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The polyuric child When we worry?

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

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The polyuric child When we worry?

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

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

  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) andwater ingested or produced bymetabolism in excess of needs 2.The ability to concetrate or dilute theurine

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

  6. 1.Active sodium chloridetransport in the thick ascending limb of loop of Henle (TΑL) 5.In the presenceof ADH, collectingtubule highlypermeant to water TΑL 3. Water permeablesegment in the thin descending limb of loop of Henle 4. Urea reabsorption in the collecting tubule 2. Passive reabsorption of sodium in the thin ascendinglimb of loop of Henle

  7. POLYURIA • Water diuresis(urine osmolality <250mOsm/kg) • Solute diuresis(urineosmolality >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 neurohypophysisto synthesize or secrete ADH) Nephrogenic(failure of the kidney torespond 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 ofwater (treatment of nephrolithiasis , or with drugs as CP) • Defect in the thirst center (in thehypothalamus of CNS) Excessive fluid intake will supress vasopressin secretion and induce polyuria (normoNa patients with normal or reduced plasma osmolality)

  10. DIABETESINSIPIDUS • Neurogenic (central) DI Primary Secondary • Nephrogenic DI Congenital (hereditary) Acquired(Secondary)

  11. NEUROGENIC (CENTRAL)DIABETES INSIPIDUSPRIMARY • 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 INSIPIDUSSECONDARY Neurosurgery Trauma (head injury) Infection(meningitis,encephalitis,CNS abscess,congenital infection.) Tumor(craniopharyngioma,glioma ,germinoma,metastasis) CNS granulomatous disease(sarcoidosis,,histiocytosis X) Hypoxia Intracranialhemorrhage(aneurysm,thrombosis,embolus) Drugs (phenyntoin,clonidine,alcohol)

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

  14. Peter Agre and Roderick McKinnon, (the 2003Nobel Prize in Chemistry) answered 2 questions • How does a cell let one type of ion through the lipid membrane to the exclusion ofothers? • How does water permeate the cell withoution? These 2 problems are relevant to the molecular understanding of 2 types of hereditarynephrogenic DI

  15. Vasopressin makes the cortical and medullarycollecting ducts permeable to water

  16. Mechanisms for blocking proton permeation by aquaporin • The water channels letwater 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 mutationsX-linked

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

  20. COMPLEXE Nephrogenic diabetes insipidusSeparation of salt and water in thick ascendinglimb (TAL) of loop of Henle

  21. ABNORMALITIES IN ANY OF THESE PROTEINSOF THE TALCANLEAD TO SALT –LOSINGNEPHROPATHY 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 theparacelullar space • COMPLEX POLYURIC DISORDERS

  22. NEPRHOGENIC DIABETES INSIPIDUSSECONDARY • 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 inorganicsolutes in urine) Organic • Glycose (diabetes mellitus, renal glycosuria) • Urea (large protein intake increasedcatabolism relief of obstruction) • Mannitol Inorganic • Sodium chloride(diuretics, mineralocorticoid deficiency salt-losing renal diseases)

  24. 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> 1020or 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

  29. 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 givenbefore the plasma osmolality has reached 295 mosm/kg • Ifurineosmol.>100% complete central DI 15-50%partial central DI partial nephrogenic DI <10%complete nephrogenic DI

  30. Polyuria- Laboratory Investigations Plasma ADH measurement beforeand after water restriction test • NEPHROGENIC DI is excluded if there is an appropriaterelationship between the rise in urineosmolality andplasma ADH • CENTRAL DIis 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 andsurrounding structures (serial) • Investigation of anterior pituitary hormonedeficits (GH,TSH,ACTH,FSH,LH) • Patients with nephrogenic DI • Renal ultrasound • Bladder function tests

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