM2, this is high, above 1020 mmol/L, whereas in neurogenic
DI urine is hypotonic, i.e., with a density less than 1010mmol/L. In our patient’s case, the symptoms of polyuria and
polydipsia, alteration in arterial pressure, being overweight and slight hyperglycemia aroused suspicion of DM2, so
treatment was initiated. The patient experienced side effects due to the use of oral hyperglycemic agents and rigorous
diet. When he started treatment at our medical clinic, his urinary density of 1005 g/mLindicated DI. The plasma
sodium level of 143mEq/L, characteristic of hypernatremia, wasan important differential indicator ofCDI; in
hypernatremia, plasma sodium levels are greater than 135 mEq/L, whereas in NDI, hyponatremia is observed [31].
Another differential parameter was plasma osmolality, calculated by the formula POSM=2×(Na+K)+(glycemia/18),
which, in our patient’s case was 300.74mOsm/kg. When osmolality is greater than 282mOsm/kg, the thirst
mechanism is activated, and the POSMreference value varies between 280 and 295 mOsm/kg. POSM is a
measurement that indirectly assesses a patient’s degree of hydration. The patient’s urinary osmolality was
110mOsm/kg, and, in central DI, the reference value is below 300mOsm/kg. PP is another possible differential
diagnosis. Nonetheless, an important aspect encountered by the patient was intense nocturia, which harmed his sleep
quality, a complaint that is infrequent in PP patients.
Nocturia is the first symptom to manifest in DI. However, most patients do not complain about it until diuresis
exceeds 4000mL/ day. CDI is characterized by polyuria and polydipsia, which exacerbates excessive nocturia, leading
to alteration of sleep patterns, fatigue and irritability. The patient ingested 7250mL of fluid and had diuresis of
7500mL. Therefore, diuresis was 87.2mL/kg, which falls within the definition of polyuria, a volume of urine greater
than 45-50mL/kg in 24h. Total AVP deficiency would lead to diuresis greater than 18,000mL/24h. Slightly elevated
diuresis suggests partial AVP deficiency, which may explain why the AVP value in this case was 1.5pg/mL. The
reference value for CDI is below 1.0pg/dL. The next step was cranial MRIto confirm disease etiology. The most
common hypophyseal alterations in DI are thickening of the pituitary stalk and fading of the posterior pituitary bright
spot visualized in a T1 weighted image on MRI. The thickening of the pituitary stalk confirmed the diagnosis, and AVP
replacement treatment was initiated.
Today, most of CDI previously classified as idiopathic have been now verified as an autoimmune etiology. Some features of
the present case suggest an autoimmune pathogenesis. The imaging findings on MRI, showing a thickened pituitary stalk
and a reduction of hyperintense neurohypophysis signal, favor an autoimmune CDI caused by a lymphocytic infundibulo-
neurohypohysitis. To search for the presence of antihypothalamus and antipituitary antibodies in patient’s serum could
have contributed to clarify these aspects, unfortunately the patient did not perform these exams.

Mara C, Ana R S, Sabrina P F, Moacir B, Larissa B P C d S, et al. Key points in Diabetes Insipidus´ Diagnosis. Biomed J Sci
&Tech Res 2(1)- 2018. BJSTR. MS.ID.000684. DOI : 10.26717/BJSTR.2018.02.000684

TAMBAHAN DAFPUS

Aleksandrov N, Audibert F, Bedard MJ, Mahone M, Goffinet F, et al. Gestational diabetes insipidus: a review of
an underdiagnosed condition. J Obstet Gynaecol Can. 2010;32:225-231.

Arima H, Wakabayashi T, Nagatani T, Fujii M, Hirakawa A, Murase T. Adipsia increases risk of death in
patients with central diabetes insipidus. Endocr J. 2014;61(2):143-8.

A. C. De Bragana, Z. P. Moyses, and A. J. Magaldi, “Carbamazepine can induce kidney water absorption by
increasing aquaporin 2 expression,” Nephrology Dialysis Transplantation.2010;25:3840–5,
Gambar patof Saifan C, Nasr R, Mehta S, Acharya PS, Perrera I, Faddoul G, et al. Diabetes
Insipidus: A Challenging Diagnosis with New Drug Therapies. ISRN Nephrology Volume
2013, Article ID 797620,

Di Iorgi N, Napoli F, Allegri AEM, Olivieri I, Bertelli A, Gallizia A.Diabetes Insipidus – Diagnosis and
Management.Horm Res Paediatr 2012;77:69–84
DD Saifan C, Nasr R, Mehta S, Acharya PS, Perrera I, Faddoul G, et al. Diabetes Insipidus: A
Challenging Diagnosis with New Drug Therapies. ISRN Nephrology Volume 2013, Article
ID 797620,