1. The polyuric child When we worry?
ESPN, Lyon-Sept.2008
Andromachi Mitsioni
Departement of Pediatric Nephrology
”P. & A. Kyriakou” Children’s Hospital
Athens - GREECE
"P. & A. Kyriakou" Children's Hospital, Athens
Division of Pediatric Nephrology

2. POLYURIA is defined as an increase in total daily outpout of urine
Urine outpout > 40 ml/kg/24h
or > 2000 ml/m2/24h
preschool children >1l/24h
school children >2l/24h
adults >3l/24h

3. Polyuria
Distinguish from:
frequent micturition
nocturia
enuresis
Are not associated with an increase in the total urine output

4. Polyuria The volume of urine depends upon:
1.The amount of solute (solute load) and water ingested or produced by metabolism in excess of needs
2.The ability to concetrate or dilute the urine

5. The ability to concetrate the urine depends on:
the presence of antidiuretic hormone (ADH) and
A hyperosmolar medullary interstitium
with an intact countercurrent multiplier
system

6. 1. Active sodium chloride transport in the thick ascending limb of loop of Henle (TΑL)
5. In the presence of ADH, collecting tubule highly permeant to water
3. Water permeable segment in the thin descending limb of loop of Henle
4. Urea reabsorption in the collecting tubule
2. Passive reabsorption of sodium in the thin ascending limb of loop of Henle

7. Water diuresis (urine osmolality
POLYURIA
Water diuresis (urine osmolality
<250mOsm/kg)
Solute diuresis (urine osmolality
>250 mOsm/kg)
More than one abnormality may be present in any form of polyuria

8. Water diuresis may be due to:
PRIMARY POLYDIPSIA
DIABETES INSIPIDUS
Neurogenic (failure of neurohypophysis to synthesize or secrete ADH)
Nephrogenic (failure of the kidney to respond appropriately to ADH)
partial to complete

9. Primary polydipsia Compulsive water drinking
(rare in children,most commonly in adolescents with a psychological distiburbance)
Treatment with large quantities of water
(treatment of nephrolithiasis , or with drugs as CP)
Defect in the thirst center (in the hypothalamus of CNS)
Excessive fluid intake will supress vasopressin secretion and induce
polyuria (normoNa patients with normal or reduced plasma osmolality)

10. Neurogenic (central) DI
DIABETES INSIPIDUS
Neurogenic (central) DI
Primary
Secondary
Nephrogenic DI
Congenital (hereditary)
Acquired(Secondary)

11. NEUROGENIC (CENTRAL)DIABETES INSIPIDUS PRIMARY
Idiopathic (30-50% in children)
autoimmune process
+/-presence of cytoplasmic antibodies against VS
Familial (5% )
autosomal dominant disease caused by mutations
in the arginine-vasopressin gene(chromosome 20)
DIDMOAD (Wolfran syndrome)
Neurogenic DI,Diabetes Mellitus,Optic Atrophy
Deafness.
autosomal recessive trait

12. NEUROGENIC(CENTRAL)DIABETES INSIPIDUS SECONDARY
Neurosurgery
Trauma (head injury)
Infection(meningitis,encephalitis,CNS abscess,congenital infection.)
Tumor(craniopharyngioma,glioma ,germinoma,metastasis)
CNS granulomatous disease(sarcoidosis,,histiocytosis X)
Hypoxia
Intracranial hemorrhage(aneurysm,thrombosis,embolus)
Drugs (phenyntoin,clonidine,alcohol)

13. NEPHROGENIC DIABETES INSIPIDUS HEREDITARY(CONGENITAL)
a PURE type characterized by loss of water only
a COMPLEX type characterized by loss of water and ions(Na+,Cl-,Ca++,K+,Mg+)

14. How does a cell let one type of ion through
Peter Agre and Roderick McKinnon, (the 2003 Nobel Prize in Chemistry) answered 2 questions
How does a cell let one type of ion through
the lipid membrane to the exclusion of others?
How does water permeate the cell without ion?
These 2 problems are relevant to the molecular understanding of 2 types of hereditary nephrogenic DI

15. Vasopressin makes the cortical and medullary collecting ducts permeable to water

16. Mechanisms for blocking proton permeation by aquaporin
The water channels let water go through but not protons. Protons are jumping from one water molecule to another, but due to the special arrangement of these two asparagines ,there is a link and the protons cannot jump to the next water molecule.

17. PURE Gongenital Nephrogenic DI
X-linked(90-95%)
mutation of V2 receptor gene (AVPR2)
chromosome region Xq28
Autosomal dominant or autosomal recessive
5-10% of patients
mutation of aquaporin 2 gene (AQP2)
chromosome region 12q13

18. 183 AVPR2 mutations X-linked

19. Aquaporin-2: 26 mutations responsible for autosomal dominant and autosomal recessive forms of NDI

20. COMPLEXE Nephrogenic diabetes insipidus Separation of salt and water in thick ascending limb (TAL) of loop of Henle

21. ABNORMALITIES IN ANY OF THESE PROTEINS OF THE TAL CAN LEAD TO SALT –LOSING NEPHROPATHY
As a result of these different molecular alterations:
NaCl is lost into the lumen
positive voltage is abolished
Ca++,Mg++ ,K+,NH4+ cannot be reabsorbed in the paracelullar space
COMPLEX POLYURIC DISORDERS

22. NEPRHOGENIC DIABETES INSIPIDUS SECONDARY
Acquired metabolic aberrations
hypokaliemia, hypercalcemia
Drugs
lithium,αmphotericin Β,diphenylhydantoin,foscarnet,
cidofovir
Medullary damage
chronic pyelonephritis ,cystinosis, sickle cell disease
chronic renal failure, obstructive nephropathy,
infiltrative disease (leukemia,lymphoma,amyloidosis)

23. SOLUTE DIURESIS (accumulation of organic or inorganic solutes in urine)
Glycose (diabetes mellitus,
renal glycosuria)
Urea (large protein intake
increased catabolism
relief of obstruction)
Mannitol
Inorganic
Sodium chloride(diuretics,
mineralocorticoid deficiency
salt-losing renal diseases)

24. Larger quantities of urine± dehydration
CLINICAL EVALUATION
Larger quantities of urine± dehydration
infancy - excessively heavy diapers
irritability, seizures
unexplained fever
constipation, vomiting
failure to thrive,mental retardation
children - polydipsia
enuresis, nocturia
non obstructive hydronephrosis ,hydroureter and megacystis by the large urinary volumes

25. DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS
Onset of polyuria
Hereditary nephrogenic DI first week of life
Familial central DI after the first year of life
ADULTS Central DI abrupt onset
Aquired nephrogenic DI gradual onset
Primary polydipsia gradual onset
Onset of nocturia is often the first clue to DI
Relationship with CNS injury
Family history
Plasma sodium concentration
Presence of polyhydramnios

26. Laboratory Investigations
24hour urine collection
Serum glycose,urea and creatinine
Κ, Ca, Na,biccarbonates
Urine(first morning) osmolality , urinalysis
Serum osmolality
Water restriction test
Test of dDAVP
Plasma ADH measurement
Genetic studies

27. Osmoregulation of ADH
The normal physiologic response is based upon the following observations:
Raising the plasma osmolality leads to a progressive elevation in ADH release and an increase in urine osmolality in normals
Once the plasma osmolality reaches 295 to 300 mOsmol/kg ,the effect of endogenous ADH on the kidney is maximal. At this point administering ADH
will no further elevate the urine osmolality unless endogenous ADH release is impaired (central DI)

28. WATER RESTRICTION TEST
Is not performed in newborns or very young infants
Is not performed when plasma Na>145 mEq/l
It should be performed in the hospital under medical supervision
The test is terminated when one of the end points are attained:
Urine SG> or Urine osmolality > 600mOsm/kg ( infant ) >500
Plasma osmolality >295 mOsm/kg or plasma Na >147mEq/l
Loss of 5% of body weight or signs of volume depletion
Period of water restriction
6hours in infants < 6months of age
8 hours months -2 years
12 hours >2 years

29. TEST dDAVP <10% complete nephrogenic DI
Children who continue to have impaired urinary concentration despite reaching a plasma osmolality 295mosmol/kg or sodium of 150meq/L
5-10μg desmopressin by nasal insufflation (20μg/m2)
or 2,5-5U aqueous vasopressin subcutaneously
Accurate interpretation requires that exogenous ADH not given before the plasma osmolality has reached 295 mosm/kg
If urine osmol. >100% complete central DI
15-50% partial central DI
partial nephrogenic DI
<10% complete nephrogenic DI

30. Polyuria- Laboratory Investigations
Plasma ADH measurement before and after water restriction test
NEPHROGENIC DI is excluded if there is an appropriate relationship between the rise in urine osmolality and plasma ADH
CENTRAL DI is excluded if there is an appropriate rise in plasma ADH with the rise in plasma sodium or plasma osmolality

31. Polyuria-Laboratory Investigations
Patients with central DI
MRI scans of pituitary gland, hypothalamus and surrounding structures (serial)
Investigation of anterior pituitary hormone deficits (GH,TSH,ACTH,FSH,LH)
Patients with nephrogenic DI
Renal ultrasound
Bladder function tests