The polyuric childWhen we worry?

Andromachi Mitsioni Andromachi Mitsioni

Departement of Pediatric NephrologyDepartement of Pediatric Nephrology

””P. & A. Kyriakou” Children’s Hospital P. & A. Kyriakou” Children’s Hospital

Athens - GREECEAthens - GREECE

ESPN, Lyon-Sept.2008

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

Polyuria

Distinguish from: frequent micturition nocturia enuresis

Are not associated with an increase in the total urine output

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

the presence of antidiuretic hormone (ADH) and

A hyperosmolar medullary interstitium with an intact countercurrent multiplier

system

The ability to concetrate the urine depends on:

TΑL

1. Active sodium chloride transport in the thick ascending limb of loop of Henle (TΑL)

2. Passive reabsorption of sodium in the thin ascending limb of loop of Henle

3. Water permeable segment in the thin descending limb of loop of Henle

4. Urea reabsorption in the collecting tubule

5. In the presence of ADH, collecting tubule highly permeant to water

POLYURIA

Water diuresis (urine osmolality <250mOsm/kg)

Solute diuresis (urine osmolality

>250 mOsm/kg) More than one abnormality may be present in More than one abnormality may be present in

any form of polyuriaany form of polyuria

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

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)

DIABETES INSIPIDUS

Neurogenic (central) DI Primary Secondary Nephrogenic DI Congenital (hereditary) Acquired(Secondary)

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

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)

NEPHROGENIC DIABETES INSIPIDUSNEPHROGENIC DIABETES INSIPIDUS HEREDITARY(CONGENITAL)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+)

Peter Agre and Roderick McKinnon, (the 2003 Nobel Prize in Chemistry) answered 2 questions

How does a cell let one type of ion How does a cell let one type of ion throughthrough

the lipid membrane to the exclusion ofthe lipid membrane to the exclusion of others?others?

How does water permeate the cell How does water permeate the cell withoutwithout ion?ion?

These 2 problems are relevant to the molecular These 2 problems are relevant to the molecular understanding of understanding of 2 types of hereditary2 types of hereditary nephrogenic DInephrogenic DI

Vasopressin makes the cortical and medullary collecting ducts permeable to water

Mechanisms for blocking proton permeation by aquaporin

The water channels letThe water channels let water go through but water go through but not protons. Protons are not protons. Protons are jumping from one water jumping from one water molecule to another, molecule to another, but due to the special but due to the special arrangement ofarrangement of these these two asparaginestwo asparagines ,there ,there is a link and the protons is a link and the protons cannot jump to the cannot jump to the next water moleculenext water molecule..

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

183 AVPR2 mutationsX-linked

Aquaporin-2: 26 mutations responsible for autosomal dominant

and autosomal recessive forms of NDI

COMPLEXE Nephrogenic diabetes insipidusSeparation of salt and water in thick ascending limb (TAL) of loop of Henle

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

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)

SOLUTE DIURESISSOLUTE DIURESIS (accumulation of organic or inorganic solutes in urine)

Organic 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)

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

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

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

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)

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> 1020 or Urine osmolality > 600mOsm/kg

( infant ) 1015 >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 6 months -2 years 12 hours >2 years

TEST dDAVP

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

Polyuria- Laboratory Investigations

Plasma ADH measurement beforePlasma ADH measurement before and after and after water restriction testwater 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

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