JURNAL READING

DIVISI ENDOKRIN
I Gede Vendi Cahyadi Riandika
INTRODUCTION
 DIABETES INSIPIDUS
POLYURIA POLYDIPSIA SYNDROME

This syndrome is defined by an output of >50 mL/kg

body weight per 24 h of hypotonic urine (<300
mOsm/kg H2O), which is accompanied by polydipsia
of >3 L a day
Differential Diagnosis

Central DI
Hypotonic Nephrogenic DI
Polyuria
Primary Polydipsia
 Water Deprivation Test as “Gold Standart”
 has several limitations leading to a rather low diagnostic accuracy of only
around 70%

 Zerbe and Robertson proposed in the 1980s to directly measure arginine

vasopressin (AVP) upon osmotic stimulation with hypertonic saline
 measurement of AVP did not enter clinical practice, mainly due to technical
limitations of the AVP assay and due to the fact that reliable assays are mostly
not commercially available.
THE POLYURIA POLIDIPSIA SYNDROME
CENTRAL DI
• Insufficient secretion of AVP
• Most often induced by lesions of
the posterior pituitary or the
hypothalamic
• trauma, surgery of the pituitary,
neoplastic, vascular,
autoimmune, infectious, or
granulomatous diseases
NEPHROGENIC DI PRIMARY POLYDIPSIA
• AVP levels are normally • AVP secretion and renal action
secreted, but there is a resistance are not affected
toward the action of AVP at the
level of the kidneys • The primary problem is an
excessive fluid intake over a
• most often acquired, with the longer period of time
best
known cause being drug-induced
nephrogenic DI
• it can also be inherited
 DIFFERENTIAL DIAGNOSIS BY WATER
DEPRIVATION TEST

 urinary osmolality below 300 mOsm/ kg : complete DI.

 increase urinary osmolality >50% after exogenous AVP : complete central DI
 increase urinary osmolality <50% after exogenous AVP : complete nephrogenic DI
 Urinary osmolalities increased to values between 300 and 800 mOsm/kg upon water deprivation : partial
central DI or primary polydipsia
 Partial central DI increased upon exogenous AVP administration >9%, whereas patients with primary
polydipsia increased <9%.

Miller M, Dalakos T, Moses AM, Fellerman H, Streeten DH. Recognition of partial defects in antidiuretic hormone secretion. Ann Intern Med. 1970 Nov;73(5):721–9.
DIRECT TEST

 Zerbe and Robertson proposed the direct test

 plasma AVP is measured upon osmotic stimulation not only by thirsting, but by stimulation with hypertonic
saline infusion.
 Patients with osmotically stimulated plasma AVP levels above the area of normality are diagnosed as
nephrogenic DI, patients with levels below the area of normality as central DI, and patients with levels
within the normal area as primary polydipsia
 a correct diagnosis was only reached in 38% of patients and a diagnostic accuracy was especially low in the
differentiation between partial central DI and primary polydipsia
NEW CONCEPT
COPEPTIN: A NEW SURROGATE
MARKER FOR AVP

 Originally detected 1972

 strongly correlates with plasma AVP
 the release of plasma copeptin and plasma AVP into circulation is
regulated by the same physiological stimuli
 There are also nonosmotic stimuli for AVP and copeptin such as
nausea, hypovolemia, and hypotension ~ ischemic stroke, myocardial
infarction, or pneumonia
COPEPTIN: A NEW SURROGATE
MARKER FOR AVP
COPEPTIN: A NEW SURROGATE
MARKER FOR AVP

ASSAYS
SANDWICH
IMMUNOFLUORESCEN
IMMUNOLUMINOMETR
T
IC ASSAY
COPEPTIN: A NEW SURROGATE
MARKER FOR AVP
SMALL SAMPLE NO NO
VOLUME EXTRACTION PREANALYTICA
(50 μL) STEP L PROCEDURES

RESULT MORE STABLE

AVAILABLE < 2 7 DAYS ROOM TEMPERATURE
HOURS 14 DAYS AT 4’C
 CONCEPT

FIRST CONCEPT: SECOND CONCEPT: THIRD CONCEPT:

BASELINE COPEPTIN NONOSMOTIC NONOSMOTIC
TO IDENTIFY STIMULATION WITH STRESS-INDUCED
NEPHROGENIC DI ARGININE PLUS COPEPTIN TO
AND HYPERTONIC COPEPTIN DIAGNOSE
SALINE INFUSION MEASUREMENT TO POSTSURGICAL DI
PLUS COPEPTIN DIAGNOSE DI
MEASUREMENT TO
DIAGNOSE DI
FIRST CONCEPT:
BASELINE COPEPTIN TO
IDENTIFY NEPHROGENIC DI
AND HYPERTONIC SALINE
INFUSION PLUS COPEPTIN
MEASUREMENT TO DIAGNOSE
DI
• it was concluded that the
hypertonic saline test plus copeptin
measurement might replace the
classical water deprivation test in
the future differential diagnosis of
hypotonic polyuria
• the majority of patients preferred
the hypertonic saline stimulation
with copeptin measurement over
the standard water deprivation test
Water deprivation test + saline 3%
Target plasma sodium > 147mmol/L
first finding
nephrogenic DI single baseline copeptin level of >21.4 pmol/L
second finding
upon osmotic stimulation, a copeptin level of >4.9 pmol/L differentiated
patients with central DI from patients with primary polydipsia with a
high diagnostic accuracy of 96%.
Only Hipertonic saline 3%
Target plasma sodium minimum 150mmol/L
97% of the patients were correctly diagnosed with the predefined
copeptin cutoff level of >4.9 pmol/L. The diagnostic accuracy was
similar in the differential diagnosis of patients with partial DI and
patients with primary polydipsia with a correct diagnosis in 95%
SECOND CONCEPT: Arginine is known to stimulate various hormones secreted by the
NONOSMOTIC STIMULATION anterior pituitary gland
WITH ARGININE PLUS hypothesized that arginine would also stimulate the
COPEPTIN MEASUREMENT TO posterior pituitary
DIAGNOSE DI
Healthy adults, median baseline copeptin levels were 5.2 pmol/L (3.3–
10.9) and increased within the first 60 min after arginine stimulation to
9.8 pmol/L (6.4 19.6; p < 0.001) and plateaued thereafter

In patients with polyuria polydipsia syndrome, the highest diagnostic

accuracy for differentiating between DI and
primary polydipsia was observed for a copeptin cutoff of 3.8
pmol/L, measured at 60 min after arginine stimulation, 93%

the highest diagnostic accuracy for differentiating

between partial DI and primary polydipsia was found for a
copeptin cutoff of 3.8 pmol/L, measured at 60 min after arginine
stimulation, 90%
THIRD CONCEPT: in patients after pituitary surgery, an insulin tolerance test
NONOSMOTIC STRESS- inducing hypoglycemia and therefore a nonosmotic stress
INDUCED COPEPTIN TO led to a significant induction of copeptin levels in those
patients with an intact posterior pituitary function, but
DIAGNOSE POSTSURGICAL DI copeptin levels remained low in patients with postsurgical DI

Copeptin levels of patients with intact posterior pituitary showed a

maximal increase to 11.1 ± 4.6
pmol/L, while copeptin levels in patients with central DI
remained low upon hypoglycemia at 3.7 ± 0.7 pmol/L. A
hypoglycemic stimulated copeptin level <4.75 pmol/L
had an optimal diagnostic accuracy to detect central DI
of 100%.

The post hoc derived copeptin cutoff level of <2.5

pmol/L had a positive predictive value for development
of central DI of 81% and a specificity of 97%, while a
level >30 pmol/L excluded it with a negative predictive
value of 95% and a sensitivity of 94%
At the moment, a step-wise approach may be
recommended, with the easier arginine stimulation test
as first test and the hypertonic saline infusion test in
unclear cases as the second test. A respective algorithm
is proposed in Figure
MANAGEMENT
General Management of DI by Specialist

 DESMOPRESSIN
 First dose given at bedtime to reduce nocturia
 Usually lifelong treatment in Central DI
 DI after neurosurgery, should therefore not receive a fixed dose of desmopressin, but instead their degree of polyuria
must be observed carefully. If the polyuria becomes less pronounced or ceases, desmopressin can be tapered or
withdrawn.
 can be administered intranasally, orally, subcutaneously or intravenously. Usually, start with an oral or intranasal
preparation is recommended.
General Management of DI by Specialist

 HYPONATREMIA
 The major complication of desmopressin
 27% of central DI patients show mild hyponatraemia on routine electrolyte testing and 15% develop more severe
hyponatraemia, over longterm follow-up
 regular electrolyte checks are recommended during initiation of therapy
 Annual electrolyte checking is recommended for long-term follow-up
Management of DI for nonspecialists
(with a focus on emergency management in hospitals)

 HYPERNATRAEMIA
 the rate of hypernatraemia during hospital admission is clearly higher
 increased mortality in intensive care units associated with hypernatraemia
 poor prognostic sign in patients who develop DI following head injury
 Results of a retrospective audit of patients hospitalized with central DI showed that desmopressin treatment had been
missed or delayed in 88% of admissions and that 35% of patients consequently developed dysnatraemia
Management of DI for nonspecialists
(with a focus on emergency management in hospitals)

 DESMOPRESSIN
 mild disease, alert and able to drink, complications should not be expected.
 In case of pneumonia or other respiratory complications : ORAL > NASAL
 In patients with severe illness, desmopressin should be given parenterally. The intravenous route is generally preferred
Management of DI for nonspecialists
(with a focus on emergency management in hospitals)

 FLUID
 Persistent fever and tachypnoea, insensible water losses increased >> increased fluid intake
 Impaired cognitive function >> intravenously
 Urine osmolality and urine volume should be monitored to ascertain whether the dose was effective, and the plasma
sodium measured at frequent intervals to ensure the improvement of hypernatraemia.
 severe dehydration should be treated with hypotonic fluids : enterally or intravenously
 Hypotonic fluids should be administered as an intravenous infusion, with the rate adjusted to exceed the hourly urine
output and reverse the calculated total body water deficit. The usual aim is to provide just enough water to safely
normalize serum sodium at a rate of < 0.5 mmol/L per h (<10–12 mmol/L per day)
Management of DI for nonspecialists
(with a focus on emergency management in hospitals)

 Low Molecular Weight Heparin

 Hypernatraemic dehydration is associated with a hypercoagulable state, the risk of venous thrombosis, and pulmonary
embolism
 recommended to routinely prescribe prophylactic subcutaneous low molecular weight heparin during episodes of
hypernatraemic dehydration, until eunatraemia is restored.
Management of DI for nonspecialists
(with a focus on emergency management in hospitals)

 NEPHROGENIC DI
 resistance to AVP agents
 response to (sub)maximal dosed desmopressin treatment may be seen in some patients
 low-sodium diet leading to modest hypovolaemia, which again stimulates isotonic proximal tubular reabsorption and
thereby reduces solute delivery to the distal parts of the nephron.
 Thiazide diuretics are sometimes efficient due to induced natriuresis, mainly if combined with a low sodium diet
 Nonsteroidal anti-inflammatory agents can also be used since they block prostaglandin synthesis, thereby increasing
non-AVP dependent water reabsorption.
Management of DI for nonspecialists
(with a focus on emergency management in hospitals)

 no reasonable medical therapeutic options can be offered to patients with primary polydipsia. These patients
continue to be thirsty and to drink even in the presence of plasma osmolalities low enough to suppress AVP
secretion, which may lead to severe complications such as water intoxication and severe electrolyte
disturbances.
TERIMAKASIH